Identification of heat shock protein 90 inhibitors to sensitize drug resistant side population tumor cells using a cell based assay platform

Cancer Lett. 2012 Apr 1;317(1):78-88. doi: 10.1016/j.canlet.2011.11.009. Epub 2011 Nov 13.

Abstract

Current cancer therapeutics are identified based on initial tumor regression screens that mostly kill differentiated tumor cells, sparing the rare cancer stem cells (CSCs). Being rare and difficult to characterize, it remains a challenge to identify compounds active against them. Side population (SP) cells identified in multiple cancer cell line panels expressing mitochondrial Cytochrome C-EGFP were evaluated for identifying possible drug candidates utilizing high-throughput imaging. We identified heat shock protein 90 inhibitors as potential agents to sensitize SP cells to anticancer drugs. Hsp90 inhibitors induced down regulation of Akt leading to proteasomal degradation of survivin and consequent mitochondrial apoptosis. A successful screening platform for identifying compounds targeting drug resistant side population cells was developed.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cytochromes c / genetics
  • Cytochromes c / metabolism
  • Drug Resistance, Neoplasm*
  • Female
  • Flow Cytometry
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • HCT116 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • High-Throughput Screening Assays*
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Proteasome Endopeptidase Complex / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Side-Population Cells / drug effects*
  • Side-Population Cells / metabolism
  • Side-Population Cells / pathology
  • Survivin
  • Transfection

Substances

  • Antineoplastic Agents
  • BIRC5 protein, human
  • HSP90 Heat-Shock Proteins
  • Inhibitor of Apoptosis Proteins
  • Recombinant Fusion Proteins
  • Survivin
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Cytochromes c
  • Proto-Oncogene Proteins c-akt
  • Proteasome Endopeptidase Complex