Targeting ALDH2 with disulfiram/copper reverses the resistance of cancer cells to microtubule inhibitors

Exp Cell Res. 2018 Jan 1;362(1):72-82. doi: 10.1016/j.yexcr.2017.11.004. Epub 2017 Nov 16.

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.

Keywords: ALDH2; Cancer; DSF/Cu; Microtubule inhibitor resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Aldehyde Dehydrogenase, Mitochondrial / antagonists & inhibitors*
  • Animals
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Copper / administration & dosage*
  • Disulfiram / administration & dosage*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Molecular Targeted Therapy / methods
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology
  • Tubulin Modulators / therapeutic use*
  • Xenograft Model Antitumor Assays

Substances

  • Tubulin Modulators
  • Copper
  • Aldehyde Dehydrogenase, Mitochondrial
  • Disulfiram