The autophagy inhibitor chloroquine targets cancer stem cells in triple negative breast cancer by inducing mitochondrial damage and impairing DNA break repair

Cancer Lett. 2016 Jul 1;376(2):249-58. doi: 10.1016/j.canlet.2016.04.002. Epub 2016 Apr 6.

Abstract

Triple negative breast cancer (TNBC), characterized by an abundance of treatment-resistant breast cancer stem cells (CSCs), has a poorer prognosis than other types of breast cancers. Despite its aggressiveness, no effective targeted therapy exists for TNBC. Here, we demonstrate that CQ effectively targets CSCs via autophagy inhibition, mitochondrial structural damage, and impairment of double-stranded DNA break repair. Electron microscopy demonstrates CQ-induced mitochondrial cristae damage, which leads to mitochondrial membrane depolarization with a significant reduction in the activity of cytochrome c oxidase and accumulation of superoxide and double-stranded DNA breaks. CQ effectively diminishes the TNBC cells' ability to metastasize in vitro and in a TNBC xenograft model. When administered in combination with carboplatin, CQ effectively inhibits carboplatin-induced autophagy. This combination treatment significantly diminishes the expression of DNA repair proteins in CSC subpopulations, resulting in tumor growth reduction in carboplatin-resistant BRCA1 wild-type TNBC orthotopic xenografts. As TNBC's high treatment failure rate has been attributed to enrichment of CSCs, CQ, an autophagy inhibitor with anti-CSC effects, may be an effective adjunct to current TNBC chemotherapy regimens with carboplatin.

Keywords: Breast cancer stem cells; Chloroquine; Mitochondrial damage; Oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Autophagy / drug effects*
  • Carboplatin / pharmacology
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Chloroquine / pharmacology*
  • DNA Damage*
  • DNA Repair / drug effects*
  • Dose-Response Relationship, Drug
  • Electron Transport Complex IV / metabolism
  • Female
  • Histones / metabolism
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Mice, SCID
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondria / ultrastructure
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / ultrastructure
  • Superoxides / metabolism
  • Time Factors
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / metabolism
  • Triple Negative Breast Neoplasms / ultrastructure
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • H2AX protein, human
  • Histones
  • Superoxides
  • Chloroquine
  • Carboplatin
  • Electron Transport Complex IV