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Updated: May 13, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Extracellular Hsp90 (eHsp90) as the actual target in clinical trials: intentionally or unintentionally
Wei Li1, Fred Tsen, Divya Sahu
1Department of Dermatology, USC-Norris Comprehensive Cancer Center, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. wli@usc.edu
Abstract:
Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of "eHsp90-dependent" cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.
Insights
Cancer cells
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The differential sensitivity of cancer cells versus normal cells to Heat Shock Protein 90 (Hsp90) inhibitors remains poorly understood.
- Current Hsp90 inhibitors non-discriminatively target both intracellular and extracellular Hsp90, leading to significant toxicity.
- The specific mechanisms driving selective cancer cell sensitivity to Hsp90 inhibition are yet to be fully elucidated.
Purpose of the Study:
- To investigate the hypothesis that extracellular Hsp90 (eHsp90) inhibition, rather than intracellular Hsp90 inhibition, underlies the selective sensitivity of certain cancer cells to Hsp90 inhibitors.
- To explore the potential for developing targeted therapies that specifically inhibit eHsp90 for improved cancer treatment efficacy and reduced toxicity.
Main Methods:
- Review and analysis of recent studies investigating Hsp90 inhibitor mechanisms.
- Correlation of cancer cell sensitivity to Hsp90 inhibitors with their reliance on extracellular Hsp90 for critical functions.
Main Results:
- Evidence suggests that Hsp90 inhibitors selectively target extracellular Hsp90 (eHsp90) in sensitive cancer cells.
- Cancer cells utilizing eHsp90 for motility, invasion, and metastasis are identified as the sensitive subgroup.
- Normal cells, which do not extensively rely on eHsp90, exhibit lower sensitivity to these inhibitors.
Conclusions:
- The selective sensitivity of specific cancer cells to Hsp90 inhibitors is attributed to the inhibition of extracellular Hsp90 (eHsp90).
- Targeting eHsp90 selectively could lead to more effective anti-cancer drugs with reduced side effects compared to current broad-spectrum Hsp90 inhibitors.
- Future development of pharmaceutical agents specifically targeting eHsp90 holds promise for improved cancer therapy.
