老药新用:双硫仑抗肿瘤的新角色
|
摘要
双硫仑(disulfiram,DSF)是一种安全有效的戒酒药物,具有明显的抗肿瘤作用,机制主要包括抑制肿瘤干细胞、诱导肿瘤细胞凋亡、诱导细胞周期阻滞、抑制蛋白酶体、抑制肿瘤血管生成、逆转肿瘤细胞耐药性、增加放疗敏感性等。然而,DSF在体内的不稳定性限制了其临床应用,因此近年的研究聚焦于药物的运载系统、药物的联合应用及局部用药。DSF具有高效低毒且廉价的特点,有望成为一种新的抗肿瘤药物。
Disulfiram( DSF),a safe and effective antialcoholic,exerts significant anti-tumor effect,and its underlying mechanisms are associated with the suppression of tumor stem cells,induction of tumor cells apoptosis,induction of cell cycle arrest,inhibition of proteasomes,reversion of drug resistance,anti-angiogenesis,and increase of sensitivity on radiotherapy,etc. However,its instability in the body limits its clinic application. Thus,its research in recent years has focused on transport system of the drug,combination of drugs,and local medication. DSF may serve as a new type of anti-tumor drug due to its high effectiveness,low toxicity and low price.
Disulfiram( DSF),a safe and effective antialcoholic,exerts significant anti-tumor effect,and its underlying mechanisms are associated with the suppression of tumor stem cells,induction of tumor cells apoptosis,induction of cell cycle arrest,inhibition of proteasomes,reversion of drug resistance,anti-angiogenesis,and increase of sensitivity on radiotherapy,etc. However,its instability in the body limits its clinic application. Thus,its research in recent years has focused on transport system of the drug,combination of drugs,and local medication. DSF may serve as a new type of anti-tumor drug due to its high effectiveness,low toxicity and low price.
引文
[1] Hald J,Jacobsen E. A drug sensitizing the organism to ethyl alcohol[J]. Lancet(London,England),1948,2(6539):1001-1004.
[2] Skrott Z,Mistrik M,Andersen KK,et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4[J]. Nature,2017,552(7684):194-199.
[3] Cvek B. Nonprofit drugs as the salvation of the world's healthcare systems:The case of Antabuse(disulfiram)[J]. Drug Discovery Today,2012,17(9-10):409-412.
[4] Liu P,Brown S,Goktug T,et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancerstem-like cells[J]. British Journal of Cancer,2012,107(9):1488-1497.
[5] Wehbe M,Anantha M,Shi M,et al. Development and optimization of an injectable formulation of copper diethyldithiocarbamate,an active anticancer agent[J]. International Journal of Nanomedicine,2017,12:4129-4146.
[6] Safi R,Nelson ER,Chitneni SK,et al. Copper signaling axis as a target for prostate cancer therapeutics[J]. Cancer Research,2014,74(20):5819-5831.
[7] Xu B,Shi P,Fombon IS,et al. Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J]. Blood Cells,Molecules&Diseases,2011,47(4):264-269.
[8] Zhang L,Tian B,Li Y,et al. A copper-mediated disulfiramloaded p H-triggered PEG-shedding TAT peptide-modified lipid nanocapsules for use in tumor therapy[J]. ACS Applied Materials&Interfaces,2015,7(45):25147-25161.
[9] Koppaka V,Thompson DC,Chen Y,et al. Aldehyde dehydrogenase inhibitors:A comprehensive review of the pharmacology,mechanism of action,substrate specificity,and clinical application[J]. Pharmacological Reviews,2012,64(3):520-539.
[10] Schmitt SM,Frezza M,Dou QP. New applications of old metalbinding drugs in the treatment of human cancer[J]. Frontiers in Bioscience(Scholar edition),2012,4:375-391.
[11] Triscott J,Rose Pambid M,Dunn SE. Concise review:Bullseye:Targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram[J]. Stem cells(Dayton,Ohio),2015,33(4):1042-1046.
[12] Liu X,Wang L,Cui W,et al. Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells[J]. Oncotarget,2016,7(36):58516-58530.
[13] Yip NC,Fombon IS,Liu P,et al. Disulfiram modulated ROSMAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties[J]. British Journal of Cancer,2011,104(10):1564-1574.
[14] Kim YJ,Kim JY,Lee N,et al. Disulfiram suppresses cancer stem-like properties and STAT3 signaling in triple-negative breast cancer cells[J]. Biochemical and Biophysical Research Communications,2017,486(4):1069-1076.
[15] Kim JY,Cho Y,Oh E,et al. Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer[J]. Cancer Letters,2016,379(1):39-48.
[16] Han D,Wu G,Chang C,et al. Disulfiram inhibits TGF-beta-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-kappaB/Snail pathway[J]. Oncotarget,2015,6(38):40907-40919.
[17] Allensworth JL,Evans MK,Bertucci F,et al. Disulfiram(DSF)acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer[J]. Molecular Oncology,2015,9(6):1155-1168.
[18] Yang Y,Zhang K,Wang Y,et al. Disulfiram chelated with copper promotes apoptosis in human breast cancer cells by impairing the mitochondria functions[J]. Scanning,2016,38(6):825-836.
[19] Kim JY,Lee N,Kim YJ,et al. Disulfiram induces anoikis and suppresses lung colonization in triple-negative breast cancer via calpain activation[J]. Cancer Etters,2017,386:151-160.
[20] Fasehee H,Zarrinrad G,Tavangar SM,et al. The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth:Different administration routes[J]. Materials s Science&Engineering C,Materials for Biological Applications,2016,63:587-595.
[21] Hoda M,Pajaniradje S,Shakya G,et al. Anti-proliferative and apoptosis-triggering potential of disulfiram and disulfiram-loaded polysorbate 80-stabilized PLGA nanoparticles on hepatocellular carcinoma Hep3B cell line[J]. Nanomedicine:Nanotechnology,Biology,and Medicine,2016,12(6):1641-1650.
[22] Lovborg H,Oberg F,Rickardson L,et al. Inhibition of proteasome activity,nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram[J]. International Journal of Cancer,2006,118(6):1577-1580.
[23] Jivan R,Damelin LH,Birkhead M,et al. Disulfiram/copper-disulfiram damages multiple protein degradation and turnover pathways and cytotoxicity is enhanced by metformin in oesophageal squamous cell carcinoma cell lines[J]. Journal of Cellular Biochemistry,2015,116(10):2334-2343.
[24] Chen D,Cui QC,Yang H,et al. 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[J]. Cancer Research,2006,66(21):10425-10433.
[25] Skrott Z,Cvek B. Diethyldithiocarbamate complex with copper:The mechanism of action in cancer cells[J]. Mini Reviews in Medicinal Chemistry,2012,12(12):1184-1192.
[26] Li Y,Fu SY,Wang LH,et al. Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas[J]. Cancer Letters,2015,369(1):86-96.
[27] Shian SG,Kao YR,Wu FY,et al. Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram[J]. Molecular Pharmacology,2003,64(5):1076-1084.
[28] Duan X,Xiao J,Yin Q,et al. Smart pH-sensitive and temporalcontrolled polymeric micelles for effective combination therapy of doxorubicin and disulfiram[J]. ACS Nano,2013,7(7):5858-5869.
[29] Loo TW,Bartlett MC,Clarke DM. Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein[J]. Molecular Pharmaceutics,2004,1(6):426-433.
[30] Huo Q,Zhu J,Niu Y,et al. p H-triggered surface chargeswitchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer[J]. International Journal of Nanomedicine,2017,12:8631-8647.
[31] Cvek B. Comment on'cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stemlike cells'[J]. British Journal of Cancer,2013,108(4):993.
[32] Wang NN,Wang LH,Li Y,et al. Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors[J]. Experimental Cell Research,2018,362(1):72-82.
[33] Lun X,Wells JC,Grinshtein N,et al. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma[J]. Clinical cancer research:An official Journal of the American Association for Cancer Research,2016,22(15):3860-3875.
[34] Tesson M,Anselmi G,Bell C,et al. Cell cycle specific radiosensitisation by the disulfiram and copper complex[J]. Oncotarget,2017,8(39):65900-65916.
[35] Lee YE,Choi SA,Kwack PA,et al. Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor[J]. Neuro-Oncology,2017,19(8):1079-1087.
[36] Rae C,Tesson M,Babich JW,et al. The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells[J].Journal of Nuclear Medicine:Official Publication,Society of Nuclear Medicine,2013,54(6):953-960.
[37] Choi SA,Choi JW,Wang KC,et al. Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors[J]. Neuro-Oncology,2015,17(6):810-821.
[38] Fasehee H,Dinarvand R,Ghavamzadeh A,et al. Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles:In vitro and in vivo investigations[J].Journal of Nanobiotechnology,2016,14:32.
[39] Miao L,Su J,Zhuo X,et al. m PEG5k-b-PLGA2k/PCL3. 4k/MCT mixed micelles as carriers of disulfiram for improving plasma stability and antitumor effect in vivo[J]. Molecular Pharmaceutics,2018,15(4):1556-1564.
[40] Fasehee H,Ghavamzadeh A,Alimoghaddam K,et al. A comparative cytotoxic evaluation of disulfiram encapsulated PLGA nanoparticles on MCF-7 cells[J]. International Journal of Hematology-Oncology and Stem Cell Research,2017,11(2):102-107.
[41] He H,Markoutsa E,Li J,et al. Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly[J]. Acta Biomaterialia,2018,68:113-124.
[42] Abu-Serie MM,El-Rashidy FH. In vitro collapsing colon cancer cells by selectivity of disulfiram-loaded charge switchable nanoparticles against cancer stem cells[J]. Recent Patents on Anti-Cancer Drug Discovery 2017,12(3):260-271.
[43] Nechushtan H,Hamamreh Y,Nidal S,et al. A phaseⅡbtrial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer[J]. The Oncologist,2015,20(4):366-367.
[44] Jiao Y,Hannafon BN,Zhang RR,et al. Docosahexaenoic acid and disulfiram act in concert to kill cancer cells:A mutual enhancement of their anticancer actions[J]. Oncotarget,2017,8(11):17908-17920.
[45] Huang H,Liao Y,Liu N,et al. Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo[J]. Oncotarget,2016,7(3):2796-2808.
[46] Wu X,Xue X,Wang L,et al. Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer[J]. European Journal of Pharmacology,2018,827:1-12.
[47] Muralidharan P,Malapit M,Mallory E,et al. Inhalable nanoparticulate powders for respiratory delivery[J]. Nanomedicine:Nanotechnology,Biology,and Medicine,2015,11(5):1189-1199.
[48] Wang C,Yang J,Han H,et al. Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer[J]. International Journal of Nanomedicine,2017,12:827-837.
[49] Boyd P,Major I,Wang W,et al. Development of disulfiram-loaded vaginal rings for the localised treatment of cervical cancer[J].European Journal of Pharmaceutics and Biopharmaceuticsv,2014,88(3):945-953.
[50] Baffoe CS,Nguyen N,Boyd P,et al. Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer[J]. The Journal of Pharmacy and Pharmacology,2015,67(2):189-198.
[2] Skrott Z,Mistrik M,Andersen KK,et al. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4[J]. Nature,2017,552(7684):194-199.
[3] Cvek B. Nonprofit drugs as the salvation of the world's healthcare systems:The case of Antabuse(disulfiram)[J]. Drug Discovery Today,2012,17(9-10):409-412.
[4] Liu P,Brown S,Goktug T,et al. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancerstem-like cells[J]. British Journal of Cancer,2012,107(9):1488-1497.
[5] Wehbe M,Anantha M,Shi M,et al. Development and optimization of an injectable formulation of copper diethyldithiocarbamate,an active anticancer agent[J]. International Journal of Nanomedicine,2017,12:4129-4146.
[6] Safi R,Nelson ER,Chitneni SK,et al. Copper signaling axis as a target for prostate cancer therapeutics[J]. Cancer Research,2014,74(20):5819-5831.
[7] Xu B,Shi P,Fombon IS,et al. Disulfiram/copper complex activated JNK/c-jun pathway and sensitized cytotoxicity of doxorubicin in doxorubicin resistant leukemia HL60 cells[J]. Blood Cells,Molecules&Diseases,2011,47(4):264-269.
[8] Zhang L,Tian B,Li Y,et al. A copper-mediated disulfiramloaded p H-triggered PEG-shedding TAT peptide-modified lipid nanocapsules for use in tumor therapy[J]. ACS Applied Materials&Interfaces,2015,7(45):25147-25161.
[9] Koppaka V,Thompson DC,Chen Y,et al. Aldehyde dehydrogenase inhibitors:A comprehensive review of the pharmacology,mechanism of action,substrate specificity,and clinical application[J]. Pharmacological Reviews,2012,64(3):520-539.
[10] Schmitt SM,Frezza M,Dou QP. New applications of old metalbinding drugs in the treatment of human cancer[J]. Frontiers in Bioscience(Scholar edition),2012,4:375-391.
[11] Triscott J,Rose Pambid M,Dunn SE. Concise review:Bullseye:Targeting cancer stem cells to improve the treatment of gliomas by repurposing disulfiram[J]. Stem cells(Dayton,Ohio),2015,33(4):1042-1046.
[12] Liu X,Wang L,Cui W,et al. Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells[J]. Oncotarget,2016,7(36):58516-58530.
[13] Yip NC,Fombon IS,Liu P,et al. Disulfiram modulated ROSMAPK and NFkappaB pathways and targeted breast cancer cells with cancer stem cell-like properties[J]. British Journal of Cancer,2011,104(10):1564-1574.
[14] Kim YJ,Kim JY,Lee N,et al. Disulfiram suppresses cancer stem-like properties and STAT3 signaling in triple-negative breast cancer cells[J]. Biochemical and Biophysical Research Communications,2017,486(4):1069-1076.
[15] Kim JY,Cho Y,Oh E,et al. Disulfiram targets cancer stem-like properties and the HER2/Akt signaling pathway in HER2-positive breast cancer[J]. Cancer Letters,2016,379(1):39-48.
[16] Han D,Wu G,Chang C,et al. Disulfiram inhibits TGF-beta-induced epithelial-mesenchymal transition and stem-like features in breast cancer via ERK/NF-kappaB/Snail pathway[J]. Oncotarget,2015,6(38):40907-40919.
[17] Allensworth JL,Evans MK,Bertucci F,et al. Disulfiram(DSF)acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer[J]. Molecular Oncology,2015,9(6):1155-1168.
[18] Yang Y,Zhang K,Wang Y,et al. Disulfiram chelated with copper promotes apoptosis in human breast cancer cells by impairing the mitochondria functions[J]. Scanning,2016,38(6):825-836.
[19] Kim JY,Lee N,Kim YJ,et al. Disulfiram induces anoikis and suppresses lung colonization in triple-negative breast cancer via calpain activation[J]. Cancer Etters,2017,386:151-160.
[20] Fasehee H,Zarrinrad G,Tavangar SM,et al. The inhibitory effect of disulfiram encapsulated PLGA NPs on tumor growth:Different administration routes[J]. Materials s Science&Engineering C,Materials for Biological Applications,2016,63:587-595.
[21] Hoda M,Pajaniradje S,Shakya G,et al. Anti-proliferative and apoptosis-triggering potential of disulfiram and disulfiram-loaded polysorbate 80-stabilized PLGA nanoparticles on hepatocellular carcinoma Hep3B cell line[J]. Nanomedicine:Nanotechnology,Biology,and Medicine,2016,12(6):1641-1650.
[22] Lovborg H,Oberg F,Rickardson L,et al. Inhibition of proteasome activity,nuclear factor-KappaB translocation and cell survival by the antialcoholism drug disulfiram[J]. International Journal of Cancer,2006,118(6):1577-1580.
[23] Jivan R,Damelin LH,Birkhead M,et al. Disulfiram/copper-disulfiram damages multiple protein degradation and turnover pathways and cytotoxicity is enhanced by metformin in oesophageal squamous cell carcinoma cell lines[J]. Journal of Cellular Biochemistry,2015,116(10):2334-2343.
[24] Chen D,Cui QC,Yang H,et al. 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[J]. Cancer Research,2006,66(21):10425-10433.
[25] Skrott Z,Cvek B. Diethyldithiocarbamate complex with copper:The mechanism of action in cancer cells[J]. Mini Reviews in Medicinal Chemistry,2012,12(12):1184-1192.
[26] Li Y,Fu SY,Wang LH,et al. Copper improves the anti-angiogenic activity of disulfiram through the EGFR/Src/VEGF pathway in gliomas[J]. Cancer Letters,2015,369(1):86-96.
[27] Shian SG,Kao YR,Wu FY,et al. Inhibition of invasion and angiogenesis by zinc-chelating agent disulfiram[J]. Molecular Pharmacology,2003,64(5):1076-1084.
[28] Duan X,Xiao J,Yin Q,et al. Smart pH-sensitive and temporalcontrolled polymeric micelles for effective combination therapy of doxorubicin and disulfiram[J]. ACS Nano,2013,7(7):5858-5869.
[29] Loo TW,Bartlett MC,Clarke DM. Disulfiram metabolites permanently inactivate the human multidrug resistance P-glycoprotein[J]. Molecular Pharmaceutics,2004,1(6):426-433.
[30] Huo Q,Zhu J,Niu Y,et al. p H-triggered surface chargeswitchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer[J]. International Journal of Nanomedicine,2017,12:8631-8647.
[31] Cvek B. Comment on'cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stemlike cells'[J]. British Journal of Cancer,2013,108(4):993.
[32] Wang NN,Wang LH,Li Y,et al. Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors[J]. Experimental Cell Research,2018,362(1):72-82.
[33] Lun X,Wells JC,Grinshtein N,et al. Disulfiram when combined with copper enhances the therapeutic effects of temozolomide for the treatment of glioblastoma[J]. Clinical cancer research:An official Journal of the American Association for Cancer Research,2016,22(15):3860-3875.
[34] Tesson M,Anselmi G,Bell C,et al. Cell cycle specific radiosensitisation by the disulfiram and copper complex[J]. Oncotarget,2017,8(39):65900-65916.
[35] Lee YE,Choi SA,Kwack PA,et al. Repositioning disulfiram as a radiosensitizer against atypical teratoid/rhabdoid tumor[J]. Neuro-Oncology,2017,19(8):1079-1087.
[36] Rae C,Tesson M,Babich JW,et al. The role of copper in disulfiram-induced toxicity and radiosensitization of cancer cells[J].Journal of Nuclear Medicine:Official Publication,Society of Nuclear Medicine,2013,54(6):953-960.
[37] Choi SA,Choi JW,Wang KC,et al. Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors[J]. Neuro-Oncology,2015,17(6):810-821.
[38] Fasehee H,Dinarvand R,Ghavamzadeh A,et al. Delivery of disulfiram into breast cancer cells using folate-receptor-targeted PLGA-PEG nanoparticles:In vitro and in vivo investigations[J].Journal of Nanobiotechnology,2016,14:32.
[39] Miao L,Su J,Zhuo X,et al. m PEG5k-b-PLGA2k/PCL3. 4k/MCT mixed micelles as carriers of disulfiram for improving plasma stability and antitumor effect in vivo[J]. Molecular Pharmaceutics,2018,15(4):1556-1564.
[40] Fasehee H,Ghavamzadeh A,Alimoghaddam K,et al. A comparative cytotoxic evaluation of disulfiram encapsulated PLGA nanoparticles on MCF-7 cells[J]. International Journal of Hematology-Oncology and Stem Cell Research,2017,11(2):102-107.
[41] He H,Markoutsa E,Li J,et al. Repurposing disulfiram for cancer therapy via targeted nanotechnology through enhanced tumor mass penetration and disassembly[J]. Acta Biomaterialia,2018,68:113-124.
[42] Abu-Serie MM,El-Rashidy FH. In vitro collapsing colon cancer cells by selectivity of disulfiram-loaded charge switchable nanoparticles against cancer stem cells[J]. Recent Patents on Anti-Cancer Drug Discovery 2017,12(3):260-271.
[43] Nechushtan H,Hamamreh Y,Nidal S,et al. A phaseⅡbtrial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer[J]. The Oncologist,2015,20(4):366-367.
[44] Jiao Y,Hannafon BN,Zhang RR,et al. Docosahexaenoic acid and disulfiram act in concert to kill cancer cells:A mutual enhancement of their anticancer actions[J]. Oncotarget,2017,8(11):17908-17920.
[45] Huang H,Liao Y,Liu N,et al. Two clinical drugs deubiquitinase inhibitor auranofin and aldehyde dehydrogenase inhibitor disulfiram trigger synergistic anti-tumor effects in vitro and in vivo[J]. Oncotarget,2016,7(3):2796-2808.
[46] Wu X,Xue X,Wang L,et al. Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer[J]. European Journal of Pharmacology,2018,827:1-12.
[47] Muralidharan P,Malapit M,Mallory E,et al. Inhalable nanoparticulate powders for respiratory delivery[J]. Nanomedicine:Nanotechnology,Biology,and Medicine,2015,11(5):1189-1199.
[48] Wang C,Yang J,Han H,et al. Disulfiram-loaded porous PLGA microparticle for inhibiting the proliferation and migration of non-small-cell lung cancer[J]. International Journal of Nanomedicine,2017,12:827-837.
[49] Boyd P,Major I,Wang W,et al. Development of disulfiram-loaded vaginal rings for the localised treatment of cervical cancer[J].European Journal of Pharmaceutics and Biopharmaceuticsv,2014,88(3):945-953.
[50] Baffoe CS,Nguyen N,Boyd P,et al. Disulfiram-loaded immediate and extended release vaginal tablets for the localised treatment of cervical cancer[J]. The Journal of Pharmacy and Pharmacology,2015,67(2):189-198.