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Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors.
Exp Cell Res 2018; 362(1):72-82EC

Abstract

Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone. DSF/Cu also decreased the aldehyde dehydrogenase (ALDH) activity and the expression of P-gp and stem cell transcription factors in A549/Taxol and KB/VCR cells. Knockdown of ALDH2 attenuated the CSC characteristics of resistant cancer cells and enhanced their sensitivity to Taxol or VCR. Importantly, DSF/Cu treatment inhibited the expression of ALDH2 in vitro and in vivo. Our findings suggest that DSF/Cu reverses microtubule inhibitor resistance in cancer cells by suppressing ALDH2 expression, and Cu improves the activity of DSF.

Authors+Show Affiliations

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China. Electronic address: yangjingyu2006@gmail.com.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China; Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29155365

Citation

Wang, Nan-Nan, et al. "Targeting ALDH2 With Disulfiram/copper Reverses the Resistance of Cancer Cells to Microtubule Inhibitors." Experimental Cell Research, vol. 362, no. 1, 2018, pp. 72-82.
Wang NN, Wang LH, Li Y, et al. Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. Exp Cell Res. 2018;362(1):72-82.
Wang, N. N., Wang, L. H., Li, Y., Fu, S. Y., Xue, X., Jia, L. N., ... Wu, C. F. (2018). Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. Experimental Cell Research, 362(1), pp. 72-82. doi:10.1016/j.yexcr.2017.11.004.
Wang NN, et al. Targeting ALDH2 With Disulfiram/copper Reverses the Resistance of Cancer Cells to Microtubule Inhibitors. Exp Cell Res. 2018 01 1;362(1):72-82. PubMed PMID: 29155365.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors. AU - Wang,Nan-Nan, AU - Wang,Li-Hui, AU - Li,Yi, AU - Fu,Shi-Yuan, AU - Xue,Xue, AU - Jia,Li-Na, AU - Yuan,Xiang-Zhong, AU - Wang,Ya-Ting, AU - Tang,Xing, AU - Yang,Jing-Yu, AU - Wu,Chun-Fu, Y1 - 2017/11/16/ PY - 2017/08/21/received PY - 2017/10/28/revised PY - 2017/11/03/accepted PY - 2017/11/21/pubmed PY - 2018/9/19/medline PY - 2017/11/21/entrez KW - ALDH2 KW - Cancer KW - DSF/Cu KW - Microtubule inhibitor resistance SP - 72 EP - 82 JF - Experimental cell research JO - Exp. Cell Res. VL - 362 IS - 1 N2 - Disulfiram (DSF) in combination with copper (Cu) has been reported to override drug resistance in cancer cells, and DSF combined with chemotherapy based on the microtubule inhibitor vinorelbine appears to prolong survival in non-small cell lung cancer patients. Here, we investigated the mechanisms underlying these findings. DSF/Cu reversed the microtubule inhibitor resistance in A549/Taxol and KB/VCR cells in vitro, and had anti-tumor effects in A549/Taxol and KB/VCR xenograft mice. DSF/Cu and DSF reduced the cancer stem cell (CSC) characteristics of drug-resistant A549/Taxol and KB/VCR cells, including sphere formation, colony generation and migration, and DSF/Cu was more effective than DSF alone. DSF/Cu also decreased the aldehyde dehydrogenase (ALDH) activity and the expression of P-gp and stem cell transcription factors in A549/Taxol and KB/VCR cells. Knockdown of ALDH2 attenuated the CSC characteristics of resistant cancer cells and enhanced their sensitivity to Taxol or VCR. Importantly, DSF/Cu treatment inhibited the expression of ALDH2 in vitro and in vivo. Our findings suggest that DSF/Cu reverses microtubule inhibitor resistance in cancer cells by suppressing ALDH2 expression, and Cu improves the activity of DSF. SN - 1090-2422 UR - https://www.unboundmedicine.com/medline/citation/29155365/Targeting_ALDH2_with_disulfiram/copper_reverses_the_resistance_of_cancer_cells_to_microtubule_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4827(17)30600-6 DB - PRIME DP - Unbound Medicine ER -