Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis

Biochimie. 2014 Dec;107 Pt B:338-49. doi: 10.1016/j.biochi.2014.10.001. Epub 2014 Oct 13.

Abstract

Artemisinin (ART) is a well-known anti-malarial drug, and recently it is shown prospective to selectively kill cancer cells. But low potency makes it inappropriate for use as an anticancer drug. In this study, we modulated the ART-induced autophagy to increase Potency of ART as an anticancer agent. ART reduced the cell viability and colony forming ability of non-small lung carcinoma (A549) cells and it was non-toxic against normal lung (WI38) cells. ART induced autophagy at the early stage of treatment. Pre-treatment with chloroquine (CQ) and followed by ART treatment had synergistic combination index (CI) for cell death. Inhibition of autophagy by CQ pre-treatment led to accumulation of acidic vacuoles (AVOs) which acquainted with unprocessed damage mitochondria that subsequently promoted ROS generation, and resulted releases of Cyt C in cytosol that caused caspase-3 dependent apoptosis cell death in ART-treated A549 cells. Scavenging of ROS by antioxidant N-acetyl-cysteine (NAC) inhibited caspase-3 activity and rescued the cells from apoptosis. Similar effects were observed in other cancer cells SCC25 and MDA-MB-231. The appropriate manipulation of autophagy by using CQ provides a powerful strategy to increase the Potency of selective anticancer property of ART.

Keywords: Anticancer agent; Apoptosis; Artemisinin; Autophagy; Chloroquine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Artemisinins / administration & dosage
  • Artemisinins / pharmacology*
  • Autophagy / drug effects*
  • Cell Cycle / drug effects
  • Cell Line, Tumor / drug effects
  • Cell Survival / drug effects
  • Chloroquine / administration & dosage
  • Chloroquine / pharmacology*
  • Drug Synergism
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Reactive Oxygen Species / metabolism*

Substances

  • Artemisinins
  • Reactive Oxygen Species
  • Chloroquine
  • artemisinine