Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells

Abstract

// Xinwei Liu 1, 2 , Lihui Wang 1, 2 , Wei Cui 1 , Xiangzhong Yuan 1 , Lulu Lin 1 , Qi Cao 1 , Nannan Wang 1, 2 , Yi Li 1, 2 , Wei Guo 1 , Xun Zhang 1 , Chunfu Wu 1, 2 , Jingyu Yang 1, 2 1 Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China 2 Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China Correspondence to: Chunfu Wu, email: wucf@syphu.edu.cn Jingyu Yang, email: yangjingyu2006@gmail.com Keywords: disulfiram/copper, ALDH1A1, cancer stem cell, NSCLC, recurrence Received: February 03, 2016     Accepted: July 26, 2016     Published: August 16, 2016 ABSTRACT The existence of cancer stem cells (CSCs) in non-small cell lung cancer (NSCLC) has profound implications for cancer therapy. In this study, a disulfiram/copper (DSF/Cu) complex was evaluated in vitro and in vivo for its efficacy to inhibit CSCs, which drive recurrence of NSCLC. First, we investigated whether DSF/Cu could inhibit ALDH-positive NSCLC stem cells in vitro and tumors derived from sorted ALDH-positive CSCs in vivo . DSF/Cu (0.5/1 μmol/l) significantly inhibited the expression of stem cell transcription factors (Sox2, Oct-4 and Nanog) and reduced the capacities of NSCLC stem cells for self-renewal, proliferation and invasion in vitro . Regular injections with DSF/Cu (60/2.4 mg/kg) reduced the size of tumors derived from sorted ALDH-positive stem cells. Two other NOD/SCID xenograft models were used to determine whether DSF/Cu could target NSCLC stem cells and inhibit tumor recurrence in vivo . DSF/Cu treatment eliminated ALDH-positive cells and inhibited tumor recurrence, which was reflected by reduced tumor growth in recipient mice that were inoculated with tumor cells derived from DSF/Cu-treated cells or primary xenografts. RNA interference and overexpression of ALDH isozymes suggested that ALDH1A1, which plays a key role in ALDH-positive NSCLC stem cells, might be the target of the DSF/Cu complex. Collectively, our data demonstrate that DSF/Cu targets ALDH1A1 to inhibit NSCLC recurrence driven by ALDH-positive CSCs. Thus, the DSF/Cu complex may represent a potential therapeutic strategy for NSCLC patients.