Activation of autophagy by stress-activated signals as a cellular self-defense mechanism against the cytotoxic effects of MBIC in human breast cancer cells in vitro.

Abstract

We recently reported that methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (MBIC) is a microtubule targeting agent (MTA) with multiple mechanisms of action including apoptosis in two human breast cancer cell-lines MCF-7 and MDA-MB-231. In the present study, investigation of early molecular events following MBIC treatment demonstrated the induction of autophagy. This early (<24 h) response to MBIC was characterized by accumulation of autophagy markers; LC3-II, Beclin1, autophagic proteins (ATGs) and collection of autophagosomes but with different variations in the two cell-lines. MBIC-induced autophagy was associated with generation of reactive oxygen species (ROS). In parallel, an increased activation of SAPK/JNK pathway was detected, as an intersection of ROS production and induction of autophagy. The cytotoxic effect of MBIC was enhanced by inhibition of autophagy through blockage of SAPK/JNK signaling, suggesting that MBIC-induced autophagy, is a possible cellular self-defense mechanism against toxicity of this agent in both breast cancer cell-lines. The present findings suggest that inhibition of autophagy eliminates the cytoprotective activity of MDA-MB-231 and MCF-7 cells, and sensitizes both the aggressive and non-aggressive human breast cancer cell-lines to the cytotoxic effects of MBIC.

• Authors: Mohadeseh Hasanpourghadi, Nazia Abdul Majid, Mohd Rais Mustafa
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 152 Pg. 174-186 (06 2018) ISSN: 1873-2968 [Electronic] England
• PMID: 29608909 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Benzimidazoles
• Carboxylic Acids
• Reactive Oxygen Species
• methyl 2-(-5-fluoro-2-hydroxyphenyl)-1 H-benzo(d)imidazole-5-carboxylate
• Extracellular Signal-Regulated MAP Kinases

Topics

• Antineoplastic Agents (pharmacology)
• Autophagy
• Benzimidazoles (pharmacology)
• Breast Neoplasms (drug therapy)
• Carboxylic Acids (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Extracellular Signal-Regulated MAP Kinases (genetics, metabolism)
• Female
• Humans
• Microscopy, Electron, Transmission
• Reactive Oxygen Species