Khz（灵芝，猪苓融合菌丝体提取物）诱导人类癌细胞凋亡的机制
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摘要
目的和意义：Khz是从灵芝和猪苓融合菌丝体中提取的混合物。近年来研究表明,天然混合物灵芝三萜类化合物可抑制人肿瘤细胞的增殖。其具有细胞毒性,可诱导人乳腺癌细胞MCF-7,前列腺癌细胞PC-3凋亡,并阻滞细胞周期进程。猪苓菌的水提取物有利尿作用,其甲醇提取物对人胃癌细胞具有细胞毒作用。灵芝和猪苓的抗癌活性物质是在固态培养的融合菌丝体中提取的液体成分,称为液体Khz。本研究旨在探讨Khz是否具有抗癌作用,其抗癌作用机制是否与诱导细胞凋亡有关。
研究方法：HepG2细胞、SNU-1细胞分别经Khz和Khz-cp处理后,采用免疫印迹分析其caspase或PARP、细胞色素C、p47phox和p67phox、JNK (HepG2)和p38(SNU-1)的表达；流式细胞仪分析细胞凋亡。用JNK-1和p38的siRNA分别转染HepG2和SNU-1细胞后再分别检测其表达。HepG2和SUN-1细胞先经不同的方法进行预处理,再分别经Khz和Khz-cp处理后,用荧光显微镜或流式细胞仪分析细胞凋亡；采用多种方法检测细胞质和线粒体内ROS含量。同时采用数字成像显微镜分析Ca2+水平。人乳腺癌细胞系MCF-7经不同浓度的Khz处理后,采用MTT方法检测其生长；流式细胞仪检测其凋亡和Ca2+水平；采用免疫印迹分析caspase7,8,9的表达,流式细胞仪或荧光显微镜检测ROS水平。人肺癌细胞系A549和结肠癌细胞系HCT116经1：2稀释的Khz处理后,采用MTT方法检测其生长；流式细胞仪检测细胞周期、线粒体膜电位和Ca2+水平；采用免疫印迹分析caspase3,9、P53、Bax. Bcl-2(A549细胞)和caspase3,7,9、Bcl-2、PARP (HCT116细胞)的表达,流式细胞仪或荧光显微镜检测ROS水平,且结肠癌检测了细胞凋亡。
结果：体外实验显示,Khz可诱导转化细胞凋亡,而对非转化细胞无促凋亡作用。在HepG2细胞中,Khz诱导细胞凋亡的机制与增加[Ca2+]浓度、激活JNK通路以及通过NADPH氧化酶和线粒体产生活性氧自由基有关。在MCF-7细胞中,Khz降低MMP表达水平,并激活半胱天冬酶,同时增加活性氧自由基和细胞内钙离子浓度。在A549细胞,KHZ降低MMP表达水平,并促进钙和活性氧的生成,增加P53及Bax蛋白的表达,降低了Bcl-2蛋白表达水平。在HCT-116细胞,Khz诱导细胞凋亡机制与增加活性氧自由基,激活caspase3蛋白,增加Ca2+浓度有关。在SNU-1细胞,Khz-CP(灵芝和猪苓融合菌丝粗多糖提取物)通过增加细胞内钙表达水平,并激活P38和NADPH依赖性氧化酶产生的活性氧,从而诱导细胞凋亡。
结论：Khz具有明显的抑制人类癌症细胞生长的作用,其作用机制与诱导癌细胞凋亡有关。Khz具有新型抗癌药物的潜力,值得进一步探讨。
Objective:Khz is an extract mixture from the mycelia of a Ganoderma lucidum and Polyporus umbellatu nuclear fusion. Recently, some studies have shown that a natural mixture of Ganoderma and triterpenoids can exert anti-proliferative effects against malignant cells. Its cytotoxic can induce apoptosis and block cell cycle progression of human breast cancer cells MCF-7and prostate cancer cells PC-3. Water extract of Polyporus bacteria have an effect on diuretic and methanols extract of Polyporus bacteria play a cytotoxic role on gastric cancer. Liquid Khz is liquid component that anti-cancer active substance of Ganoderma and Polyporus is extracted from the fusion mycelia in solid medium. The aim of this study is to examine whether Khz causes apoptosis in human cancer cells and, if so, to identify the signaling mechanisms involved.
Methods:HepG2cells and SNU-1cells were treated via Khz and Khz-CP. The expression of caspase or PARP, cell pigment C, p47phox and p67phox, JNK (HepG2), and p38(SNU-1) were analyzed by Western blot analysis. HepG2cells and SUN-1cells were transfected with siRNA of JNK-1and p38, respectively. HepG2cells and SUN-1cells were pre-treated by different methods and then treated via Khz and Khz-CP. Fluorescence microscopy or flow cytometry were used to analyze apoptosis, a various methods were used to detect cytoplasm and mitochondria reactive oxygen species (ROS) levels, and digital imaging microscopy were used to analyze Ca2+levels. Human breast cancer cell lines MCF-7were treated with different concentrations of Khz. Its growth were detected with MTT, its apoptosis and Ca2+levels were analyzed by flow cytometry, the expression of caspase7,8and9were determined by Western blot analysis, and ROS levels were detected by flow cytometry or fluorescence microscopy. Human lung cancer cell lines A549and human colon cancer cell lines HCT116were treated with Khz diluted1:2in the media. MTT were used to detect their growth. Flow cytometry were used to analyze cell cycle, mitochondrial membrane potential, and Ca2+levels. Western blot analysis were used to determine the expression of caspase3and9, P53, Bax, Bcl-2in A549cells, and caspase3,7and9, Bcl-2, PARP in HCT116cells, respectively. Flow cytometry or fluorescence microscopy was also used to detect ROS levels. And apoptosis were detected in colon cancer.
Results:The results of the present study showed that Khz induced apoptosis preferentially in transformed cells with only minimal effects on non-transformed cells. In HepG2cells, the signaling mechanisms involved an increase in [Ca2+]i, JNK activation, and ROS generation via NADPH oxidase and mitochondria. In MCF-7cells, Khz reduced MMP levels and increased the caspase activation. And also Khz increased ROS and intracellular calcium levels. In A549cells, Khz reduced MMP levels and increased the calcium and ROS generation. Khz also increased p53, Bax and reduced Bcl-2protein levels. In HCT-116cells, Khz induced apoptosis accompanied by an increase in ROS, activation of caspase3proteins and increase of Ca2+levels. In SNU-1cells, Khz-CP (crude polysaccharide extract obtained from the mycelia of Ganoderma lucidum and Polyporus umbellatus nuclear fusion) induced apoptosis by increasing intracellular calcium levels and activating P38and NADPH oxidase-dependent generation of reactive oxygen species.
Conclusions:Khz have profound effects on inhibition of growth of human cancer cells and involve in the signaling mechanisms of apoptosis of human cancer cells, suggesting those worthwhile for further exploration as potential anti-cancer agents.
研究方法：HepG2细胞、SNU-1细胞分别经Khz和Khz-cp处理后,采用免疫印迹分析其caspase或PARP、细胞色素C、p47phox和p67phox、JNK (HepG2)和p38(SNU-1)的表达；流式细胞仪分析细胞凋亡。用JNK-1和p38的siRNA分别转染HepG2和SNU-1细胞后再分别检测其表达。HepG2和SUN-1细胞先经不同的方法进行预处理,再分别经Khz和Khz-cp处理后,用荧光显微镜或流式细胞仪分析细胞凋亡；采用多种方法检测细胞质和线粒体内ROS含量。同时采用数字成像显微镜分析Ca2+水平。人乳腺癌细胞系MCF-7经不同浓度的Khz处理后,采用MTT方法检测其生长；流式细胞仪检测其凋亡和Ca2+水平；采用免疫印迹分析caspase7,8,9的表达,流式细胞仪或荧光显微镜检测ROS水平。人肺癌细胞系A549和结肠癌细胞系HCT116经1：2稀释的Khz处理后,采用MTT方法检测其生长；流式细胞仪检测细胞周期、线粒体膜电位和Ca2+水平；采用免疫印迹分析caspase3,9、P53、Bax. Bcl-2(A549细胞)和caspase3,7,9、Bcl-2、PARP (HCT116细胞)的表达,流式细胞仪或荧光显微镜检测ROS水平,且结肠癌检测了细胞凋亡。
结果：体外实验显示,Khz可诱导转化细胞凋亡,而对非转化细胞无促凋亡作用。在HepG2细胞中,Khz诱导细胞凋亡的机制与增加[Ca2+]浓度、激活JNK通路以及通过NADPH氧化酶和线粒体产生活性氧自由基有关。在MCF-7细胞中,Khz降低MMP表达水平,并激活半胱天冬酶,同时增加活性氧自由基和细胞内钙离子浓度。在A549细胞,KHZ降低MMP表达水平,并促进钙和活性氧的生成,增加P53及Bax蛋白的表达,降低了Bcl-2蛋白表达水平。在HCT-116细胞,Khz诱导细胞凋亡机制与增加活性氧自由基,激活caspase3蛋白,增加Ca2+浓度有关。在SNU-1细胞,Khz-CP(灵芝和猪苓融合菌丝粗多糖提取物)通过增加细胞内钙表达水平,并激活P38和NADPH依赖性氧化酶产生的活性氧,从而诱导细胞凋亡。
结论：Khz具有明显的抑制人类癌症细胞生长的作用,其作用机制与诱导癌细胞凋亡有关。Khz具有新型抗癌药物的潜力,值得进一步探讨。
Objective:Khz is an extract mixture from the mycelia of a Ganoderma lucidum and Polyporus umbellatu nuclear fusion. Recently, some studies have shown that a natural mixture of Ganoderma and triterpenoids can exert anti-proliferative effects against malignant cells. Its cytotoxic can induce apoptosis and block cell cycle progression of human breast cancer cells MCF-7and prostate cancer cells PC-3. Water extract of Polyporus bacteria have an effect on diuretic and methanols extract of Polyporus bacteria play a cytotoxic role on gastric cancer. Liquid Khz is liquid component that anti-cancer active substance of Ganoderma and Polyporus is extracted from the fusion mycelia in solid medium. The aim of this study is to examine whether Khz causes apoptosis in human cancer cells and, if so, to identify the signaling mechanisms involved.
Methods:HepG2cells and SNU-1cells were treated via Khz and Khz-CP. The expression of caspase or PARP, cell pigment C, p47phox and p67phox, JNK (HepG2), and p38(SNU-1) were analyzed by Western blot analysis. HepG2cells and SUN-1cells were transfected with siRNA of JNK-1and p38, respectively. HepG2cells and SUN-1cells were pre-treated by different methods and then treated via Khz and Khz-CP. Fluorescence microscopy or flow cytometry were used to analyze apoptosis, a various methods were used to detect cytoplasm and mitochondria reactive oxygen species (ROS) levels, and digital imaging microscopy were used to analyze Ca2+levels. Human breast cancer cell lines MCF-7were treated with different concentrations of Khz. Its growth were detected with MTT, its apoptosis and Ca2+levels were analyzed by flow cytometry, the expression of caspase7,8and9were determined by Western blot analysis, and ROS levels were detected by flow cytometry or fluorescence microscopy. Human lung cancer cell lines A549and human colon cancer cell lines HCT116were treated with Khz diluted1:2in the media. MTT were used to detect their growth. Flow cytometry were used to analyze cell cycle, mitochondrial membrane potential, and Ca2+levels. Western blot analysis were used to determine the expression of caspase3and9, P53, Bax, Bcl-2in A549cells, and caspase3,7and9, Bcl-2, PARP in HCT116cells, respectively. Flow cytometry or fluorescence microscopy was also used to detect ROS levels. And apoptosis were detected in colon cancer.
Results:The results of the present study showed that Khz induced apoptosis preferentially in transformed cells with only minimal effects on non-transformed cells. In HepG2cells, the signaling mechanisms involved an increase in [Ca2+]i, JNK activation, and ROS generation via NADPH oxidase and mitochondria. In MCF-7cells, Khz reduced MMP levels and increased the caspase activation. And also Khz increased ROS and intracellular calcium levels. In A549cells, Khz reduced MMP levels and increased the calcium and ROS generation. Khz also increased p53, Bax and reduced Bcl-2protein levels. In HCT-116cells, Khz induced apoptosis accompanied by an increase in ROS, activation of caspase3proteins and increase of Ca2+levels. In SNU-1cells, Khz-CP (crude polysaccharide extract obtained from the mycelia of Ganoderma lucidum and Polyporus umbellatus nuclear fusion) induced apoptosis by increasing intracellular calcium levels and activating P38and NADPH oxidase-dependent generation of reactive oxygen species.
Conclusions:Khz have profound effects on inhibition of growth of human cancer cells and involve in the signaling mechanisms of apoptosis of human cancer cells, suggesting those worthwhile for further exploration as potential anti-cancer agents.
引文
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[1]. Lin ZB, Zhang HN.2004. Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin 25:1387-95.
[2]. Sandodiya BS, Thakur GS, Baqhel RK, Prasad GB, Bisen PS.2009. Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol 10:717-42.
[3]. Gao Y, Gao H, Chan E, Tang W, Xu A, Yang H, Huang M, Lan J, Li X, Duan W, Xu C, Zhou S.2005. Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccarides extracted from Ganoderma lucidum, in mice. Immunol Invest 34:171-98.
[4]. Yue GG, Fung KP, Tse GM, Leung PC, Lau CB.2006. Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med.12:777-89.
[5]. Ⅲana-Esteban C.2008. The fungus maitake and its therapeutic potential. Rev Iberoam Micol.25:141-44.
[6]. Jang KJ, Han MH, Lee BH, Kim BW, Kim CH, Yoon HM, Choi YH.2010. Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. J Acupunct Meridian Stud.3:24-31.
[7]. Yue QX, Song XY, Ma C, Feng LX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Cui YJ, Guo DA.2010. Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine.17:606-13.
[8]. Zhao S, Ye G, Fu G, Cheng JX, Yang BB, Peng C.2011. Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol 38:1319-27.
[9]. Liu RM, Zhong JJ.2011 Ganoderic acid Mf and S induce mitochondria mediated apoptosis in human cervical carcinoma HeLa cells. Phytomedicine.15:349-55.
[10]. Li L, Li T, Wang XJ, Xu JP, Wang SG.2008. Effects of Ganoderma lucidum spores on HepG2 cells proliferation and growth cycle. Zhong Yao Cai.31:1514-18.
[11]. Zhao YY, Chao X, Zhang Y, Lin RC, Sun WJ.2010. Cytotoxic steroids from Polyporus umbellatus. Planta Med 76:1755-58.
[12]. Kim JE, Koo KH, Kim YH, Sohn J, Park YG.2008. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 40:709-20.
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[15]. Zhonghong Y, Ruolin Y, Yi J, Zhihui Y, Junrui Y, Qian Z, Yang L.2010. Induction of apoptosis in human promyelocytic leukemia HL60 cells by panaxynol and panaxydol. Molecules 29:5561-73.
[16].Kim TH, Kim Js, Kim Zh, Huang RB, Wang RS. Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species. PLoS One.7(10):e46208 (2012)
[1]. Lin, Z. B., Zhang, H. N. (2004). Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin,25,1387-1395
[2]. Sandodiya, B. S., Thakur, G. S., Baqhel, R. K., Prasad, G. B., Bisen, P. S. (2009). Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol,10,717-742.
[3]. Gao, Y., Gao, H., Chan, E., Tang, W., Xu, A., Yang, H., Huang, M., Lan, J., Li, X., Duan, W., Xu, C., Zhou, S. (2005). Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccharides extracted from Ganoderma lucidum, in mice.34,171-198.
[4]. Yue, G. G., Fung, K. P., Tse, G. M., Leung, P. C, Lau, C. B. (2006). Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med,12,777-789.
[5]. IIIana-Esteban, C. (2008). The fungus maitake (Grifola frondosa) and its therapeutic potential. Rev Iberoam Micol,25,141-144.
[6]. Jang, K. J., Han, M. H., Lee, B. H., Kim, B. W., Kim, C. H., Yoon, H. M., Choi, Y. H. (2010). Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. J Acupunct Meridian Stud,3,24-31.
[7]. Yue, Q. X., Song, X.Y., Ma, C., Feng, L. X., Guan, S. H., Wu, W. Y., Yang, M., Jiang, B. H., Liu, X., Cui, Y. J., Guo, D. A. (2010). Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine,17,606-613.
[8]. Zhao, S., Ye, G., Fu, G., Cheng, J. X., Yang, B. B., Peng, C. (2011). Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol,38,1319-1327.
[9]. Liu, R. M., Zhong, J. J. (2011). Ganoderic acid Mf and S induce mitochondria mediated apoptosis in human cervical carcinoma HeLa cells. Phytomedicine,15,349-355.
[10]. Li, L., Li, T., Wang, X. J., Xu, J. P., Wang, S. G. (2008). Effects of Ganoderma lucidum spores on HepG2 cells proliferation and growth cycle. Zhong Yao Cai,31,1514-1518.
[11]. Zhao, Y. Y., Chao, X., Zhang, Y., Lin, R. C, Sun, W. J. (2010). Cytotoxic steroids from Polyporus umbellatus. Planta Med,76, 1755-1758.
[12]. Ott, M., Gogvadze, V., Orrenius, S., Zhivotovsky, B. (2007). Mitochondria, oxidative stress and cell death. Apoptosis,12,913-922.
[13]. Jacobson, M. D., Raff, M. C. (1995). Programmed cell death and Bcl-2 protection in very low oxygen. Nature,374,814-816.
[14]. Ryter, S. W., Kim, H. P., Hoetzel, A, Park JW, Nakahira K, Wang X, Choi AM. (2007) Mechanisms of cell death in oxidative stress. Antioxid Redox Signal,9,49-89.
[15]. Buttke, T. M., Sandstrom, P. A. (1994). Oxidative stress as a mediator of apoptosis. Immunol Today.15,7-10.
[16]. Jacobson, M. D. (1996). Reactive oxygen species and programmed cell death. Trends Biochem Sci,21,83-86.
[17]. Miyajima, A., Nakashima, J., Yoshioka, K. (1997). Role of reactive oxygen species in cis-dichlorodiammineplatium-induced cytotoxicity on bladder cancer cells. Br J Cancer,76,206-210.
[18]. Zhou, Y., Hileman, E. O., Plunkett, W., Keating, M. J., Huang, P. (2003). Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood,101, 4098-4104.
[19]. Nicotera, P., Orrenius, S. (1998). The role of calcium in apoptosis. Cell Calcium,23,173-180.
[20]. Granfeldt, D., Samuelsson, M., Karlsson, A. (2002). Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane- and granule-localized NADPH-oxidase. J Leukoc Biol,71,611-617.
[21]. Wang, G., Anrather, J., Glass, M. J., et al. (2006). Nox2, Ca2+, and protein kinase C play a role in angiotensin II-induced free radical production in nucleus tractus solitaries. Hypertension,48,482-489.
[22]. Tsung-lang, C, Chin-cheng, S. (2010). Tanshinone IIA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Int J Mol Med,25,231-236.
[23].Kim TH, Kim Js, Kim Zh, Huang RB, Wang RS. Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species. PLoS One.7(10):e46208 (2012)
[1]. Lin ZB, Zhang HN. Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin. 25:1387-1395 (2004)
[2]. Sandodiya BS, Thakur GS, Baqhel RK, Prasad GB, Bisen PS Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol. 10:717-742 (2009)
[3]. Gao Y, Gao H, Chan E, Tang W, Xu A, Yang H, Huang M, Lan J, Li X, Duan W, Xu C, Zhou S Antitumor activity and underlying mechanisms of ganopoly,the refined polysaccarides extracted from Ganoderma lucidum, in mice. Immuno Invest.34:171-198 (2005)
[4]. Yue GG, Fung KP, Tse GM, Leung PC, Lau CB. Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med.12:777-789(2006)
[5]. Ⅲana-Esteban C. The fungus maitake (Grifola frondosa) and its therapeutic potential. Rev Iberoam Micol.25:141-144 (2008)
[6]. Jang KJ, Han MH, Lee BH, Kim BW, Kim CH, Yoon HM, Choi YH. Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. J Acupunct Meridian Stud.3:24-31 (2010)
[7]. Yue QX, Song XY, Ma C, Feng LX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Cui YJ, Guo DA. Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine. 17:606-613 (2010)
[8]. Zhao S, Ye G, Fu G, Cheng JX, Yang BB, Peng C. Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol.38:1319-1327 (2011)
[9]. Liu RM, Zhong JJ. Ganoderic acid Mf and S induce mitochondria mediated apoptosis in human cervical carcinoma HeLa cells. Phytomedicine.15:349-355(2011)
[10]. Li L, Li T, Wang XJ, Xu JP, Wang SG. Effects of Ganoderma lucidum spores on HepG2 cells proliferation and growth cycle. Zhong Yao Cai. 31:1514-1518(2008)
[11]. Zhao YY, Chao X, Zhang Y, Lin RC, Sun WJ. Cytotoxic steroids from Polyporus umbellatus Planta Med.76(15):1755-1758 (2010)
[12]. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis.12:913-922 (2007)
[13]. Jacobson MD, Raff MC. Programmed cell death and Bcl-2 protection in very low oxygen. Nature.374:814-816 (1995)
[14]. Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, Choi AM. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 9:49-89 (2007)
[15]. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today.15:7-10 (1994)
[16]. Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci.21:83-86 (1996)
[17]. Miyajima, A., Nakashima, J., Yoshioka, K. Role of reactive oxygen species in cis-dichlorodiammineplatium-induced cytotoxicity on bladder cancer cells. Br J Cancer 76:206-210 (1997)
[18]. Zhou Y, Hileman EO, Plunkett W, Keating MJ, Huang P. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood.101:4098-4104 (2003)
[19]. Nicotera P, Orrenius S. The role of calcium in apoptosis. Cell Calcium. 23:173-180(1998)
[20]. Tsung-langC, Chin-chengS. Tanshinone HA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Int J Mol Med 25:231-236(2010)
[21].Kim TH, Kim Js, Kim Zh, Huang RB, Wang RS. Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species. PLoS One.7(10):e46208 (2012)
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[3]. Mesner P, et al. Chemotherapy-induced apoptosis. Adv Pharmacol 1997; 41:461-499.
[4]. Palombo JD, et al. The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells. Cancer Lett 2002; 177:163-172."
[5]. Wasser SP, et al. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms:a modern perspective. Crit Rev Immunol 1999; 19:65-96.
[6]. Jiang J, et al. Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells. Int J Oncol.2010; 37(6):1529-36.
[7]. Lin ZB, et al. Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin 2004; 25:1387-95
[8]. Sandodiya BS, et al. Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol 2009; 10:717-42
[9]. Gao Y, et al. Antitumor activity and underlying mechanisms of ganopoly,the refined polysaccarides extracted from Ganoderma lucidum, in mice.2005; 34:171-98
[10]. Yue GG, et al. Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med.2006; 12:777-89
[11]. Zhao YY, et al. Cytotoxic steroids from Polyporus umbellatus Planta Med.2010; 76(15):1755-8.
[12]. Ryter SW, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 2007; 9:49-89
[13]. Buttke TM, et al. Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:7-10
[14]. Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci 1996;21:83-86
[15]. Miyajima, A., et al. Role of reactive oxygen species in cis-dichlorodiammineplatium-induced cytotoxicity on bladder cancer cells.' Br J Cancer 1997; 76:206-210
[16]. Zhou Y, et al. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood 2003; 101:4098-4104
[17]. Pelicano H, et al. Inhibition of mitochondrial respiration:a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 2003; 278:37832-37839
[18]. Schulze-Osthoff K, et al. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992; 267:5317-5323
[19]. Quillet-Mary A, et al. Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 1997; 272:21388-21395
[20]. Fleury C, et al. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84:131-141
[21]. Ott M, et al. Mitochondria, oxidative stress and cell death. Apoptosis 2007; 12:913-922
[22]. Hiraoka W, et al. Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells. J Clin Invest 1998; 102:1961-1968
[23]. Qin F, et al. NADPH oxidase is involved in angiotensin Ⅱ-induced apoptosis in H9C2 cardiac muscle cells:effects of apocynin. Free Radic Biol Med 2006; 40:236-246
[24]. Brennan AM, et al NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 2009;12:857-863
[25]. Nicotera P, et al. The role of calcium in apoptosis. Cell Calcium 1998; 23:173-180
[26]. Granfeldt D, et al. Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane-and granule-localized NADPH-oxidase. J Leukoc Biol 2002; 71:611-617
[27]. Wang G, et al. Nox2, Ca2+, and protein kinase C play a role in angiotensin Ⅱ-induced free radical production in nucleus tractus solitaries. Hypertension 2006;48:482-489
[28]. Kim JE, et al. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 2008;40:709—720
[29]. Klein-Szanto AJ, et al. A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells. Proc Natl Acad Sci U S A 1992; 89:6693-6697
[30]. Kelso GF, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells:antioxidant and antiapoptotic properties. J Biol Chem 2001; 276:4588-96
[31]. Matsuzawa A, et al. Redox control of cell fate by MAP kinase: physiological roles of ASK 1-MAP kinase pathway in stress signaling. Biochim Biophys Acta 2008; 1780:1325-1336
[32]. Kuppusamy P, et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res 2002; 62:307-312
[33]. Jacobson MD, et al. Programmed cell death and Bcl-2 protection in very low oxygen. Nature 1995; 374:814-816
[34]. Scorrano L, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+:a control point for apoptosis. Science 2003; 300:135-139
[35]. Yu JH, et al. NADPH oxidase and apoptosis in cerulein-stimulated pancreatic acinar AR42J cells. Free Radic Biol Med 2005; 39:590-602
[36]. Gandhi S, et al. PINK 1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 2009; 33:627-638
[37]. Benhar M, et al. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 2001; 21:6913-6926
[38]. Saeki K, et al. Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. Biochem J.2002,368:705-720
[39]. Kim TH, Kim Js, Kim Zh, Huang RB, Wang RS. Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species. PLoS One.7(10):e46208 (2012)
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[2]. Arends MJ, et al. Apoptosis:mechanisms and roles in pathology. Int Rev Exp Pathol 1991; 32:223-254.
[3]. Mesner P, et al. Chemotherapy-induced apoptosis. Adv Pharmacol 1997; 41:461-499.
[4]. Palombo JD, et al. The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells. Cancer Lett 2002; 177:163-172."
[5]. Wasser SP, et al. Therapeutic effects of substances occurring in higher Basidiomycetes mushrooms:a modern perspective. Crit Rev Immunol 1999; 19:65-96.
[6]. Jiang J, et al. Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells. Int J Oncol.2010; 37(6):1529-36.
[7]. Lin ZB, et al. Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin 2004; 25:1387-95
[8]. Sandodiya BS, et al. Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol 2009; 10:717-42
[9]. Gao Y, et al. Antitumor activity and underlying mechanisms of ganopoly,the refined polysaccarides extracted from Ganoderma lucidum, in mice.2005; 34:171-98
[10]. Yue GG, et al. Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med.2006; 12:777-89
[11]. Zhao YY, et al. Cytotoxic steroids from Polyporus umbellatus Planta Med.2010; 76(15):1755-8.
[12]. Ryter SW, et al. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal 2007; 9:49-89
[13]. Buttke TM, et al. Oxidative stress as a mediator of apoptosis. Immunol Today 1994;15:7-10
[14]. Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci 1996;21:83-86
[15]. Miyajima, A., et al. Role of reactive oxygen species in cis-dichlorodiammineplatium-induced cytotoxicity on bladder cancer cells. Br J Cancer 1997; 76:206-210
[16]. Zhou Y, et al. Free radical stress in chronic lymphocytic leukemia cells and its role in cellular sensitivity to ROS-generating anticancer agents. Blood 2003; 101:4098-4104
[17]. Pelicano H, et al. Inhibition of mitochondrial respiration:a novel strategy to enhance drug-induced apoptosis in human leukemia cells by a reactive oxygen species-mediated mechanism. J Biol Chem 2003; 278:37832-37839
[18]. Schulze-Osthoff K, et al. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem 1992; 267:5317-5323
[19]. Quillet-Mary A, et al. Implication of mitochondrial hydrogen peroxide generation in ceramide-induced apoptosis. J Biol Chem 1997; 272:21388-21395
[20]. Fleury C, et al. Mitochondrial reactive oxygen species in cell death signaling. Biochimie 2002; 84:131-141
[21]. Ott M, et al. Mitochondria, oxidative stress and cell death. Apoptosis 2007; 12:913-922
[22]. Hiraoka W, et al. Role of oxygen radicals generated by NADPH oxidase in apoptosis induced in human leukemia cells. J Clin Invest 1998; 102:1961-1968
[23]. Qin F, et al. NADPH oxidase is involved in angiotensin Ⅱ-induced apoptosis in H9C2 cardiac muscle cells:effects of apocynin. Free Radic Biol Med 2006; 40:236-246
[24]. Brennan AM, et al NADPH oxidase is the primary source of superoxide induced by NMDA receptor activation. Nat Neurosci 2009; 12:857-863
[25]. Nicotera P, et al. The role of calcium in apoptosis. Cell Calcium 1998; 23:173-180
[26]. Granfeldt D, et al. Capacitative Ca2+ influx and activation of the neutrophil respiratory burst. Different regulation of plasma membrane-and granule-localized NADPH-oxidase. J Leukoc Biol 2002; 71:611-617
[27]. Wang G, et al. Nox2, Ca2+, and protein kinase C play a role in angiotensin Ⅱ-induced free radical production in nucleus tractus solitaries. Hypertension 2006;48:482-489
[28]. Kim JE, et al. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 2008;40:709—720
[29]. Klein-Szanto AJ, et al. A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells. Proc Natl Acad Sci U S A 1992; 89:6693-6697
[30]. Kelso GF, et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells:antioxidant and antiapoptotic properties. J Biol Chem 2001; 276:4588-96
[31]. Matsuzawa A, et al. Redox control of cell fate by MAP kinase: physiological roles of ASK 1-MAP kinase pathway in stress signaling. Biochim Biophys Acta 2008; 1780:1325-1336
[32]. Kuppusamy P, et al. Noninvasive imaging of tumor redox status and its modification by tissue glutathione levels. Cancer Res 2002; 62:307-312
[33]. Jacobson MD, et al. Programmed cell death and Bcl-2 protection in very low oxygen. Nature 1995; 374:814-816
[34]. Scorrano L, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+:a control point for apoptosis. Science 2003; 300:135-139
[35], Yu JH, et al. NADPH oxidase and apoptosis in cerulein-stimulated pancreatic acinar AR42J cells. Free Radic Biol Med 2005; 39:590-602
[36]. Gandhi S, et al. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death. Mol Cell 2009; 33:627-638
[37]. Benhar M, et al. Enhanced ROS production in oncogenically transformed cells potentiates c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and sensitization to genotoxic stress. Mol Cell Biol 2001; 21:6913-6926
[38]. Saeki K, et al. Oxidation-triggered c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein (MAP) kinase pathways for apoptosis in human leukaemic cells stimulated by epigallocatechin-3-gallate (EGCG): a distinct pathway from those of chemically induced and receptor-mediated apoptosis. Biochem J.2002,368:705-720
[1]. Lin ZB, Zhang HN.2004. Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin 25:1387-95.
[2]. Sandodiya BS, Thakur GS, Baqhel RK, Prasad GB, Bisen PS.2009. Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol 10:717-42.
[3]. Gao Y, Gao H, Chan E, Tang W, Xu A, Yang H, Huang M, Lan J, Li X, Duan W, Xu C, Zhou S.2005. Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccarides extracted from Ganoderma lucidum, in mice. Immunol Invest 34:171-98.
[4]. Yue GG, Fung KP, Tse GM, Leung PC, Lau CB.2006. Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med.12:777-89.
[5]. Ⅲana-Esteban C.2008. The fungus maitake and its therapeutic potential. Rev Iberoam Micol.25:141-44.
[6]. Jang KJ, Han MH, Lee BH, Kim BW, Kim CH, Yoon HM, Choi YH.2010. Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. J Acupunct Meridian Stud.3:24-31.
[7]. Yue QX, Song XY, Ma C, Feng LX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Cui YJ, Guo DA.2010. Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine.17:606-13.
[8]. Zhao S, Ye G, Fu G, Cheng JX, Yang BB, Peng C.2011. Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol 38:1319-27.
[9]. Liu RM, Zhong JJ.2011 Ganoderic acid Mf and S induce mitochondria mediated apoptosis in human cervical carcinoma HeLa cells. Phytomedicine.15:349-55.
[10]. Li L, Li T, Wang XJ, Xu JP, Wang SG.2008. Effects of Ganoderma lucidum spores on HepG2 cells proliferation and growth cycle. Zhong Yao Cai.31:1514-18.
[11]. Zhao YY, Chao X, Zhang Y, Lin RC, Sun WJ.2010. Cytotoxic steroids from Polyporus umbellatus. Planta Med 76:1755-58.
[12]. Kim JE, Koo KH, Kim YH, Sohn J, Park YG.2008. Identification of potential lung cancer biomarkers using an in vitro carcinogenesis model. Exp Mol Med 40:709-20.
[13]. Palombo JD, Ganguly A, Bistrian BR, Menard MP.2002. The antiproliferative effects of biologically active isomers of conjugated linoleic acid on human colorectal and prostatic cancer cells. Cancer Lett 177:163-72.
[14]. Klein-Szanto AJ, Iizasa T, Momiki S, et al.1992. A tobacco-specific N-nitrosamine or cigarette smoke condensate causes neoplastic transformation of xenotransplanted human bronchial epithelial cells. Proc Natl Acad Sci U S A 89:6693-97.
[15]. Zhonghong Y, Ruolin Y, Yi J, Zhihui Y, Junrui Y, Qian Z, Yang L.2010. Induction of apoptosis in human promyelocytic leukemia HL60 cells by panaxynol and panaxydol. Molecules 29:5561-73.
[16].Kim TH, Kim Js, Kim Zh, Huang RB, Wang RS. Khz (Fusion of Ganoderma lucidum and Polyporus umbellatus Mycelia) Induces Apoptosis by Increasing Intracellular Calcium Levels and Activating JNK and NADPH Oxidase-Dependent Generation of Reactive Oxygen Species. PLoS One.7(10):e46208 (2012)
[1]. Lin, Z. B., Zhang, H. N. (2004). Anti-tumor and immunoregulatory activities of Ganoderma lucidum and its possible mechanisms. Acta Pharmacol Sin,25,1387-1395
[2]. Sandodiya, B. S., Thakur, G. S., Baqhel, R. K., Prasad, G. B., Bisen, P. S. (2009). Ganoderma lucidum:a potent pharmacological macrofungus. Curr Pharm Biotechnol,10,717-742.
[3]. Gao, Y., Gao, H., Chan, E., Tang, W., Xu, A., Yang, H., Huang, M., Lan, J., Li, X., Duan, W., Xu, C., Zhou, S. (2005). Antitumor activity and underlying mechanisms of ganopoly, the refined polysaccharides extracted from Ganoderma lucidum, in mice.34,171-198.
[4]. Yue, G. G., Fung, K. P., Tse, G. M., Leung, P. C, Lau, C. B. (2006). Comparative studies of various ganoderma species and their different parts with regard to antitumor and immunomodulating activities in vitro. J Altern Complement Med,12,777-789.
[5]. IIIana-Esteban, C. (2008). The fungus maitake (Grifola frondosa) and its therapeutic potential. Rev Iberoam Micol,25,141-144.
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[5]. Ⅲana-Esteban C. The fungus maitake (Grifola frondosa) and its therapeutic potential. Rev Iberoam Micol.25:141-144 (2008)
[6]. Jang KJ, Han MH, Lee BH, Kim BW, Kim CH, Yoon HM, Choi YH. Induction of apoptosis by ethanol extracts of Ganoderma lucidum in human gastric carcinoma cells. J Acupunct Meridian Stud.3:24-31 (2010)
[7]. Yue QX, Song XY, Ma C, Feng LX, Guan SH, Wu WY, Yang M, Jiang BH, Liu X, Cui YJ, Guo DA. Effects of triterpenes from Ganoderma lucidum on protein expression profile of HeLa cells. Phytomedicine. 17:606-613 (2010)
[8]. Zhao S, Ye G, Fu G, Cheng JX, Yang BB, Peng C. Ganoderma lucidum exerts anti-tumor effects on ovarian cancer cells and enhances their sensitivity to cisplatin. Int J Oncol.38:1319-1327 (2011)
[9]. Liu RM, Zhong JJ. Ganoderic acid Mf and S induce mitochondria mediated apoptosis in human cervical carcinoma HeLa cells. Phytomedicine.15:349-355(2011)
[10]. Li L, Li T, Wang XJ, Xu JP, Wang SG. Effects of Ganoderma lucidum spores on HepG2 cells proliferation and growth cycle. Zhong Yao Cai. 31:1514-1518(2008)
[11]. Zhao YY, Chao X, Zhang Y, Lin RC, Sun WJ. Cytotoxic steroids from Polyporus umbellatus Planta Med.76(15):1755-1758 (2010)
[12]. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B. Mitochondria, oxidative stress and cell death. Apoptosis.12:913-922 (2007)
[13]. Jacobson MD, Raff MC. Programmed cell death and Bcl-2 protection in very low oxygen. Nature.374:814-816 (1995)
[14]. Ryter SW, Kim HP, Hoetzel A, Park JW, Nakahira K, Wang X, Choi AM. Mechanisms of cell death in oxidative stress. Antioxid Redox Signal. 9:49-89 (2007)
[15]. Buttke TM, Sandstrom PA. Oxidative stress as a mediator of apoptosis. Immunol Today.15:7-10 (1994)
[16]. Jacobson MD. Reactive oxygen species and programmed cell death. Trends Biochem Sci.21:83-86 (1996)
[17]. Miyajima, A., Nakashima, J., Yoshioka, K. Role of reactive oxygen species in cis-dichlorodiammineplatium-induced cytotoxicity on bladder cancer cells. Br J Cancer 76:206-210 (1997)
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