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How Selective are Hsp90 Inhibitors for Cancer Cells over Normal Cells?

Yao Wang1, Yen Chin Koay2, Shelli R McAlpine2

  • 1Department of Medicine, University of New South Wales, 2052, Australia.

Chemmedchem
|February 1, 2017
PubMed

Insights

A new study reveals that the heat shock protein 90 (Hsp90) inhibitor AUY922 lacks tumor selectivity. In contrast, Hsp90 modulator SM258 demonstrates preferential targeting of cancer cells, offering a more selective approach for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Selective inhibition of target proteins in cancer cells over normal cells is crucial for effective cancer therapies.
  • Heat shock protein 90 (Hsp90) is a key chaperone protein implicated in cancer cell survival and proliferation.
  • Existing Hsp90 inhibitors have varying degrees of selectivity, impacting their clinical utility.

Purpose of the Study:

  • To compare the cellular effects of an N-terminal Hsp90 inhibitor (AUY922) versus a C-terminal Hsp90 modulator (SM258) in cancer cells and normal cells.
  • To determine the tumor selectivity of AUY922 and SM258.
  • To elucidate the mechanism of action for SM258 in cancer cells.

Main Methods:

  • Comparative analysis of Hsp90 inhibition-associated cellular events.
  • Evaluation of cell proliferation, apoptosis, and protein degradation.
  • Assessment of Hsp90 client protein expression and regulation of associated heat shock proteins.

Main Results:

  • AUY922 (luminespib) induced similar phenotypic characteristics in both cancer and normal cells, indicating a lack of tumor selectivity.
  • SM258 preferentially suppressed cancer cell proliferation and induced apoptosis.
  • SM258 enhanced the degradation of Hsp90 client proteins and modulated Hsp90-associated proteins selectively in cancer cells.

Conclusions:

  • AUY922 is not tumor-selective, challenging its efficacy as a targeted cancer therapeutic.
  • SM258 exhibits greater selectivity for cancer cells, likely through an Hsp90-dependent mechanism.
  • SM258 represents a promising candidate for developing more targeted Hsp90-inhibiting cancer therapies.
Keywords:
HCT116SM258anticancer agentsheat shock protein 90luminespib

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