基于铜的新型蛋白酶体抑制剂N，N-二硫代氨基甲酸盐类化合物库的合成、抗癌活性筛选及机理研究
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摘要
铜是人体组织和动物组织所必需的微量元素,是人体进行正常新陈代谢过程所不可缺少的。人体内正常铜的含量为50～100 mg,在此范围内的铜可以维持正常的人体生理功能。如果人体内的铜含量过多则会引起铜中毒。随着对癌症机理的深入研究,人们发现在癌症病人血清中铜的浓度与正常人相比普遍偏高。进一步的研究发现铜在肿瘤发生与发展过程中发挥着极其重要的作用,例如肿瘤组织中血管的形成,肿瘤细胞的转移等过程。因此越来越多的研究将铜作为一个重要的靶点来开发新的癌症治疗方法。目前针对癌症组织中铜浓度过高的治疗方法有：降低癌症病人血清中铜的浓度,减少高浓度的铜对肿瘤血管形成的影响；利用有机铜配合物作为蛋白酶体抑制剂,从而诱导肿瘤细胞的凋亡；利用肿瘤组织中铜的氧化还原反应诱导癌细胞凋亡等。
研究发现N,N-二硫代氨基甲酸盐是一种很好的铜螯合剂,其与铜生成的有机配合物是一种蛋白酶体抑制剂,能够有效的诱导肿瘤细胞的凋亡。这种结构代表性的药物就是作为戒酒药上市的药物-戒酒硫(Disulfirm, DSF)。通过对DSF抗癌活性的研究发现,这种药物能够有效的抑制肿瘤细胞的增殖,同时对正常细胞的副作用比较小。但是DSF可以与体内的醛脱氢降解酶(Aldehyde dehydrogenase, ALDH)发生反应,使其在进入人体内所发挥的抗癌作用大大降低。
本文基于现有的研究结论提出假设：合成一种新型的N,N-二硫代氨基甲酸盐化合物,能够有效的抑制肿瘤细胞的增值并诱导癌细胞凋亡；对正常细胞的毒副作用小；并且在体内与ALDH不发生反应。本论文的主要工作分为三个部分：第一部分首先合成了一个全新的N,N-二硫代氨基甲酸盐的化合物库,并对库中化合物进行了生物活性筛选,比较了不同化合物与铜结合能力的差别,对其构效关系进行了初步的探讨；第二部分通过对前一个库中发现的活性化合物优化,合成了另一个N,N-二硫代氨基甲酸盐的化合物库,筛选出了对癌细胞的生长抑制作用比较明显的化合物;通过计算机模拟筛选出了对人体内的醛脱氢降解酶没有明显抑制作用的化合物；第三部分是使用组合化学和高通量筛选的方法开发新型饮用水中除砷剂,分别利用液相组合合成和固相组合合成的方法合成了两个化合物库,并对库中化合物的除砷能力进行了评估。
论文的主要工作及其结果如下：
第一部分,合成了一个新型的N,N-二硫代氨基甲酸盐的化合物库,并对库中的化合物进行了活性筛选。筛选发现库中的化合物与铜的反应生成的配合物除了#9之外,其余的配合物都对乳腺癌细胞MDA-MB-231的增殖有明显的抑制作用,能够很好的抑制肿瘤细胞中蛋白酶体的活性并诱导细胞凋亡。化合物#1与铜的络合物在5μM作用于细胞16 h,可以抑制90%的肿瘤细胞蛋白酶体活性。利用荧光滴定的方法对化合物与铜的络合能力进行了测定,发现化合物#9可以与铜离子发生反应,但是所得到的络合物不能起到对肿瘤细胞增殖的抑制。
第二部分,经过优化后合成了第二个N,N-二硫代氨基甲酸盐化合物库,利用MDA-MB-231和DCIS两种肿瘤细胞系对库中的化合物进行了活性筛选。研究发现库中化合物的生物活性具有一定的构效关系。利用紫外滴定的方法对化合物与铜的络合常数进行了测定。通过计算化学以及计算机模拟Docking的方法研究了库中的化合物对两种醛脱氢降解酶活性的抑制作用,发现了#39化合物既能抑制癌细胞的蛋白酶体活性,又不与人体内的醛脱氢降解酶进行反应,从而最大限度的发挥了其诱导癌细胞凋亡的作用。
第三部分,运用组合化学和高通量筛选的方法开发新型的饮用水除砷剂。研究以二硫代氨基甲酸盐为核心结构,运用液相和固相两种合成方法构建化合物库,并利用高通量的方法对化合物库中的化合物与砷的结合能力进行了筛选。在化合物的构建上充分考虑到所合成的化合物在环境领域应用的特点。高通量筛选方法的选择上则本着建立全自动仪器分析方法的原则,充分体现库中化合物筛选快速的特点。
结论：
1)N,N-二硫代氨基甲酸盐不仅可以络合肿瘤细胞中高浓度的铜,同时其与铜生成的有机配合物是一种良好的蛋白酶体抑制剂,能够抑制肿瘤细胞的增殖,并且诱导细胞的凋亡;
2)通过对库中化合物进行的构效关系研究发现,化合物中N,N-二取代的取代基对其活性有着一定的影响,对我们有针对性的构建化合物库,从而筛选出理想的化合物提供了一定的理论支持。
3)通过优化先导化合物的结构,合成了一种有良好的抗癌活性、且与ALDH不发生反应的新型N,N-二硫代氨基甲酸盐类化合物,为进一步的研究工作提供了良好的工作基础。
In human and animal tissues, copper is an important essential trace element. Copper can affect many biological pathways in human body. In healthy adults, the necessary copper concentration is 50-100 mg. Copper can be absorbed from the stomach and intestine through protein transporters. Then, copper associated with albumin and transcuprein is deposited in the liver. In blood, the major copper carrying protein is ceruloplasmin and the rest of copper is transported by albumin and histidine. If the balance of copper in cell is impaired, diseases will occur. Over the past two decades, there are a lot of evidences show that the copper plays an important role in inflammation and the growth of tumors. The copper concentration in serum and tumor tissue is significant higher than that of healthy subjects. Therefore, copper became one of the important targets in anti-cancer treatment. There are some efficiently treatments, such as Copper reduction, oxidative stress, copper complexes as the inhibitors of proteasome. Some compounds demonstrate the very potent anti-cancer activity, such as tetrathiomolybdate (TM), Captoril、Zinc and Trientine, (8-hydroxyquinoline) Ox and (5-chloro-7-iodo-8-hydroxyquinoline)CQ.
Dithiocarbamates (DTCs) are a sort of metal chelating and antioxidant compounds. These compounds are usually used in treating fungal diseases and bacteria. More recently, researchers have found that various DTC compounds can induce metal uptake, especial copper, and apotosis. More evidences confirm that the DTCs-copper complexes are also an important proteasome inhibitor. Disulfiram (DSF), a disulfide derivative of N, N-diethyldithiocarbamate (deDTC), is used as the alcohol-abuse deterrent with its ability of aldehyde dehydrogenase. Evidences prove that DSF can significantly inducing apoptosis with lower side effects. But the problem is the reaction between DSF and ALDH could decrease the anti-cancer concentration of DSF.
Based on the research referred we presumed that by synthesizing and screening a novel library of PDTC analogues, we could find some compounds which have the very potent anti-cancer activity and have no reaction with ALDH. The content of this paper consists with two parts. In the first part, we synthesized and screened the first library of PDTC analogues. In this part, the binding constant between copper and PDTC analogues and structure activity relationship were discussed in this part. In the second part, another library of PDTC was synthesized and screened. Binding constant and SAR were also discussed. By doing this research, some compounds that have the very potent anti-cancer activity were found.
The last part is about applying combinatorial chemisy in environmental sciences, we use combinatorial synthesis and high-throughput screening methodologies to discover novel agents for arsenic removal.
The major research work and results of the paper are as follows:
Part 1. The anti-proliferative effects on MDA-MB-231 cell line were screened with a synthesized novel library of PDTC analogues. The complexes of PDTC analogues and copper were found to have potent anti-proliferative activity, except compound 9#. Bingding constant was determined by UV titration. Structure activity relationship was also discussed.
Part 2. The second library of PDTC analogues was synthesized. The biological data obtained from screening compounds by brease cancer cell line MDA-MB-231 and DCIS. UV titration method was used to determin the binding constant between PDTC analogues and copper. Results show that there is certain relationship between binding constant and anti-cancer activity. Computational docking was used to determin the relationship between PDTC analogues and ALDH. Finally, the compounds that have the very potent anti-cancer activity and have no reaction with ALDH were found.
Part 3. We plan to establish a platform for doing various combinatorial synthesis and characterization. By using solid phase and solution phase synthesis method to discover novel agents for arsenic removal.
Conclusions:
1) The high concentrations of copper in tumor cells can be binded with dithiocarbamates, and the copper-dithiocarbamates are effective proteasome inhibitor. The complexes can inhibit tumor cell proliferation and induce cell apoptosis.
2) Through discussing the SAR of DTCs analogues, it can be found that the substitutors are very important for the anti-cancer activity. It's helpful for us to optimize the structures of the DTCs analogues to find more potent compounds.
3) By using the combinatorial synthesis and high-through screening methods will help accelerating the speed of discover the lead compounds. By optimizing the structure of lead compounds, we can found dithiocarbamates which can inhibit the proliferation of tumor without reacting with ALDH.
研究发现N,N-二硫代氨基甲酸盐是一种很好的铜螯合剂,其与铜生成的有机配合物是一种蛋白酶体抑制剂,能够有效的诱导肿瘤细胞的凋亡。这种结构代表性的药物就是作为戒酒药上市的药物-戒酒硫(Disulfirm, DSF)。通过对DSF抗癌活性的研究发现,这种药物能够有效的抑制肿瘤细胞的增殖,同时对正常细胞的副作用比较小。但是DSF可以与体内的醛脱氢降解酶(Aldehyde dehydrogenase, ALDH)发生反应,使其在进入人体内所发挥的抗癌作用大大降低。
本文基于现有的研究结论提出假设：合成一种新型的N,N-二硫代氨基甲酸盐化合物,能够有效的抑制肿瘤细胞的增值并诱导癌细胞凋亡；对正常细胞的毒副作用小；并且在体内与ALDH不发生反应。本论文的主要工作分为三个部分：第一部分首先合成了一个全新的N,N-二硫代氨基甲酸盐的化合物库,并对库中化合物进行了生物活性筛选,比较了不同化合物与铜结合能力的差别,对其构效关系进行了初步的探讨；第二部分通过对前一个库中发现的活性化合物优化,合成了另一个N,N-二硫代氨基甲酸盐的化合物库,筛选出了对癌细胞的生长抑制作用比较明显的化合物;通过计算机模拟筛选出了对人体内的醛脱氢降解酶没有明显抑制作用的化合物；第三部分是使用组合化学和高通量筛选的方法开发新型饮用水中除砷剂,分别利用液相组合合成和固相组合合成的方法合成了两个化合物库,并对库中化合物的除砷能力进行了评估。
论文的主要工作及其结果如下：
第一部分,合成了一个新型的N,N-二硫代氨基甲酸盐的化合物库,并对库中的化合物进行了活性筛选。筛选发现库中的化合物与铜的反应生成的配合物除了#9之外,其余的配合物都对乳腺癌细胞MDA-MB-231的增殖有明显的抑制作用,能够很好的抑制肿瘤细胞中蛋白酶体的活性并诱导细胞凋亡。化合物#1与铜的络合物在5μM作用于细胞16 h,可以抑制90%的肿瘤细胞蛋白酶体活性。利用荧光滴定的方法对化合物与铜的络合能力进行了测定,发现化合物#9可以与铜离子发生反应,但是所得到的络合物不能起到对肿瘤细胞增殖的抑制。
第二部分,经过优化后合成了第二个N,N-二硫代氨基甲酸盐化合物库,利用MDA-MB-231和DCIS两种肿瘤细胞系对库中的化合物进行了活性筛选。研究发现库中化合物的生物活性具有一定的构效关系。利用紫外滴定的方法对化合物与铜的络合常数进行了测定。通过计算化学以及计算机模拟Docking的方法研究了库中的化合物对两种醛脱氢降解酶活性的抑制作用,发现了#39化合物既能抑制癌细胞的蛋白酶体活性,又不与人体内的醛脱氢降解酶进行反应,从而最大限度的发挥了其诱导癌细胞凋亡的作用。
第三部分,运用组合化学和高通量筛选的方法开发新型的饮用水除砷剂。研究以二硫代氨基甲酸盐为核心结构,运用液相和固相两种合成方法构建化合物库,并利用高通量的方法对化合物库中的化合物与砷的结合能力进行了筛选。在化合物的构建上充分考虑到所合成的化合物在环境领域应用的特点。高通量筛选方法的选择上则本着建立全自动仪器分析方法的原则,充分体现库中化合物筛选快速的特点。
结论：
1)N,N-二硫代氨基甲酸盐不仅可以络合肿瘤细胞中高浓度的铜,同时其与铜生成的有机配合物是一种良好的蛋白酶体抑制剂,能够抑制肿瘤细胞的增殖,并且诱导细胞的凋亡;
2)通过对库中化合物进行的构效关系研究发现,化合物中N,N-二取代的取代基对其活性有着一定的影响,对我们有针对性的构建化合物库,从而筛选出理想的化合物提供了一定的理论支持。
3)通过优化先导化合物的结构,合成了一种有良好的抗癌活性、且与ALDH不发生反应的新型N,N-二硫代氨基甲酸盐类化合物,为进一步的研究工作提供了良好的工作基础。
In human and animal tissues, copper is an important essential trace element. Copper can affect many biological pathways in human body. In healthy adults, the necessary copper concentration is 50-100 mg. Copper can be absorbed from the stomach and intestine through protein transporters. Then, copper associated with albumin and transcuprein is deposited in the liver. In blood, the major copper carrying protein is ceruloplasmin and the rest of copper is transported by albumin and histidine. If the balance of copper in cell is impaired, diseases will occur. Over the past two decades, there are a lot of evidences show that the copper plays an important role in inflammation and the growth of tumors. The copper concentration in serum and tumor tissue is significant higher than that of healthy subjects. Therefore, copper became one of the important targets in anti-cancer treatment. There are some efficiently treatments, such as Copper reduction, oxidative stress, copper complexes as the inhibitors of proteasome. Some compounds demonstrate the very potent anti-cancer activity, such as tetrathiomolybdate (TM), Captoril、Zinc and Trientine, (8-hydroxyquinoline) Ox and (5-chloro-7-iodo-8-hydroxyquinoline)CQ.
Dithiocarbamates (DTCs) are a sort of metal chelating and antioxidant compounds. These compounds are usually used in treating fungal diseases and bacteria. More recently, researchers have found that various DTC compounds can induce metal uptake, especial copper, and apotosis. More evidences confirm that the DTCs-copper complexes are also an important proteasome inhibitor. Disulfiram (DSF), a disulfide derivative of N, N-diethyldithiocarbamate (deDTC), is used as the alcohol-abuse deterrent with its ability of aldehyde dehydrogenase. Evidences prove that DSF can significantly inducing apoptosis with lower side effects. But the problem is the reaction between DSF and ALDH could decrease the anti-cancer concentration of DSF.
Based on the research referred we presumed that by synthesizing and screening a novel library of PDTC analogues, we could find some compounds which have the very potent anti-cancer activity and have no reaction with ALDH. The content of this paper consists with two parts. In the first part, we synthesized and screened the first library of PDTC analogues. In this part, the binding constant between copper and PDTC analogues and structure activity relationship were discussed in this part. In the second part, another library of PDTC was synthesized and screened. Binding constant and SAR were also discussed. By doing this research, some compounds that have the very potent anti-cancer activity were found.
The last part is about applying combinatorial chemisy in environmental sciences, we use combinatorial synthesis and high-throughput screening methodologies to discover novel agents for arsenic removal.
The major research work and results of the paper are as follows:
Part 1. The anti-proliferative effects on MDA-MB-231 cell line were screened with a synthesized novel library of PDTC analogues. The complexes of PDTC analogues and copper were found to have potent anti-proliferative activity, except compound 9#. Bingding constant was determined by UV titration. Structure activity relationship was also discussed.
Part 2. The second library of PDTC analogues was synthesized. The biological data obtained from screening compounds by brease cancer cell line MDA-MB-231 and DCIS. UV titration method was used to determin the binding constant between PDTC analogues and copper. Results show that there is certain relationship between binding constant and anti-cancer activity. Computational docking was used to determin the relationship between PDTC analogues and ALDH. Finally, the compounds that have the very potent anti-cancer activity and have no reaction with ALDH were found.
Part 3. We plan to establish a platform for doing various combinatorial synthesis and characterization. By using solid phase and solution phase synthesis method to discover novel agents for arsenic removal.
Conclusions:
1) The high concentrations of copper in tumor cells can be binded with dithiocarbamates, and the copper-dithiocarbamates are effective proteasome inhibitor. The complexes can inhibit tumor cell proliferation and induce cell apoptosis.
2) Through discussing the SAR of DTCs analogues, it can be found that the substitutors are very important for the anti-cancer activity. It's helpful for us to optimize the structures of the DTCs analogues to find more potent compounds.
3) By using the combinatorial synthesis and high-through screening methods will help accelerating the speed of discover the lead compounds. By optimizing the structure of lead compounds, we can found dithiocarbamates which can inhibit the proliferation of tumor without reacting with ALDH.
引文
1. Williams, R. and J. da Silva, New trends in bio-inorganic chemistry.1978: Academic Press Inc.
2. Gregoriadis, G., N. Apostolidis, A. Romanos, and T. Paradellis, A comparative study of trace elements in normal and cancerous colorectal tissues. Cancer, 1983.52(3).
3. O'dell, B., Biochemistry of copper. The Medical clinics of North America,1976. 60(4):p.687.
4. Johnson, P., D. Milne, and G. Lykken, Effects of age and sex on copper absorption, biological half-life, and status in humans.1992, Am Soc Nutrition. p.917-925.
5. Hartmann, H., K. Felix, W. Nagel, and U. Weser, Intestinal administration of copper and its transient release into venous rat blood serum concomitantly with metallothionein. BioMetals,1993.6(2):p.115-118.
6. Aust, S., L. Morehouse, and C. Thomas, Role of metals in oxygen radical reactions. Journal of free radicals in biology & medicine,1985.1(1):p.3.
7. Weiss, K. and M. Linder, Copper transport in rats involving a new plasma protein. American Journal of Physiology-Endocrinology And Metabolism,1985. 249(1):p.77-88.
8. Cousins, R., Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin.1985, Am Physiological Soc. p.238-309.
9. Barrow, L. and M. Tanner, Copper distribution among serum proteins in paediatric liver disorders and malignancies. European Journal of Clinical Investigation,1988.18(6):p.555-560.
10. Linder, M.C. and M. Hazegh-Azam, Copper biochemistry and molecular biology.1996, Am Soc Nutrition, p.797-811.
11. Saenko, E., A. Yaropolov, and E. Harris, Biological functions of ceruloplasmin expressed through copper-binding sites and a cellular receptor. Journal of Trace Elements in Experimental Medicine,1994.7:p.69-69.
12. Dijkstra, M., R.J. Vonk, and F. Kuipers, How does copper get into bile? New insights into the mechanism (s) of hepatobiliary copper transport.1996. p.109.
13. Harris, E.D., Copper transport and metabolism:An update.1998. p.163-176.
14. Coates, R.J., N.S. Weiss, J.R. Daling, R.L. Rettmer, and G.R. Warnick, Cancer risk in relation to serum copper levels. Cancer Research,1989.49(15):p. 4353-4356.
15. Gupta, S.K., V.K. Shukla, M.P. Vaidya, S.K. Roy, and S. Gupta, Serum trace elements and Cu/Zn ratio in breast cancer patients. Journal of surgical oncology, 1991.46(3).
16. Rizk, S.L. and H.H. Sky-Peck, Comparison between concentrations of trace elements in normal and neoplastic human breast tissue.1984. p.5390.
17. Tureck, L., P. Kalina, E. Uhlikova, N醡erov, and J. Kri瀔o, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer, p.187-189.
18. Nayak, S.B., V.R. Bhat, D. Upadhyay, and S.L. Udupa, Copper and ceruloplasmin status in serum of prostate and colon cancer patients.2003. p. 108.
19. Kunapuli, S.P., H. Singh, P. Singh, and A. Kumar, Ceruloplasmin gene expression in human cancer cells. Life Sci.,1987.40(23):p.2225-2228.
20. Stassar, M.J., G. Devitt, M. Brosius, L. Rinnab, J. Prang, and T. Schradin, Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br. J. Cancer,2001.85(9):p.1372-1382.
21. Yamamoto, K. and S. Kawanishi, J. Biol. Chem.,1989.264:p.15435-15440.
22. Burkitt, M.J., Copper-DNA adducts. Meth Enzymol,1994.234:p.102-106.
23. Wiliams, R.J.P. and F.J.J.R.D. Silva, New trends in bio-inorganic chemistry. New York:Academic Press,1978:p.1-10.
24. Milne, L., P. Nicotera, S. Orrenius, and M.J. Burkitt, Effects of glutathione and chelating agents on copper-mediated DNA oxidation:pro-oxidant and antioxidant properties of glutathione. Arch. Biochem. Biophys.,1993.304:p. 102-106.
25. Hiroyuki, O., S. Norimassa, I. Hiroshi, and M. Michio, Abnormal accumulation of copper in LEC rat liver induces expression of P53 and nuclear matrix-bound P2/waf1/cip1. Carcinogenesis,1996.17:p.2157-2161.
26. Theophanides, T. and J. Anastassopoulou, Copper and carcinogenesis. Critical Reviews in Oncology/Hematology,2002.42:p.57-64.
27. Da Silva, J. and R.J.P. Williams, The biological chemistry of the elements:the inorganic chemistry of life.2001:Oxford University Press, USA.
28. Folkman, J., Tumor angiogenesis:therapeutic implications. N Engl J Med,1971. 285(21):p.1182-6.
29. Brem, S., Angiogenesis and cancer control:from concept to therapeutic trial. Cancer Control,1999.6(5):p.436-458.
30. Shan, S., N.D. Robson, Y. Cao, T. Qiao, C.Y. Li, and C.D. Kontos, Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival. Faseb J,2004.18(2):p.326-328.
31. Manders, P., L. Beex, V.C.G. Tjan-Heijnen, J. Geurts-Moespot, T.H. Van Tienoven, J.A. Foekens, and C.G.J. Sweep, The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy. British journal of cancer,2002.87:p. 772-778.
32. Berns, E.M.J.J., J.G.M. Klijn, M.P. Look, N. Grebenchtchikov, R. Vossen, H. Peters, A. Geurts-Moespot, H. Portengen, I.L. van Staveren, and M.E. Meijer-van Gelder, Combined Vascular Endothelial Growth Factor and TP53 Status Predicts Poor Response to Tamoxifen Therapy in Estrogen Receptor-positive Advanced Breast Cancer 1. Clinical Cancer Research,2003. 9(4):p.1253-1258.
33. Manders, P., L.V.A.M. Beex, V.C.G. Tjan-Heijnen, P.N. Span, and C.F.G.J. Sweep, Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma. Cancer,2003. 98(10).
34. Paola, F.D., A.M. Granato, E. Scarpi, F. Monti, L. Medri, and S. Bianchi, Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer. Int. J. Cancer,2002.98(2):p.228-233.
35. McAuslan, B.R. and W. Reilly, Endothelial cell phagokinesis in response to specific metal ions. Experimental cell research,1980.130(1):p.147.
36. Hu, G., Copper stimulates proliferation of human endothelial cells under culture. Journal of cellular biochemistry,1998.69(3).
37. Parke, A., P. Bhattacherjee, R.M. Palmer, and N.R. Lazarus, Characterization and quantification of copper sulfate-induced vascularization of the rabbit cornea. The American journal of pathology,1988.130(1):p.173.
38. Ziche, M., J. Jones, and P.M. Gullino, Role of prostaglandin El and copper in angiogenesis. J. Natl. Cancer Inst.,1982.69(2):p.475-482.
39. Papetti, M. and I.M. Herman, Mechanisms of normal and tumor-derived angiogenesis. American Journal of Physiology- Cell Physiology,2002.282(5):p. 947-970.
40. Pan, Q., C.G. Kleer, K.L. van Golen, J. Irani, K.M. Bottema, C. Bias, M. De Carvalho, E.A. Mesri, D.M. Robins, and R.D. Dick, Copper Deficiency Induced by Tetrathiomolybdate Suppresses Tumor Growth and Angiogenesis 1. Cancer Research,2002.62(17):p.4854-4859.
41. Lane, T.F., SPARC is a source of copper-binding peptides that stimulate angiogenesis. Journal of Cell Biology,1994.125(4):p.929-943.
42. Soncin, F., J.D. Guitton, T. Cartwright, and J. Badet, Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells. Biochemical and Biophysical Research Communications,1997.236(3):p. 604-610.
43. Satake H., S.K., Aoki T., Otsuka M., Sugiura Y., Yamamoto T. and Inoue J., Cupric Ion Blocks NFκB Activation Through Inhibiting The Signal-Induced Phosphorylation of IκB. Biochem. Biophys. Res. Commun,1995.216:p. 568-573.
44. Maziere C., A.M., Djavaheri-Mergny M., Packer L. and Maziere J. C., Oxidized low density lipoproreininduces activation of the transcription factor NFκB in fibroblasts, endothelial and smooth muscle cells. Biochem. Mol. Biol. Int.,1996. 155(2459-2467).
45. Brewer, G.J., Wilson's disease. Current Treatment Options in Neurology,2000. 2(3):p.193-203.
46. Brewer, G.J., R.D. Dick, V. Johnson, Y. Wang, V. Yuzbasiyan-Gurkan, K. Kluin, J.K. Fink, and A. Aisen, Treatment of Wilson's disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Archives of Neurology,1994.51(6):p.545-554.
47. Brem, S.S., D. Zagzag, A.M. Tsanaclis, S. Gately, M.P. Elkouby, and S.E. Brien, Inhibition of angiogenesis and tumor growth in the brain. Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor. American Journal of Pathology,1990.137(5):p. 1121-1142.
48. Yoshida, D., Y. Ikeda, and S. Nakazawa, Copper chelation inhibits tumor angiogenesis in the experimental 9L gliosarcoma model. Neurosurgery,1995. 37(2):p.287.
49. Matsubara, T., R. Saura, K. Hirohata, and M. Ziff, Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine. Journal of Clinical Investigation,1989.83(1):p.158.
50. Kotsaki-Kovatsi, V.P., G. Koehler-Samouilidis, A. Kovatsis, and G. Rozos, Fluctuation of zinc, copper, magnesium and calcium concentrations in guinea pig tissues after administration of Captopril(SQ 14225).1997, Fischer. p.32-36.
51. Moriguchi, M., T. Nakajima, H. Kimura, T. Watanabe, H. Takashima, Y. Mitsumoto, T. Katagishi, T. Okanoue, and K. Kagawa, The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production. International Journal of Cancer,2002.102(5).
52. Hayashi, M., H. Nishiya, T. Chiba, D. Endoh, Y. Kon, and T. Okui, Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro.2007.
53. Yoshii, J., H. Yoshiji, S. Kuriyama, Y. Ikenaka, R. Noguchi, H. Okuda, H. Tsujinoue, T. Nakatani, H. Kishida, and D. Nakae, The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.2001, John Wiley & Sons, Inc. New York.
54. Yoshiji, H., S. Kuriyama, J. Yoshii, Y. Ikenaka, R. Noguchi, K. Yanase, T. Namisaki, M. Yamazaki, H. Tsujinoue, and H. Imazu, The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression. p.1369.
55. Ding, W.Q., B. Liu, J.L. Vaught, H. Yamauchi, and S.E. Lind, Anticancer activity of the antibiotic clioquinol.2005, AACR. p.3389-3395.
56. Halliwell, B. and O. Aruoma, DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS letters,1991. 281(1-2):p.9.
57. Pecheur, M.L., E. Bourdon, E. Paly, L. Farout, B. Friguet, and J. London, Oxidized SOD1 alters proteasome activities in vitro and in the cortex of SOD1 overexpressing mice. FEBS letters,2005.579(17):p.3613-3618.
58. Beretta, S., G. Sala, L. Mattavelli, C. Ceresa, A. Casciati, A. Ferri, M.T. Card, and C. Ferrarese, Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Neurobiology of Disease,2003.13(3):p.213-221.
59. Valko, M., D. Leibfritz, J. Moncol, M. Cronin, M. Mazur, and J. Telser, Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology,2007.39(1):p.44-84.
60. Chaiswing, L., J. Bourdeau-Heller, W. Zhong, and T. Oberley, Characterization of redox state of two human prostate carcinoma cell lines with different degrees of aggressiveness. Free Radical Biology and Medicine,2007.43(2):p.202-215.
61. Fang, J., H. Nakamura, and A. Iyer, Tumor-targeted induction of oxystress for cancer therapy. Journal of drug targeting; 2007.15(7-8):p.475-486.
62. Kong, Q., J. Beel, and K. Lillehei, A threshold concept for cancer therapy. Medical hypotheses,2000.55(1):p.29-35.
63. Kong, Q. and K. Lillehei, Antioxidant inhibitors for cancer therapy. Medical hypotheses,1998.51(5):p.405-409.
64. McCarty, M., J. Barroso-Aranda, and F. Contreras, A two-phase strategy for treatment of oxidant-dependent cancers. Medical hypotheses,2007.69(3):p. 489-496.
65. Starkebaum, G. and R. Root, D-Penicillamine:analysis of the mechanism of copper-catalyzed hydrogen peroxide generation. The Journal of Immunology, 1985.134(5):p.3371-3378.
66. Carvallo-Chaigneau, F., C. Trejo-Solis, C. Gomez-Ruiz, E. Rodriguez-Aguilera, L. Macias-Rosales, E. Cortes-Barberena, C. Cedillo-Pelaez, I. Gracia-Mora, L. Ruiz-Azuara, and V. Madrid-Marina, Casiopeina Ⅲ-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo.2008, Springer. p.17-28.
67. Trejo-Sol s, C., G. Palencia, S. Zuniga, A. Rodr g-Ropon, L. Osorio-Rico, S.T. Luvia, I. Gracia-Mora, L. Marquez-Rosado, A. Sanchez, and M.E. Moreno-Garc a, Cas Ⅱgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.2005. p.563-574.
68. Cory, J.G., A.H. Cory, G. Rappa, A. Lorico, M.C. Liu, T.S. Lin, and A.C. Sartorelli, Inhibitors of ribonucleotide reductase. Comparative effects of amino-and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. 1994. p.335.
69. Liu, M.C., T.S. Lin, J.G. Cory, A.H. Cory, and A.C. Sartorelli, Synthesis and biological activity of 3-and 5-amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone.1996. p.2586-2593.
70. Agrawal, S., N.K. Singh, R.C. Aggarwal, A. Sodhi, and P. Tandon, Synthesis, structure, and antitumor activity of N-salicyloyl-N'-(2-furylthiocarbonyl) hydrazine and its copper (II) complex.1986, American Chemical Society, p. 199-202.
71. Garcia-Tojal, J., A. Garcia-Orad, J.L. Serra, J.L. Pizarro, L. Lezama, M.I. Arriortua, and T. Rojo, Synthesis and spectroscopic properties of copper (II) complexes derived from thiophene-2-carbaldehyde thiosemicarbazone. Structure and biological activity of [Cu (C6H6N3S2) 2].1999, Elsevier. p.45-54.
72. Sartorelli, A.C., E.C Moore, M.S. Zedeck, and K.C Agrawal, Inhibition of ribonucleoside diphosphate reductase by 1-formylisoquinoline thiosemicarbazone and related compounds.1970, American Chemical Society. p.4492-4498.
73. Thelander, L. and A. Graslund, Mechanism of inhibition of mammalian ribonucleotide reductase by the iron chelate of 1-formylisoquinoline thiosemicarbazone. Destruction of the tyrosine free radical of the enzyme in an oxygen-requiring reaction.1983, ASBMB. p.4063-4066.
74. Bymes, R.W., M. Mohan, W.E. Antholine, R.X. Xu, and D.H. Petering, Oxidative stress induced by a copper thiosemicarbazones complex.1990. p. 7046-7053.
75. Voges, D., P. Zwickl, and W. Baumeister, The 26S proteasome:a molecular machine designed for controlled proteolysis.1999, Annual Reviews, p. 1015-1068.
76. Glotzer, M., A.W. Murray, and M.W. Kirschner, Cyclin is degraded by the ubiquitin pathway.1991. p.132-138.
77. Won, K.A. and S.I. Reed, Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E.1996, Nature Publishing Group. p.4182.
78. Diehl, J.A., F. Zindy, and C.J. Sherr, Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway.1997, Cold Spring Harbor Lab. p.957.
79. Chen, W., J. Lee, S.Y. Cho, and H.A. Fine, Proteasome-mediated destruction of the cyclin a/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo.2004, AACR. p.3949.
80. Li, B. and Q.P. Dou, Bax degradation by the ubiquitin/proteasome-dependent pathway:involvement in tumor survival and progression.2000, National Acad Sciences. p.3850.
81. Scheffner, M., B.A. Werness, J.M. Huibregtse, A.J. Levine, and P.M. Howley, The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation ofp53.1990, Cell. p.1129.
82. Chen, Z., J. Hagler, V.J. Palombella, F. Melandri, D. Scherer, D. Ballard, and T. Maniatis, Signal-induced site-specific phosphorylation targets Ⅰ kappa B alpha to the ubiquitin-proteasome pathway.1995, Cold Spring Harbor Lab. p.1586.
83. Alkalay, I., A. Yaron, A. Hatzubai, A. Orian, A. Ciechanover, and Y. Ben-Neriah, Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. 1995, National Acad Sciences. p.10599.
84. Pagano, M., S.W. Tam, A.M. Theodoras, P. Beer-Romero, G. Del Sal, V. Chau, P.R. Yew, G.F. Draetta, and M. Rolfe, Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. 1995,AAAS.p.682.
85. Adams, J., The development of proteasome inhibitors as anticancer drugs.2004, Elsevier. p.417-421.
86. Yang, H., J.A. Zonder, and Q.P. Dou, Clinical development of novel proteasome inhibitors for cancer treatment.2009. p.957-971.
87. Adams, J., The proteasome:a suitable antineoplastic target.2004. p.349-360.
88. Catley, L., Y.T. Tai, D. Chauhan, and K.C. Anderson, Perspectives for combination therapy to overcome drug-resistant multiple myeloma. Drug Resistance Updates,2005.8(4):p.205-218.
89. Ciechanover, A., A. Orian, and A.L. Schwartz, Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays,2000.22(5):p.442-451.
90. Dou,Q.P. and R.H. Goldfarb, Bortezomib (millennium pharmaceuticals). IDrugs, 2002.5(8):p.828-834.
91. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
92. Groll, M., R. Huber, and B.C.M. Potts, Crystal Structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S Proteasome Reveal Important Consequences of [beta]-Lactone Ring Opening and a Mechanism for Irreversible Binding.2006. p.5136-5141.
93. Chauhan, D., L. Catley, G. Li, K. Podar, T. Hideshima, M. Velankar, C. Mitsiades, N. Mitsiades, H. Yasui, and A. Letai, A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.2005, Elsevier. p.407-419.
94. Kuhn, D.J., Q. Chen, P.M. Voorhees, J.S. Strader, K.D. Shenk, C.M. Sun, S.D. Demo, M.K. Bennett, F.W.B. van Leeuwen, and A.A. Chanan-Khan, Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. 2007, Am Soc Hematology. p.3281.
95. Nam, S., D.M. Smith, and Q.P. Dou, Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo.2001, ASBMB. p. 13322.
96. Smith, D.M., K.G. Daniel, Z. Wang, W.C. Guida, T.H. Chan, and Q.P. Dou, Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design.2004. p.58-70.
97. Kunnumakkara, A.B., P. Anand, and B.B. Aggarwal, Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins.2008, Elsevier. p.199-225.
98. von Metzler, I., H. Krebbel, U. Kuckelkorn, U. Heider, C. Jakob, M. Kaiser, C. Fleissner, E. Terpos, and O. Sezer, Curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated ⅠκB kinase.2009, Springer, p.173-179.
99. Milacic, V., S. Banerjee, K.R. Landis-Piwowar, F.H. Sarkar, A.P.N. Majumdar, and Q.P. Dou, Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo.2008, AACR. p.7283.
100. Sarkar, F.H. and Y. Li, Mechanisms of cancer chemoprevention by soy isoflavone genistein.2002, Springer. p.265-280.
101. Yang, H., P. Zhou, H. Huang, D. Chen, N. Ma, Q.C. Cui, S. Shen, W. Dong, X. Zhang, and W. Lian, Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.2009, Wiley Subscription Services, Inc., A Wiley Company Hoboken.
102. Goy, A., A. Younes, P. McLaughlin, B. Pro, J.E. Romaguera, F. Hagemeister, L. Fayad, N.H. Dang, F. Samaniego, and M. Wang, Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. Journal of Clinical Oncology,2005.23(4):p.667.
103. Chen, D., Q.C. Cui, H. Yang, R.A. Barrea, F.H. Sarkar, S. Sheng, B. Yan, G. Reddy, and Q.P. Dou, Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts.2007, AACR. p.1636.
104. Chen, S.H., S.H. Liu, Y.C. Liang, J.K. Lin, and S.Y. Lin-Shiau, Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu2+ complex in the cultured rat cortical astrocytes. Glia,2000.31(3).
105. Erl, W., C. Weber, and G.K. Hansson, Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu2+ and Zn2+. American Journal of Physiology- Cell Physiology,2000.278(6):p.1116-1125.
106. Nobel, C.S.I., M. Kimland, B. Lind, S. Orrenius, and A.F.G. Slater, Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper. Journal of Biological Chemistry,1995.270(44):p. 26202.
107. Schreck, R., B. Meier, D.N. Mannel, W. Droge, and P.A. Baeuerle, Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. Journal of Experimental Medicine,1992.175(5):p.1181-1194.
108. Cvek, B., V. Milacic, J. Taraba, and Q. Dou, Ni (II), Cu (II), and Zn (II) Diethyldithiocarbamate Complexes Show Various Activities Against the Proteasome in Breast Cancer Cells. Journal of Medicinal Chemistry,2008. 51(20):p.6256-6258.
109. Cen, D., D. Brayton, B. Shahandeh, F.L. Meyskens, and P.J. Farmer, Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells. J. Med. Chem.,2004.47:p.6914-6920.
110. Johansson, B., A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.1992, MUNKSGAARD INTERNATIONAL PUBLISHERS LTD. p.15-15.
111. Kaplan, C.S., E.A. Petersen, D. Yocum, and E.M. Hersh, A randomized, controlled dose response study of intravenous sodium diethyldithiocarbamate in patients with advanced human immunodeficiency virus infection.1989, Elsevier.
112. Reisinger, E.C., P. Kern, M. Dietrich, M. Ernst, H.D. Flad, and P. Bock, Inhibition of HIV progression by dithiocarb.1990, Elsevier. p.679-682.
113. Sunderman Sr, F.W., Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS.1991, Assoc Clin Scientists. p. 70.
114. Loo, T.W., M.C. Bartlett, and D.M. Clarke, Disulfiram metabolites permanently inactivate the human multidrug resistance P-Glycoprotein. Molecular Pharmaceutics,2004.1(6):p.426-433.
115. Daniel, K.G., D. Chen, S. Orlu, Q.C. Cui, F.R. Miller, and Q.P. Dou, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells.2005, Biomed Central. p. R897.
116. Daniel, K.G., P. Gupta, R.H. Harbach, W.C. Guida, and Q.P. Dou, Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells.2004, Elsevier. p.1139-1151.
117. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
118. Turecky, L., P. Kalina, E. Uhlikova, Namerova, and J. Kri ko, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer. p.187-189.
119. Shian, S.G., Y.R. Kao, F.Y.H. Wu, and C.W. Wu, Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram.2003, ASPET. p.1076.
120. Brar, S.S., C. Grigg, K.S. Wilson, W.D. Holder, D. Dreau, C. Austin, M. Foster, A.J. Ghio, A.R. Whorton, and G.W. Stowell, Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease.2004, AACR. p.1049.
121. Pang, H., D. Chen, Q.C. Cui, and Q.P. Dou, Sodium diethyldithiocarbamate, an AIDS progression inhibitor and a copper-binding compound, has proteasome-inhibitory and apoptosis-inducing activities in cancer cells.2007. p. 809.
122. Yan, B., G. Kumaravel, H. Anjaria, A. Wu, R.C. Petter, C.R. Jewell, and J.R. Wareing, Infreared spectrum of a single resin bead for real-time monitoring of solid-phase reactions. J. Org. Chem.,1995.60:p.5736-5738.
1. Schreck, R., B. Meier, D.N. Mannel, W. Droge, and P.A. Baeuerle, Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells.1992, Rockefeller Univ Press. p.1181.
2. Malaguarnera, L., M.R. Pilastro, R. DiMarco, C. Scifo, M. Renis, M.C. Mazzarino, and A. Messina, Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate.2003, Springer. p.539-545.
3. Parodi, F.E., D. Mao, T.L. Ennis, M.A. Bartoli, and R.W. Thompson, Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-KB. 2005, Elsevier. p.479-489.
4. Daniel, K.G., D. Chen, S. Orlu, Q.C. Cui, F.R. Miller, and Q.P. Dou, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells.2005, Biomed Central. p. R897.
5. Chen, D., F. Peng, Q.C. Cui, K.G. Daniel, S. Orlu, J. Liu, and Q.P. Dou, Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis.2005. p.2932-2939.
6. Cen, D., D. Brayton, B. Shahandeh, F.L. Meyskens Jr, and P.J. Farmer, Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells.2004. p.6914-6920.
7. Jacobson, M.D., M. Weil, and M.C. Raff, Programmed cell death in animal development. Cell,1997.88:p.347-354.
8. Thatte, U. and S. Dahanukar, Apotosis-clinical relevance and pharmacological manipulation. Drugs.1997.54:p.511-532.
9. Song, Z. and H. Steller, Death by design:mechanism and control of apoptosis. Trends Cell Biol,1999.9:p.511-532.
10. Orlowski, R.Z. and E.C. Dees, Applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer. Breast Cancer Res,2003.5:p.1-7.
11. Ciechanover, A., R.D. Everett, A. Orr, C.M. Preston, I. Arnold, K. Pfeiffer, W. Neupert, R.A. Stuart, H. Sch gger, and F.S. Wouters, The ubiquitin-proteasome pathway:on protein death and cell life FREE.1998. p.7151-7160.
12. Seemuller, E., A. Lupas, D. Stock, J. Lowe, R. Huber, and W. Baumeister, Proteasome from Thermoplasma acidophilum:a threonine protease. Science, 1995.268:p.579-582.
13. An, B., R.H. Goldfarb, R. Siman, and Q.P. Dou, Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ,1998.5:p.1062-1075.
14. Lopes, U.G., P. Erhardt, R. Yao, and G.M. Cooper, p53-dependent induction of apoptosis by proteasome inhibitors.1997, ASBMB. p.12893.
15. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
16. Almond, J.B. and G.M. Cohen, The proteasome:a novel target for cancer chemotherapy.2002. p.433-443.
17. Dou, Q.P. and B. Li, Proteasome inhibitors as potential novel anticancer agents. 1999, Elsevier. p.215-223.
18. Daniel, K.G., P. Gupta, R.H. Harbach, W.C. Guida, and Q.P. Dou, Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells.2004, Elsevier. p.1139-1151.
19. An, B., R.H. Goldfarb, R. Siman, and Q.P. Dou, Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts.1998. p.1062.
20. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.
21. Milacic, V., D. Chen, L. Ronconi, K.R. Landis-Piwowar, D. Fregona, and Q.P. Dou, A novel anticancer gold (III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts.2006, AACR. p.10478.
22. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
23. Chen, D., K.G. Daniel, M.S. Chen, D.J. Kuhn, K.R. Landis-Piwowar, and Q.P. Dou, Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells.2005, Elsevier. p.1421-1432.
24. Gao, G. and Q.P. Dou, N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death.2001. p.53-72.
25. Wood, D.E. and E.W. Newcomb, Cleavage of Bax enhances its cell death function.2000, Elsevier. p.375-382.
26. Pink, J.J., S. Wuerzberger-Davis, C. Tagliarino, S.M. Planchon, X.H. Yang, C.J. Froelich, and D.A. Boothman, Activation of a cysteine protease in MCF-7 and T47D breast cancer cells during β-lapachone-mediated apoptosis.2000, Elsevier. p.144-155.
27. Landis-Piwowar, K.R., V. Milacic, D. Chen, H. Yang, Y. Zhao, T.H. Chan, B. Yan, and Q.P. Dou, The proteasome as a potential target for novel anticancer drugs and chemosensitizers.2006, Elsevier. p.263-273.
28. Orlowski, R.Z., J.R. Eswara, A. Lafond-Walker, M.R. Grever, M. Orlowski, and C.V. Dang, Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor.1998, AACR. p.4342.
29. Canfield, S.E., K. Zhu, S.A. Williams, and D.J. McConkey, Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells.2006, AACR. p.2043.
1. Jacobson, M.D., M. Weil, and M.C. Raff, Programmed Cell Death Review in Animal Development.1997. p.347-354.
2. Thatte, U. and S. Dahanukar, Apoptosis:clinical relevance and pharmacological manipulation.1997. p.511.
3. Song, Z. and H. Steller, Death by design:mechanism and control of apoptosis. 1999, Elsevier. p.49-52.
4. Gregoriadis, GC., N.S. Apostolidis, A.N. Romanos, and T.P. Paradellis, A comparative study of trace elements in normal and cancerous colorectal tissues. p.508-519.
5. Tapiero, H. and K.D. Tew, Trace elements in human physiology and pathology: zinc and metallothioneins.2003, Elsevier. p.399-411.
6. Labbe, S. and D.J. Thiele, Pipes and wiring:the regulation of copper uptake and distribution in yeast.1999, Elsevier Ltd. p.500-505.
7. Rizk, S.L. and H.H. Sky-Peck, Comparison between concentrations of trace elements in normal and neoplastic human breast tissue.1984. p.5390.
8. Turecky, L., P. Kalina, E. Uhlikova, Namerova, and J. Kri ko, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer. p.187-189.
9. Nayak, S.B., V.R. Bhat, D. Upadhyay, and S.L. Udupa, Copper and ceruloplasmin status in serum of prostate and colon cancer patients.2003. p. 108.
10. Huang, Y.L., J.Y. Sheu, and T.H. Lin, Association between oxidative stress and changes of trace elements in patients with breast cancer.1999, Elsevier. p. 131-136.
11. Scanni, A., L. Licciardello, M. Trovato, M. Tomirotti, and M. Biraghi, Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung. p.175.
12. Gupta, S.K., V. Shukla, and M.P. Vaidya, Serum trace elements and Cu/Zn ratio in breast cancer patients. p.178-181.
13. Adsule, S., V. Barve, F. Ahmed, Q.P. Dou, S. Padhye, and F.H. Sarkar, Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells.2006. p.7242-7246.
14. Brewer, G.J., Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.2005, Bentham Science Publishers. p. 195-202.
15. Werner Goedde, H. and D.P. Agarwal, Pharmacogenetics of aldehyde dehydrogenase(ALDH).1989, Elsevier. p.345-371.
16. Weiner, H. and X. Wang, Aldehyde dehydrogenase and acetaldehyde metabolism. 1994. p.141.
17. Yang, H., J.A. Zonder, and Q.P. Dou, Clinical development of novel proteasome inhibitors for cancer treatment.2009. p.957-971.
18. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.
19. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
20. Almond, J.B. and G.M. Cohen, The proteasome:a novel target for cancer chemotherapy.2002. p.433-443.
21. Adams, J., The development of proteasome inhibitors as anticancer drugs.2004, Elsevier. p.417-421.
22. Adams, J., The proteasome:a suitable antineoplastic target.2004. p.349-360.
23. Lopes, U.G., P. Erhardt, R. Yao, and G.M. Cooper, p53-dependent induction of apoptosis by proteasome inhibitors.1997, ASBMB. p.12893.
24. Tanimoto, Y., Y. Onishi, S. Hashimoto, and H. Kizaki, Peptidyl aldehyde inhibitors ofproteasome induce apoptosis rapidly in mouse lymphoma RVC cells. 1997, Jpn Biochemical Soc. p.542.
25. Adams, J., Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer.2002, Elsevier. p.493-500.
26. Dou, Q.P. and R.H. Goldfarb, Bortezomib (millennium pharmaceuticals).2002. p.828.
27. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
28. Chen, S.H., J.K. Lin, Y.C. Liang, M.H. Pan, S.H. Liu, and S.Y. Lin-Shiau, Involvement of activating transcription factors JNK, NF-κB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex.2008, Elsevier.
29. Daniel, K.G., R.H. Harbach, W.C. Guida, and Q.P. Dou, Copper storage diseases: Menkes, Wilsons, and cancer.2004. p.2652-2662.
1. Chen, S.L., S.R. Dzeng, M.H. Yang, K.H. Chiu, G.M. Shieh, and C.M. Wai, Arsenic species in groundwaters of the blackfoot disease area, Taiwan.1994, American Chemical Society. p.877-881.
2. Chen, S.L., S.J. Yeh, M.H. Yang, and T.H. Lin, Trace element concentration and arsenic speciation in the well water of a Taiwan area with endemic blackfoot disease.1995, Springer. p.263-274.
3. Huang, Y.K., K.H. Lin, H.W. Chen, C.C. Chang, C.W. Liu, M.H. Yang, and Y.M. Hsueh, Arsenic species contents at aquaculture farm and in farmed mouthbreeder (Oreochromis mossambicus) in blackfoot disease hyperendemic areas.2003, Elsevier. p.1491-1500.
4. Pontius, F.W., Water quality and treatment:a handbook of community water supplies. in.1990.
5. Tseng, W.P., Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic.1977, National Institute of Environmental Health Science. p.109.
6. Hsueh, Y.M., GS. Cheng, M.M. Wu, H.S. Yu, T.L. Kuo, and C.J. Chen, Multiple risk factors associated with arsenic-induced skin cancer:effects of chronic liver disease and malnutritional status.1995, London:HK Lewis and Co. p.109-114.
7. Morton, W., G Starr, D. Pohl, J. Stoner, S. Wagner, and D. Weswig, Skin cancer and water arsenic in Lane County, Oregon.1976. p.2523.
8. Gordon, E.M., R.W. Barrett, W.J. Dower, S.P.A. Fodor, and M.A. Gallop, Applications of combinatorial technologies to drug discovery.2. Combinatorial organic synthesis, library screening strategies, and future directions.1994, American Chemical Society. p.1385-1401.
9. Thompson, L.A. and J.A. Ellman, Synthesis and applications of small molecule libraries.1996. p.555-600.
10. Nefzi, A., C. Dooley, J.M. Ostresh, and R.A. Houghten, Combinatorial chemistry:from peptides and peptidomimetics to small organic and heterocyclic compounds.1998, Elsevier. p.2273-2278.
11. Lam, K.S., M. Lebl, and V. Krchnak, The "one-bead-one-compound" combinatorial library method.1997. p.411-448.
12. Yan, B., New combichem QC standards guard the supply of compounds and ensure HTS results.2004. p.30-34.
13. Yan, B., N. Collins, J. Wheatley, M. Irving, K. Leopold, C. Chan, A. Shornikov, L. Fang, A. Lee, and M. Stock, High-throughput purification of combinatorial libraries Ⅰ:A high-throughput purification system using an accelerated retention window approach.2004. p.255-261.
14. Yan, B., L. Fang, M. Irving, S. Zhang, A.M. Boldi, F. Woolard, C.R. Johnson, T. Kshirsagar, GM. Figliozzi, and C.A. Krueger, Quality control in combinatorial chemistry:determination of the quantity, purity, and quantitative purity of compounds in combinatorial libraries.2003. p.547-559.
15. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.
2. Gregoriadis, G., N. Apostolidis, A. Romanos, and T. Paradellis, A comparative study of trace elements in normal and cancerous colorectal tissues. Cancer, 1983.52(3).
3. O'dell, B., Biochemistry of copper. The Medical clinics of North America,1976. 60(4):p.687.
4. Johnson, P., D. Milne, and G. Lykken, Effects of age and sex on copper absorption, biological half-life, and status in humans.1992, Am Soc Nutrition. p.917-925.
5. Hartmann, H., K. Felix, W. Nagel, and U. Weser, Intestinal administration of copper and its transient release into venous rat blood serum concomitantly with metallothionein. BioMetals,1993.6(2):p.115-118.
6. Aust, S., L. Morehouse, and C. Thomas, Role of metals in oxygen radical reactions. Journal of free radicals in biology & medicine,1985.1(1):p.3.
7. Weiss, K. and M. Linder, Copper transport in rats involving a new plasma protein. American Journal of Physiology-Endocrinology And Metabolism,1985. 249(1):p.77-88.
8. Cousins, R., Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin.1985, Am Physiological Soc. p.238-309.
9. Barrow, L. and M. Tanner, Copper distribution among serum proteins in paediatric liver disorders and malignancies. European Journal of Clinical Investigation,1988.18(6):p.555-560.
10. Linder, M.C. and M. Hazegh-Azam, Copper biochemistry and molecular biology.1996, Am Soc Nutrition, p.797-811.
11. Saenko, E., A. Yaropolov, and E. Harris, Biological functions of ceruloplasmin expressed through copper-binding sites and a cellular receptor. Journal of Trace Elements in Experimental Medicine,1994.7:p.69-69.
12. Dijkstra, M., R.J. Vonk, and F. Kuipers, How does copper get into bile? New insights into the mechanism (s) of hepatobiliary copper transport.1996. p.109.
13. Harris, E.D., Copper transport and metabolism:An update.1998. p.163-176.
14. Coates, R.J., N.S. Weiss, J.R. Daling, R.L. Rettmer, and G.R. Warnick, Cancer risk in relation to serum copper levels. Cancer Research,1989.49(15):p. 4353-4356.
15. Gupta, S.K., V.K. Shukla, M.P. Vaidya, S.K. Roy, and S. Gupta, Serum trace elements and Cu/Zn ratio in breast cancer patients. Journal of surgical oncology, 1991.46(3).
16. Rizk, S.L. and H.H. Sky-Peck, Comparison between concentrations of trace elements in normal and neoplastic human breast tissue.1984. p.5390.
17. Tureck, L., P. Kalina, E. Uhlikova, N醡erov, and J. Kri瀔o, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer, p.187-189.
18. Nayak, S.B., V.R. Bhat, D. Upadhyay, and S.L. Udupa, Copper and ceruloplasmin status in serum of prostate and colon cancer patients.2003. p. 108.
19. Kunapuli, S.P., H. Singh, P. Singh, and A. Kumar, Ceruloplasmin gene expression in human cancer cells. Life Sci.,1987.40(23):p.2225-2228.
20. Stassar, M.J., G. Devitt, M. Brosius, L. Rinnab, J. Prang, and T. Schradin, Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br. J. Cancer,2001.85(9):p.1372-1382.
21. Yamamoto, K. and S. Kawanishi, J. Biol. Chem.,1989.264:p.15435-15440.
22. Burkitt, M.J., Copper-DNA adducts. Meth Enzymol,1994.234:p.102-106.
23. Wiliams, R.J.P. and F.J.J.R.D. Silva, New trends in bio-inorganic chemistry. New York:Academic Press,1978:p.1-10.
24. Milne, L., P. Nicotera, S. Orrenius, and M.J. Burkitt, Effects of glutathione and chelating agents on copper-mediated DNA oxidation:pro-oxidant and antioxidant properties of glutathione. Arch. Biochem. Biophys.,1993.304:p. 102-106.
25. Hiroyuki, O., S. Norimassa, I. Hiroshi, and M. Michio, Abnormal accumulation of copper in LEC rat liver induces expression of P53 and nuclear matrix-bound P2/waf1/cip1. Carcinogenesis,1996.17:p.2157-2161.
26. Theophanides, T. and J. Anastassopoulou, Copper and carcinogenesis. Critical Reviews in Oncology/Hematology,2002.42:p.57-64.
27. Da Silva, J. and R.J.P. Williams, The biological chemistry of the elements:the inorganic chemistry of life.2001:Oxford University Press, USA.
28. Folkman, J., Tumor angiogenesis:therapeutic implications. N Engl J Med,1971. 285(21):p.1182-6.
29. Brem, S., Angiogenesis and cancer control:from concept to therapeutic trial. Cancer Control,1999.6(5):p.436-458.
30. Shan, S., N.D. Robson, Y. Cao, T. Qiao, C.Y. Li, and C.D. Kontos, Responses of vascular endothelial cells to angiogenic signaling are important for tumor cell survival. Faseb J,2004.18(2):p.326-328.
31. Manders, P., L. Beex, V.C.G. Tjan-Heijnen, J. Geurts-Moespot, T.H. Van Tienoven, J.A. Foekens, and C.G.J. Sweep, The prognostic value of vascular endothelial growth factor in 574 node-negative breast cancer patients who did not receive adjuvant systemic therapy. British journal of cancer,2002.87:p. 772-778.
32. Berns, E.M.J.J., J.G.M. Klijn, M.P. Look, N. Grebenchtchikov, R. Vossen, H. Peters, A. Geurts-Moespot, H. Portengen, I.L. van Staveren, and M.E. Meijer-van Gelder, Combined Vascular Endothelial Growth Factor and TP53 Status Predicts Poor Response to Tamoxifen Therapy in Estrogen Receptor-positive Advanced Breast Cancer 1. Clinical Cancer Research,2003. 9(4):p.1253-1258.
33. Manders, P., L.V.A.M. Beex, V.C.G. Tjan-Heijnen, P.N. Span, and C.F.G.J. Sweep, Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma. Cancer,2003. 98(10).
34. Paola, F.D., A.M. Granato, E. Scarpi, F. Monti, L. Medri, and S. Bianchi, Vascular endothelial growth factor and prognosis in patients with node-negative breast cancer. Int. J. Cancer,2002.98(2):p.228-233.
35. McAuslan, B.R. and W. Reilly, Endothelial cell phagokinesis in response to specific metal ions. Experimental cell research,1980.130(1):p.147.
36. Hu, G., Copper stimulates proliferation of human endothelial cells under culture. Journal of cellular biochemistry,1998.69(3).
37. Parke, A., P. Bhattacherjee, R.M. Palmer, and N.R. Lazarus, Characterization and quantification of copper sulfate-induced vascularization of the rabbit cornea. The American journal of pathology,1988.130(1):p.173.
38. Ziche, M., J. Jones, and P.M. Gullino, Role of prostaglandin El and copper in angiogenesis. J. Natl. Cancer Inst.,1982.69(2):p.475-482.
39. Papetti, M. and I.M. Herman, Mechanisms of normal and tumor-derived angiogenesis. American Journal of Physiology- Cell Physiology,2002.282(5):p. 947-970.
40. Pan, Q., C.G. Kleer, K.L. van Golen, J. Irani, K.M. Bottema, C. Bias, M. De Carvalho, E.A. Mesri, D.M. Robins, and R.D. Dick, Copper Deficiency Induced by Tetrathiomolybdate Suppresses Tumor Growth and Angiogenesis 1. Cancer Research,2002.62(17):p.4854-4859.
41. Lane, T.F., SPARC is a source of copper-binding peptides that stimulate angiogenesis. Journal of Cell Biology,1994.125(4):p.929-943.
42. Soncin, F., J.D. Guitton, T. Cartwright, and J. Badet, Interaction of human angiogenin with copper modulates angiogenin binding to endothelial cells. Biochemical and Biophysical Research Communications,1997.236(3):p. 604-610.
43. Satake H., S.K., Aoki T., Otsuka M., Sugiura Y., Yamamoto T. and Inoue J., Cupric Ion Blocks NFκB Activation Through Inhibiting The Signal-Induced Phosphorylation of IκB. Biochem. Biophys. Res. Commun,1995.216:p. 568-573.
44. Maziere C., A.M., Djavaheri-Mergny M., Packer L. and Maziere J. C., Oxidized low density lipoproreininduces activation of the transcription factor NFκB in fibroblasts, endothelial and smooth muscle cells. Biochem. Mol. Biol. Int.,1996. 155(2459-2467).
45. Brewer, G.J., Wilson's disease. Current Treatment Options in Neurology,2000. 2(3):p.193-203.
46. Brewer, G.J., R.D. Dick, V. Johnson, Y. Wang, V. Yuzbasiyan-Gurkan, K. Kluin, J.K. Fink, and A. Aisen, Treatment of Wilson's disease with ammonium tetrathiomolybdate. I. Initial therapy in 17 neurologically affected patients. Archives of Neurology,1994.51(6):p.545-554.
47. Brem, S.S., D. Zagzag, A.M. Tsanaclis, S. Gately, M.P. Elkouby, and S.E. Brien, Inhibition of angiogenesis and tumor growth in the brain. Suppression of endothelial cell turnover by penicillamine and the depletion of copper, an angiogenic cofactor. American Journal of Pathology,1990.137(5):p. 1121-1142.
48. Yoshida, D., Y. Ikeda, and S. Nakazawa, Copper chelation inhibits tumor angiogenesis in the experimental 9L gliosarcoma model. Neurosurgery,1995. 37(2):p.287.
49. Matsubara, T., R. Saura, K. Hirohata, and M. Ziff, Inhibition of human endothelial cell proliferation in vitro and neovascularization in vivo by D-penicillamine. Journal of Clinical Investigation,1989.83(1):p.158.
50. Kotsaki-Kovatsi, V.P., G. Koehler-Samouilidis, A. Kovatsis, and G. Rozos, Fluctuation of zinc, copper, magnesium and calcium concentrations in guinea pig tissues after administration of Captopril(SQ 14225).1997, Fischer. p.32-36.
51. Moriguchi, M., T. Nakajima, H. Kimura, T. Watanabe, H. Takashima, Y. Mitsumoto, T. Katagishi, T. Okanoue, and K. Kagawa, The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin-8 production. International Journal of Cancer,2002.102(5).
52. Hayashi, M., H. Nishiya, T. Chiba, D. Endoh, Y. Kon, and T. Okui, Trientine, a copper-chelating agent, induced apoptosis in murine fibrosarcoma cells in vivo and in vitro.2007.
53. Yoshii, J., H. Yoshiji, S. Kuriyama, Y. Ikenaka, R. Noguchi, H. Okuda, H. Tsujinoue, T. Nakatani, H. Kishida, and D. Nakae, The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells.2001, John Wiley & Sons, Inc. New York.
54. Yoshiji, H., S. Kuriyama, J. Yoshii, Y. Ikenaka, R. Noguchi, K. Yanase, T. Namisaki, M. Yamazaki, H. Tsujinoue, and H. Imazu, The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression. p.1369.
55. Ding, W.Q., B. Liu, J.L. Vaught, H. Yamauchi, and S.E. Lind, Anticancer activity of the antibiotic clioquinol.2005, AACR. p.3389-3395.
56. Halliwell, B. and O. Aruoma, DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS letters,1991. 281(1-2):p.9.
57. Pecheur, M.L., E. Bourdon, E. Paly, L. Farout, B. Friguet, and J. London, Oxidized SOD1 alters proteasome activities in vitro and in the cortex of SOD1 overexpressing mice. FEBS letters,2005.579(17):p.3613-3618.
58. Beretta, S., G. Sala, L. Mattavelli, C. Ceresa, A. Casciati, A. Ferri, M.T. Card, and C. Ferrarese, Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Neurobiology of Disease,2003.13(3):p.213-221.
59. Valko, M., D. Leibfritz, J. Moncol, M. Cronin, M. Mazur, and J. Telser, Free radicals and antioxidants in normal physiological functions and human disease. International Journal of Biochemistry and Cell Biology,2007.39(1):p.44-84.
60. Chaiswing, L., J. Bourdeau-Heller, W. Zhong, and T. Oberley, Characterization of redox state of two human prostate carcinoma cell lines with different degrees of aggressiveness. Free Radical Biology and Medicine,2007.43(2):p.202-215.
61. Fang, J., H. Nakamura, and A. Iyer, Tumor-targeted induction of oxystress for cancer therapy. Journal of drug targeting; 2007.15(7-8):p.475-486.
62. Kong, Q., J. Beel, and K. Lillehei, A threshold concept for cancer therapy. Medical hypotheses,2000.55(1):p.29-35.
63. Kong, Q. and K. Lillehei, Antioxidant inhibitors for cancer therapy. Medical hypotheses,1998.51(5):p.405-409.
64. McCarty, M., J. Barroso-Aranda, and F. Contreras, A two-phase strategy for treatment of oxidant-dependent cancers. Medical hypotheses,2007.69(3):p. 489-496.
65. Starkebaum, G. and R. Root, D-Penicillamine:analysis of the mechanism of copper-catalyzed hydrogen peroxide generation. The Journal of Immunology, 1985.134(5):p.3371-3378.
66. Carvallo-Chaigneau, F., C. Trejo-Solis, C. Gomez-Ruiz, E. Rodriguez-Aguilera, L. Macias-Rosales, E. Cortes-Barberena, C. Cedillo-Pelaez, I. Gracia-Mora, L. Ruiz-Azuara, and V. Madrid-Marina, Casiopeina Ⅲ-ia induces apoptosis in HCT-15 cells in vitro through caspase-dependent mechanisms and has antitumor effect in vivo.2008, Springer. p.17-28.
67. Trejo-Sol s, C., G. Palencia, S. Zuniga, A. Rodr g-Ropon, L. Osorio-Rico, S.T. Luvia, I. Gracia-Mora, L. Marquez-Rosado, A. Sanchez, and M.E. Moreno-Garc a, Cas Ⅱgly induces apoptosis in glioma C6 cells in vitro and in vivo through caspase-dependent and caspase-independent mechanisms.2005. p.563-574.
68. Cory, J.G., A.H. Cory, G. Rappa, A. Lorico, M.C. Liu, T.S. Lin, and A.C. Sartorelli, Inhibitors of ribonucleotide reductase. Comparative effects of amino-and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. 1994. p.335.
69. Liu, M.C., T.S. Lin, J.G. Cory, A.H. Cory, and A.C. Sartorelli, Synthesis and biological activity of 3-and 5-amino derivatives of pyridine-2-carboxaldehyde thiosemicarbazone.1996. p.2586-2593.
70. Agrawal, S., N.K. Singh, R.C. Aggarwal, A. Sodhi, and P. Tandon, Synthesis, structure, and antitumor activity of N-salicyloyl-N'-(2-furylthiocarbonyl) hydrazine and its copper (II) complex.1986, American Chemical Society, p. 199-202.
71. Garcia-Tojal, J., A. Garcia-Orad, J.L. Serra, J.L. Pizarro, L. Lezama, M.I. Arriortua, and T. Rojo, Synthesis and spectroscopic properties of copper (II) complexes derived from thiophene-2-carbaldehyde thiosemicarbazone. Structure and biological activity of [Cu (C6H6N3S2) 2].1999, Elsevier. p.45-54.
72. Sartorelli, A.C., E.C Moore, M.S. Zedeck, and K.C Agrawal, Inhibition of ribonucleoside diphosphate reductase by 1-formylisoquinoline thiosemicarbazone and related compounds.1970, American Chemical Society. p.4492-4498.
73. Thelander, L. and A. Graslund, Mechanism of inhibition of mammalian ribonucleotide reductase by the iron chelate of 1-formylisoquinoline thiosemicarbazone. Destruction of the tyrosine free radical of the enzyme in an oxygen-requiring reaction.1983, ASBMB. p.4063-4066.
74. Bymes, R.W., M. Mohan, W.E. Antholine, R.X. Xu, and D.H. Petering, Oxidative stress induced by a copper thiosemicarbazones complex.1990. p. 7046-7053.
75. Voges, D., P. Zwickl, and W. Baumeister, The 26S proteasome:a molecular machine designed for controlled proteolysis.1999, Annual Reviews, p. 1015-1068.
76. Glotzer, M., A.W. Murray, and M.W. Kirschner, Cyclin is degraded by the ubiquitin pathway.1991. p.132-138.
77. Won, K.A. and S.I. Reed, Activation of cyclin E/CDK2 is coupled to site-specific autophosphorylation and ubiquitin-dependent degradation of cyclin E.1996, Nature Publishing Group. p.4182.
78. Diehl, J.A., F. Zindy, and C.J. Sherr, Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway.1997, Cold Spring Harbor Lab. p.957.
79. Chen, W., J. Lee, S.Y. Cho, and H.A. Fine, Proteasome-mediated destruction of the cyclin a/cyclin-dependent kinase 2 complex suppresses tumor cell growth in vitro and in vivo.2004, AACR. p.3949.
80. Li, B. and Q.P. Dou, Bax degradation by the ubiquitin/proteasome-dependent pathway:involvement in tumor survival and progression.2000, National Acad Sciences. p.3850.
81. Scheffner, M., B.A. Werness, J.M. Huibregtse, A.J. Levine, and P.M. Howley, The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation ofp53.1990, Cell. p.1129.
82. Chen, Z., J. Hagler, V.J. Palombella, F. Melandri, D. Scherer, D. Ballard, and T. Maniatis, Signal-induced site-specific phosphorylation targets Ⅰ kappa B alpha to the ubiquitin-proteasome pathway.1995, Cold Spring Harbor Lab. p.1586.
83. Alkalay, I., A. Yaron, A. Hatzubai, A. Orian, A. Ciechanover, and Y. Ben-Neriah, Stimulation-dependent I kappa B alpha phosphorylation marks the NF-kappa B inhibitor for degradation via the ubiquitin-proteasome pathway. 1995, National Acad Sciences. p.10599.
84. Pagano, M., S.W. Tam, A.M. Theodoras, P. Beer-Romero, G. Del Sal, V. Chau, P.R. Yew, G.F. Draetta, and M. Rolfe, Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. 1995,AAAS.p.682.
85. Adams, J., The development of proteasome inhibitors as anticancer drugs.2004, Elsevier. p.417-421.
86. Yang, H., J.A. Zonder, and Q.P. Dou, Clinical development of novel proteasome inhibitors for cancer treatment.2009. p.957-971.
87. Adams, J., The proteasome:a suitable antineoplastic target.2004. p.349-360.
88. Catley, L., Y.T. Tai, D. Chauhan, and K.C. Anderson, Perspectives for combination therapy to overcome drug-resistant multiple myeloma. Drug Resistance Updates,2005.8(4):p.205-218.
89. Ciechanover, A., A. Orian, and A.L. Schwartz, Ubiquitin-mediated proteolysis: biological regulation via destruction. Bioessays,2000.22(5):p.442-451.
90. Dou,Q.P. and R.H. Goldfarb, Bortezomib (millennium pharmaceuticals). IDrugs, 2002.5(8):p.828-834.
91. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
92. Groll, M., R. Huber, and B.C.M. Potts, Crystal Structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S Proteasome Reveal Important Consequences of [beta]-Lactone Ring Opening and a Mechanism for Irreversible Binding.2006. p.5136-5141.
93. Chauhan, D., L. Catley, G. Li, K. Podar, T. Hideshima, M. Velankar, C. Mitsiades, N. Mitsiades, H. Yasui, and A. Letai, A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib.2005, Elsevier. p.407-419.
94. Kuhn, D.J., Q. Chen, P.M. Voorhees, J.S. Strader, K.D. Shenk, C.M. Sun, S.D. Demo, M.K. Bennett, F.W.B. van Leeuwen, and A.A. Chanan-Khan, Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. 2007, Am Soc Hematology. p.3281.
95. Nam, S., D.M. Smith, and Q.P. Dou, Ester bond-containing tea polyphenols potently inhibit proteasome activity in vitro and in vivo.2001, ASBMB. p. 13322.
96. Smith, D.M., K.G. Daniel, Z. Wang, W.C. Guida, T.H. Chan, and Q.P. Dou, Docking studies and model development of tea polyphenol proteasome inhibitors: applications to rational drug design.2004. p.58-70.
97. Kunnumakkara, A.B., P. Anand, and B.B. Aggarwal, Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins.2008, Elsevier. p.199-225.
98. von Metzler, I., H. Krebbel, U. Kuckelkorn, U. Heider, C. Jakob, M. Kaiser, C. Fleissner, E. Terpos, and O. Sezer, Curcumin diminishes human osteoclastogenesis by inhibition of the signalosome-associated ⅠκB kinase.2009, Springer, p.173-179.
99. Milacic, V., S. Banerjee, K.R. Landis-Piwowar, F.H. Sarkar, A.P.N. Majumdar, and Q.P. Dou, Curcumin inhibits the proteasome activity in human colon cancer cells in vitro and in vivo.2008, AACR. p.7283.
100. Sarkar, F.H. and Y. Li, Mechanisms of cancer chemoprevention by soy isoflavone genistein.2002, Springer. p.265-280.
101. Yang, H., P. Zhou, H. Huang, D. Chen, N. Ma, Q.C. Cui, S. Shen, W. Dong, X. Zhang, and W. Lian, Shikonin exerts antitumor activity via proteasome inhibition and cell death induction in vitro and in vivo.2009, Wiley Subscription Services, Inc., A Wiley Company Hoboken.
102. Goy, A., A. Younes, P. McLaughlin, B. Pro, J.E. Romaguera, F. Hagemeister, L. Fayad, N.H. Dang, F. Samaniego, and M. Wang, Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin's lymphoma. Journal of Clinical Oncology,2005.23(4):p.667.
103. Chen, D., Q.C. Cui, H. Yang, R.A. Barrea, F.H. Sarkar, S. Sheng, B. Yan, G. Reddy, and Q.P. Dou, Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts.2007, AACR. p.1636.
104. Chen, S.H., S.H. Liu, Y.C. Liang, J.K. Lin, and S.Y. Lin-Shiau, Death signaling pathway induced by pyrrolidine dithiocarbamate-Cu2+ complex in the cultured rat cortical astrocytes. Glia,2000.31(3).
105. Erl, W., C. Weber, and G.K. Hansson, Pyrrolidine dithiocarbamate-induced apoptosis depends on cell type, density, and the presence of Cu2+ and Zn2+. American Journal of Physiology- Cell Physiology,2000.278(6):p.1116-1125.
106. Nobel, C.S.I., M. Kimland, B. Lind, S. Orrenius, and A.F.G. Slater, Dithiocarbamates induce apoptosis in thymocytes by raising the intracellular level of redox-active copper. Journal of Biological Chemistry,1995.270(44):p. 26202.
107. Schreck, R., B. Meier, D.N. Mannel, W. Droge, and P.A. Baeuerle, Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells. Journal of Experimental Medicine,1992.175(5):p.1181-1194.
108. Cvek, B., V. Milacic, J. Taraba, and Q. Dou, Ni (II), Cu (II), and Zn (II) Diethyldithiocarbamate Complexes Show Various Activities Against the Proteasome in Breast Cancer Cells. Journal of Medicinal Chemistry,2008. 51(20):p.6256-6258.
109. Cen, D., D. Brayton, B. Shahandeh, F.L. Meyskens, and P.J. Farmer, Disulfiram Facilitates Intracellular Cu Uptake and Induces Apoptosis in Human Melanoma Cells. J. Med. Chem.,2004.47:p.6914-6920.
110. Johansson, B., A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites.1992, MUNKSGAARD INTERNATIONAL PUBLISHERS LTD. p.15-15.
111. Kaplan, C.S., E.A. Petersen, D. Yocum, and E.M. Hersh, A randomized, controlled dose response study of intravenous sodium diethyldithiocarbamate in patients with advanced human immunodeficiency virus infection.1989, Elsevier.
112. Reisinger, E.C., P. Kern, M. Dietrich, M. Ernst, H.D. Flad, and P. Bock, Inhibition of HIV progression by dithiocarb.1990, Elsevier. p.679-682.
113. Sunderman Sr, F.W., Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS.1991, Assoc Clin Scientists. p. 70.
114. Loo, T.W., M.C. Bartlett, and D.M. Clarke, Disulfiram metabolites permanently inactivate the human multidrug resistance P-Glycoprotein. Molecular Pharmaceutics,2004.1(6):p.426-433.
115. Daniel, K.G., D. Chen, S. Orlu, Q.C. Cui, F.R. Miller, and Q.P. Dou, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells.2005, Biomed Central. p. R897.
116. Daniel, K.G., P. Gupta, R.H. Harbach, W.C. Guida, and Q.P. Dou, Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells.2004, Elsevier. p.1139-1151.
117. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
118. Turecky, L., P. Kalina, E. Uhlikova, Namerova, and J. Kri ko, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer. p.187-189.
119. Shian, S.G., Y.R. Kao, F.Y.H. Wu, and C.W. Wu, Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram.2003, ASPET. p.1076.
120. Brar, S.S., C. Grigg, K.S. Wilson, W.D. Holder, D. Dreau, C. Austin, M. Foster, A.J. Ghio, A.R. Whorton, and G.W. Stowell, Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease.2004, AACR. p.1049.
121. Pang, H., D. Chen, Q.C. Cui, and Q.P. Dou, Sodium diethyldithiocarbamate, an AIDS progression inhibitor and a copper-binding compound, has proteasome-inhibitory and apoptosis-inducing activities in cancer cells.2007. p. 809.
122. Yan, B., G. Kumaravel, H. Anjaria, A. Wu, R.C. Petter, C.R. Jewell, and J.R. Wareing, Infreared spectrum of a single resin bead for real-time monitoring of solid-phase reactions. J. Org. Chem.,1995.60:p.5736-5738.
1. Schreck, R., B. Meier, D.N. Mannel, W. Droge, and P.A. Baeuerle, Dithiocarbamates as potent inhibitors of nuclear factor kappa B activation in intact cells.1992, Rockefeller Univ Press. p.1181.
2. Malaguarnera, L., M.R. Pilastro, R. DiMarco, C. Scifo, M. Renis, M.C. Mazzarino, and A. Messina, Cell death in human acute myelogenous leukemic cells induced by pyrrolidinedithiocarbamate.2003, Springer. p.539-545.
3. Parodi, F.E., D. Mao, T.L. Ennis, M.A. Bartoli, and R.W. Thompson, Suppression of experimental abdominal aortic aneurysms in mice by treatment with pyrrolidine dithiocarbamate, an antioxidant inhibitor of nuclear factor-KB. 2005, Elsevier. p.479-489.
4. Daniel, K.G., D. Chen, S. Orlu, Q.C. Cui, F.R. Miller, and Q.P. Dou, Clioquinol and pyrrolidine dithiocarbamate complex with copper to form proteasome inhibitors and apoptosis inducers in human breast cancer cells.2005, Biomed Central. p. R897.
5. Chen, D., F. Peng, Q.C. Cui, K.G. Daniel, S. Orlu, J. Liu, and Q.P. Dou, Inhibition of prostate cancer cellular proteasome activity by a pyrrolidine dithiocarbamate-copper complex is associated with suppression of proliferation and induction of apoptosis.2005. p.2932-2939.
6. Cen, D., D. Brayton, B. Shahandeh, F.L. Meyskens Jr, and P.J. Farmer, Disulfiram facilitates intracellular Cu uptake and induces apoptosis in human melanoma cells.2004. p.6914-6920.
7. Jacobson, M.D., M. Weil, and M.C. Raff, Programmed cell death in animal development. Cell,1997.88:p.347-354.
8. Thatte, U. and S. Dahanukar, Apotosis-clinical relevance and pharmacological manipulation. Drugs.1997.54:p.511-532.
9. Song, Z. and H. Steller, Death by design:mechanism and control of apoptosis. Trends Cell Biol,1999.9:p.511-532.
10. Orlowski, R.Z. and E.C. Dees, Applying drugs that affect the ubiquitin-proteasome pathway to the therapy of breast cancer. Breast Cancer Res,2003.5:p.1-7.
11. Ciechanover, A., R.D. Everett, A. Orr, C.M. Preston, I. Arnold, K. Pfeiffer, W. Neupert, R.A. Stuart, H. Sch gger, and F.S. Wouters, The ubiquitin-proteasome pathway:on protein death and cell life FREE.1998. p.7151-7160.
12. Seemuller, E., A. Lupas, D. Stock, J. Lowe, R. Huber, and W. Baumeister, Proteasome from Thermoplasma acidophilum:a threonine protease. Science, 1995.268:p.579-582.
13. An, B., R.H. Goldfarb, R. Siman, and Q.P. Dou, Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts. Cell Death Differ,1998.5:p.1062-1075.
14. Lopes, U.G., P. Erhardt, R. Yao, and G.M. Cooper, p53-dependent induction of apoptosis by proteasome inhibitors.1997, ASBMB. p.12893.
15. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
16. Almond, J.B. and G.M. Cohen, The proteasome:a novel target for cancer chemotherapy.2002. p.433-443.
17. Dou, Q.P. and B. Li, Proteasome inhibitors as potential novel anticancer agents. 1999, Elsevier. p.215-223.
18. Daniel, K.G., P. Gupta, R.H. Harbach, W.C. Guida, and Q.P. Dou, Organic copper complexes as a new class of proteasome inhibitors and apoptosis inducers in human cancer cells.2004, Elsevier. p.1139-1151.
19. An, B., R.H. Goldfarb, R. Siman, and Q.P. Dou, Novel dipeptidyl proteasome inhibitors overcome Bcl-2 protective function and selectively accumulate the cyclin-dependent kinase inhibitor p27 and induce apoptosis in transformed, but not normal, human fibroblasts.1998. p.1062.
20. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.
21. Milacic, V., D. Chen, L. Ronconi, K.R. Landis-Piwowar, D. Fregona, and Q.P. Dou, A novel anticancer gold (III) dithiocarbamate compound inhibits the activity of a purified 20S proteasome and 26S proteasome in human breast cancer cell cultures and xenografts.2006, AACR. p.10478.
22. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
23. Chen, D., K.G. Daniel, M.S. Chen, D.J. Kuhn, K.R. Landis-Piwowar, and Q.P. Dou, Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells.2005, Elsevier. p.1421-1432.
24. Gao, G. and Q.P. Dou, N-terminal cleavage of bax by calpain generates a potent proapoptotic 18-kDa fragment that promotes bcl-2-independent cytochrome C release and apoptotic cell death.2001. p.53-72.
25. Wood, D.E. and E.W. Newcomb, Cleavage of Bax enhances its cell death function.2000, Elsevier. p.375-382.
26. Pink, J.J., S. Wuerzberger-Davis, C. Tagliarino, S.M. Planchon, X.H. Yang, C.J. Froelich, and D.A. Boothman, Activation of a cysteine protease in MCF-7 and T47D breast cancer cells during β-lapachone-mediated apoptosis.2000, Elsevier. p.144-155.
27. Landis-Piwowar, K.R., V. Milacic, D. Chen, H. Yang, Y. Zhao, T.H. Chan, B. Yan, and Q.P. Dou, The proteasome as a potential target for novel anticancer drugs and chemosensitizers.2006, Elsevier. p.263-273.
28. Orlowski, R.Z., J.R. Eswara, A. Lafond-Walker, M.R. Grever, M. Orlowski, and C.V. Dang, Tumor growth inhibition induced in a murine model of human Burkitt's lymphoma by a proteasome inhibitor.1998, AACR. p.4342.
29. Canfield, S.E., K. Zhu, S.A. Williams, and D.J. McConkey, Bortezomib inhibits docetaxel-induced apoptosis via a p21-dependent mechanism in human prostate cancer cells.2006, AACR. p.2043.
1. Jacobson, M.D., M. Weil, and M.C. Raff, Programmed Cell Death Review in Animal Development.1997. p.347-354.
2. Thatte, U. and S. Dahanukar, Apoptosis:clinical relevance and pharmacological manipulation.1997. p.511.
3. Song, Z. and H. Steller, Death by design:mechanism and control of apoptosis. 1999, Elsevier. p.49-52.
4. Gregoriadis, GC., N.S. Apostolidis, A.N. Romanos, and T.P. Paradellis, A comparative study of trace elements in normal and cancerous colorectal tissues. p.508-519.
5. Tapiero, H. and K.D. Tew, Trace elements in human physiology and pathology: zinc and metallothioneins.2003, Elsevier. p.399-411.
6. Labbe, S. and D.J. Thiele, Pipes and wiring:the regulation of copper uptake and distribution in yeast.1999, Elsevier Ltd. p.500-505.
7. Rizk, S.L. and H.H. Sky-Peck, Comparison between concentrations of trace elements in normal and neoplastic human breast tissue.1984. p.5390.
8. Turecky, L., P. Kalina, E. Uhlikova, Namerova, and J. Kri ko, Serum ceruloplasmin and copper levels in patients with primary brain tumors.1984, Springer. p.187-189.
9. Nayak, S.B., V.R. Bhat, D. Upadhyay, and S.L. Udupa, Copper and ceruloplasmin status in serum of prostate and colon cancer patients.2003. p. 108.
10. Huang, Y.L., J.Y. Sheu, and T.H. Lin, Association between oxidative stress and changes of trace elements in patients with breast cancer.1999, Elsevier. p. 131-136.
11. Scanni, A., L. Licciardello, M. Trovato, M. Tomirotti, and M. Biraghi, Serum copper and ceruloplasmin levels in patients with neoplasias localized in the stomach, large intestine or lung. p.175.
12. Gupta, S.K., V. Shukla, and M.P. Vaidya, Serum trace elements and Cu/Zn ratio in breast cancer patients. p.178-181.
13. Adsule, S., V. Barve, F. Ahmed, Q.P. Dou, S. Padhye, and F.H. Sarkar, Novel Schiff base copper complexes of quinoline-2 carboxaldehyde as proteasome inhibitors in human prostate cancer cells.2006. p.7242-7246.
14. Brewer, G.J., Copper lowering therapy with tetrathiomolybdate as an antiangiogenic strategy in cancer.2005, Bentham Science Publishers. p. 195-202.
15. Werner Goedde, H. and D.P. Agarwal, Pharmacogenetics of aldehyde dehydrogenase(ALDH).1989, Elsevier. p.345-371.
16. Weiner, H. and X. Wang, Aldehyde dehydrogenase and acetaldehyde metabolism. 1994. p.141.
17. Yang, H., J.A. Zonder, and Q.P. Dou, Clinical development of novel proteasome inhibitors for cancer treatment.2009. p.957-971.
18. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.
19. Adams, J., Potential for proteasome inhibition in the treatment of cancer.2003, Elsevier. p.307-315.
20. Almond, J.B. and G.M. Cohen, The proteasome:a novel target for cancer chemotherapy.2002. p.433-443.
21. Adams, J., The development of proteasome inhibitors as anticancer drugs.2004, Elsevier. p.417-421.
22. Adams, J., The proteasome:a suitable antineoplastic target.2004. p.349-360.
23. Lopes, U.G., P. Erhardt, R. Yao, and G.M. Cooper, p53-dependent induction of apoptosis by proteasome inhibitors.1997, ASBMB. p.12893.
24. Tanimoto, Y., Y. Onishi, S. Hashimoto, and H. Kizaki, Peptidyl aldehyde inhibitors ofproteasome induce apoptosis rapidly in mouse lymphoma RVC cells. 1997, Jpn Biochemical Soc. p.542.
25. Adams, J., Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer.2002, Elsevier. p.493-500.
26. Dou, Q.P. and R.H. Goldfarb, Bortezomib (millennium pharmaceuticals).2002. p.828.
27. Chen, D., Q.C. Cui, H. Yang, and Q.P. Dou, Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. 2006, AACR. p.10425.
28. Chen, S.H., J.K. Lin, Y.C. Liang, M.H. Pan, S.H. Liu, and S.Y. Lin-Shiau, Involvement of activating transcription factors JNK, NF-κB, and AP-1 in apoptosis induced by pyrrolidine dithiocarbamate/Cu complex.2008, Elsevier.
29. Daniel, K.G., R.H. Harbach, W.C. Guida, and Q.P. Dou, Copper storage diseases: Menkes, Wilsons, and cancer.2004. p.2652-2662.
1. Chen, S.L., S.R. Dzeng, M.H. Yang, K.H. Chiu, G.M. Shieh, and C.M. Wai, Arsenic species in groundwaters of the blackfoot disease area, Taiwan.1994, American Chemical Society. p.877-881.
2. Chen, S.L., S.J. Yeh, M.H. Yang, and T.H. Lin, Trace element concentration and arsenic speciation in the well water of a Taiwan area with endemic blackfoot disease.1995, Springer. p.263-274.
3. Huang, Y.K., K.H. Lin, H.W. Chen, C.C. Chang, C.W. Liu, M.H. Yang, and Y.M. Hsueh, Arsenic species contents at aquaculture farm and in farmed mouthbreeder (Oreochromis mossambicus) in blackfoot disease hyperendemic areas.2003, Elsevier. p.1491-1500.
4. Pontius, F.W., Water quality and treatment:a handbook of community water supplies. in.1990.
5. Tseng, W.P., Effects and dose-response relationships of skin cancer and blackfoot disease with arsenic.1977, National Institute of Environmental Health Science. p.109.
6. Hsueh, Y.M., GS. Cheng, M.M. Wu, H.S. Yu, T.L. Kuo, and C.J. Chen, Multiple risk factors associated with arsenic-induced skin cancer:effects of chronic liver disease and malnutritional status.1995, London:HK Lewis and Co. p.109-114.
7. Morton, W., G Starr, D. Pohl, J. Stoner, S. Wagner, and D. Weswig, Skin cancer and water arsenic in Lane County, Oregon.1976. p.2523.
8. Gordon, E.M., R.W. Barrett, W.J. Dower, S.P.A. Fodor, and M.A. Gallop, Applications of combinatorial technologies to drug discovery.2. Combinatorial organic synthesis, library screening strategies, and future directions.1994, American Chemical Society. p.1385-1401.
9. Thompson, L.A. and J.A. Ellman, Synthesis and applications of small molecule libraries.1996. p.555-600.
10. Nefzi, A., C. Dooley, J.M. Ostresh, and R.A. Houghten, Combinatorial chemistry:from peptides and peptidomimetics to small organic and heterocyclic compounds.1998, Elsevier. p.2273-2278.
11. Lam, K.S., M. Lebl, and V. Krchnak, The "one-bead-one-compound" combinatorial library method.1997. p.411-448.
12. Yan, B., New combichem QC standards guard the supply of compounds and ensure HTS results.2004. p.30-34.
13. Yan, B., N. Collins, J. Wheatley, M. Irving, K. Leopold, C. Chan, A. Shornikov, L. Fang, A. Lee, and M. Stock, High-throughput purification of combinatorial libraries Ⅰ:A high-throughput purification system using an accelerated retention window approach.2004. p.255-261.
14. Yan, B., L. Fang, M. Irving, S. Zhang, A.M. Boldi, F. Woolard, C.R. Johnson, T. Kshirsagar, GM. Figliozzi, and C.A. Krueger, Quality control in combinatorial chemistry:determination of the quantity, purity, and quantitative purity of compounds in combinatorial libraries.2003. p.547-559.
15. Bousquet, E.W., Esters of dithiocarbamic acids.1938, Google Patents.