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Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer.
Eur J Pharmacol 2018; 827:1-12EJ

Abstract

Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells. The present study is designed to investigate whether DSF/Cu can induce autophagy in NSCLC cells and to determine the relationship between autophagy and apoptosis. First, we observed that DSF/Cu induced significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells, accompanied by the formation of vacuoles in the cytoplasm. Next, we investigated the levels of autophagic markers, including LC3II (microtubule-associated protein 1 light chain 3), ATG5 and p62 with or without chloroquine by Western blot. In addition, we observed co-localization of LC3 and the lysosomal protein LAMP2 (lysosome-associated membrane protein 2) after treatment with DSF/Cu. The results showed that DSF/Cu induced autophagy. Finally, we demonstrated that DSF/Cu-induced apoptosis was greatly enhanced when autophagy was suppressed with Atg5 siRNA or 3-MA in NSCLC cells. This synergistic effect of DSF/Cu and 3-MA was further confirmed in the NSCLC xenograft model. Taken together, our results show that DSF/Cu stimulates autophagy in NSCLC cells, which is an impediment to DSF/Cu-induced apoptosis.

Authors+Show Affiliations

Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China; Shenzhen Institute for Drug Control, Shenzhen 518057, PR China.Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300050, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: yangjingyu2006@gmail.com.Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: wucf@syphu.edu.cn.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29547841

Citation

Wu, Xi, et al. "Suppressing Autophagy Enhances Disulfiram/copper-induced Apoptosis in Non-small Cell Lung Cancer." European Journal of Pharmacology, vol. 827, 2018, pp. 1-12.
Wu X, Xue X, Wang L, et al. Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. Eur J Pharmacol. 2018;827:1-12.
Wu, X., Xue, X., Wang, L., Wang, W., Han, J., Sun, X., ... Wu, C. (2018). Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. European Journal of Pharmacology, 827, pp. 1-12. doi:10.1016/j.ejphar.2018.02.039.
Wu X, et al. Suppressing Autophagy Enhances Disulfiram/copper-induced Apoptosis in Non-small Cell Lung Cancer. Eur J Pharmacol. 2018 May 15;827:1-12. PubMed PMID: 29547841.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppressing autophagy enhances disulfiram/copper-induced apoptosis in non-small cell lung cancer. AU - Wu,Xi, AU - Xue,Xue, AU - Wang,Lihui, AU - Wang,Wenjing, AU - Han,Jian, AU - Sun,Xiaoxue, AU - Zhang,Haotian, AU - Liu,Yueyang, AU - Che,Xiaohang, AU - Yang,Jingyu, AU - Wu,Chunfu, Y1 - 2018/03/13/ PY - 2017/09/20/received PY - 2018/02/26/revised PY - 2018/02/27/accepted PY - 2018/3/17/pubmed PY - 2018/10/10/medline PY - 2018/3/17/entrez KW - Apoptosis KW - Autophagy KW - Copper KW - Disulfiram KW - Non-small cell lung cancer SP - 1 EP - 12 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 827 N2 - Autophagy, a cellular survival mechanism, is thought to allow the recycling of cellular breakdown products when cancer cells are subjected to chemotherapy, thus decreasing drug-induced apoptosis. Disulfiram (DSF), a drug widely used to control alcoholism, possesses anticancer activity by inducing apoptosis in vitro and in vivo in a copper (Cu)-dependent manner. Our previous studies proved that DSF/Cu exerts increased anti-tumor effects on non-small cell lung cancer (NSCLC) xenograft models, and inhibits NSCLC recurrence driven by ALDH-positive cancer stem cells. The present study is designed to investigate whether DSF/Cu can induce autophagy in NSCLC cells and to determine the relationship between autophagy and apoptosis. First, we observed that DSF/Cu induced significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells, accompanied by the formation of vacuoles in the cytoplasm. Next, we investigated the levels of autophagic markers, including LC3II (microtubule-associated protein 1 light chain 3), ATG5 and p62 with or without chloroquine by Western blot. In addition, we observed co-localization of LC3 and the lysosomal protein LAMP2 (lysosome-associated membrane protein 2) after treatment with DSF/Cu. The results showed that DSF/Cu induced autophagy. Finally, we demonstrated that DSF/Cu-induced apoptosis was greatly enhanced when autophagy was suppressed with Atg5 siRNA or 3-MA in NSCLC cells. This synergistic effect of DSF/Cu and 3-MA was further confirmed in the NSCLC xenograft model. Taken together, our results show that DSF/Cu stimulates autophagy in NSCLC cells, which is an impediment to DSF/Cu-induced apoptosis. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/29547841/Suppressing_autophagy_enhances_disulfiram/copper_induced_apoptosis_in_non_small_cell_lung_cancer_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(18)30125-0 DB - PRIME DP - Unbound Medicine ER -