Pharmacologic screens reveal metformin that suppresses GRP78-dependent autophagy to enhance the anti-myeloma effect of bortezomib

Leukemia. 2015 Nov;29(11):2184-91. doi: 10.1038/leu.2015.157. Epub 2015 Jun 25.

Abstract

Although the therapeutic benefit of proteasome inhibition in multiple myeloma remains unchallenged, drug resistance inevitably emerges through mechanisms that remain elusive. Bortezomib provokes unwanted protein accumulation and the endoplasmic reticulum stress to activate the unfolded protein response (UPR) and autophagy as compensatory mechanisms that restore protein homeostasis. High-throughput screens to detect pharmacologics that modulated autophagy to enhance the anti-myeloma effect of bortezomib revealed metformin, a widely used antidiabetic agent with proven efficacy and limited adverse effects. Metformin co-treatment with bortezomib suppressed induction of the critical UPR effector glucose-regulated protein 78 (GRP78) to impair autophagosome formation and enhance apoptosis. Gene expression profiling of newly diagnosed myeloma patient tumors further correlated the hyperexpression of GRP78-encoding HSPA5 with reduced clinical response to bortezomib. The effect of bortezomib was enhanced with metformin co-treatment using myeloma patient tumor cells and the chemoresistant, stem cell-like side population that may contribute to disease recurrence. The relevance of the findings was confirmed in vivo as shown by metformin co-treatment with bortezomib that delayed the growth of myeloma xenotransplants. Taken together, our results suggest that metformin suppresses GRP78, a key driver of bortezomib-induced autophagy, and support the pharmacologic repositioning of metformin to enhance the anti-myeloma benefit of bortezomib.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Autophagy / drug effects*
  • Bortezomib / pharmacology*
  • Cell Line, Tumor
  • Drug Synergism
  • Female
  • Heat-Shock Proteins / antagonists & inhibitors*
  • Heat-Shock Proteins / physiology
  • Humans
  • Metformin / pharmacology*
  • Mice
  • Multiple Myeloma / drug therapy*
  • Phosphatidylinositol 3-Kinases / physiology

Substances

  • Antineoplastic Agents
  • Heat-Shock Proteins
  • Bortezomib
  • Metformin
  • Phosphatidylinositol 3-Kinases
  • molecular chaperone GRP78