title: Targeting ALDH1A1 by disulfiram/copper complex inhibits non-small cell lung cancer recurrence driven by ALDH-positive cancer stem cells.
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.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Xinwei
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Xiangzhong
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Lulu
authors.initials: L
authors.lastname: Lin
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Nannan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.
authors.forename: Xun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, P.R. China.|Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Benxi, P.R. China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002469:Cell Separation; D003300:Copper / Q000737:chemistry*; D004221:Disulfiram / Q000737:chemistry*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015994:Incidence; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D034622:RNA Interference; D050697:Retinal Dehydrogenase
chemical_list: D007527:Isoenzymes; D003300:Copper; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase; D004221:Disulfiram
keywords: ALDH1A1; NSCLC; cancer stem cell; disulfiram/copper; recurrence