Inhibiting the transcription factor HSF1 as an anticancer strategy

Expert Opin Ther Targets. 2009 Apr;13(4):469-78. doi: 10.1517/14728220902832697.

Abstract

Background: In mammals, the cytoprotective heat-shock response is regulated primarily by heat shock factor 1 (HSF1). Unfortunately, the effects of HSF1 also support the ability of cancer cells to accommodate imbalances in signaling and alterations in DNA, protein and energy metabolism associated with oncogenesis. The malignant lifestyle confers dependence on this 'non-oncogene', suggesting a therapeutic role for HSF1 inhibitors.

Objective/methods: We begin with an overview of how HSF1 affects cancer biology and how its activity is regulated. We then summarize progress in discovery and development of HSF1 inhibitors, their current limitations and potential as anticancer agents with a fundamentally different scope of action from other clinically validated modulators of protein homeostasis.

Results/conclusions: It is likely that within the next 5 years usable inhibitors of HSF1 will be identified and in early pre-clinical evaluation.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Survival / physiology
  • Cell Transformation, Neoplastic
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology
  • Diterpenes / pharmacology
  • Diterpenes / therapeutic use
  • Drug Delivery Systems
  • Drug Design
  • Epoxy Compounds / pharmacology
  • Epoxy Compounds / therapeutic use
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins / biosynthesis
  • Heat-Shock Proteins / genetics
  • Humans
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / physiology
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / physiology
  • Phenanthrenes / pharmacology
  • Phenanthrenes / therapeutic use
  • Quercetin / pharmacology
  • Quercetin / therapeutic use
  • Stress, Physiological / genetics
  • Transcription Factors / antagonists & inhibitors*
  • Transcription Factors / deficiency
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transcription, Genetic / drug effects*

Substances

  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Diterpenes
  • Epoxy Compounds
  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins
  • Hsf1 protein, mouse
  • Molecular Chaperones
  • Neoplasm Proteins
  • Phenanthrenes
  • Transcription Factors
  • triptolide
  • Quercetin