Oncotarget

Research Papers:

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

Xinwei Liu, Lihui Wang, Wei Cui, Xiangzhong Yuan, Lulu Lin, Qi Cao, Nannan Wang, Yi Li, Wei Guo, Xun Zhang, Chunfu Wu _ and Jingyu Yang

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Oncotarget. 2016; 7:58516-58530. https://doi.org/10.18632/oncotarget.11305

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Abstract

Xinwei Liu1,2, Lihui Wang1,2, Wei Cui1, Xiangzhong Yuan1, Lulu Lin1, Qi Cao1, Nannan Wang1,2, Yi Li1,2, Wei Guo1, Xun Zhang1, Chunfu Wu1,2, Jingyu Yang1,2

1Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China

2Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China

Correspondence to:

Chunfu Wu, email: [email protected]

Jingyu Yang, email: [email protected]

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.


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