Preferential killing of triple-negative breast cancer cells in vitro and in vivo when pharmacological aggravators of endoplasmic reticulum stress are combined with autophagy inhibitors

Simmy Thomas, Natasha Sharma, Encouse B. Golden, Heeyeon Cho, Puneet Agarwal, Kevin J. Gaffney, Nicos A. Petasis, Thomas C. Chen, Florence M. Hofman, Stan G. Louie, Axel H. Schönthal

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The cellular processes of autophagy and endoplasmic reticulum stress (ERS) appear to be interconnected, and it has been proposed that autophagy may serve to reduce ERS via removal of terminally misfolded and aggregated proteins. Conversely, there are indications that blockage of autophagy may increase ERS. Based on earlier work demonstrating that pharmacologically aggravated ERS can result in tumor cell killing, we investigated whether blockage of autophagy would enhance this effect in a therapeutically useful manner. We therefore combined chloroquine (CQ), a pharmacological inhibitor of autophagy, with other drugs known to act as ERS aggravators (ERSA), namely nelfinavir (an HIV protease inhibitor) and celecoxib (a cyclooxygenase-2 inhibitor) or its non-coxib analog 2,5-dimethyl-celecoxib (DMC), and investigated combination drug effects in a variety of breast cancer cell lines. We found that the addition of CQ resulted in synergistic enhancement of tumor cell killing by ERSA compounds, particularly in triple-negative breast cancer (TNBC) cells. This combination effect could also be confirmed in an in vivo model, where CQ boosted low-dose ERSA effects, resulting in rapid deterioration of xenografted tumors in mice. Altogether, our results indicate that combinations of an autophagy inhibitor with pharmacological ERSA (i.e. compounds that lead to ER stress aggravation) should be further explored for potential therapy of otherwise difficult-to-treat TNBC.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalCancer Letters
Volume325
Issue number1
DOIs
StatePublished - Dec 1 2012
Externally publishedYes

Keywords

  • Autophagy inhibitor
  • Breast cancer
  • Chloroquine
  • Endoplasmic reticulum stress
  • Nelfinavir

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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