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Updated: Jul 13, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Inhibition of Hsp90: a multitarget approach to radiosensitization
Kevin Camphausen1, Philip J Tofilon
1Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA.
Abstract:
Hsp90, the 90 kDa heat shock protein, is a highly expressed molecular chaperone that modulates the stability and/or transport of a diverse set of critical cellular regulatory proteins. Among Hsp90 clients are a number of proteins, which in a cell type-dependent manner, contribute to tumor cell radioresistance. Exposure of a variety of solid tumor cell lines to clinically relevant Hsp90 inhibitors results in the simultaneous loss of these radioresponse-associated proteins, which is accompanied by an increase in radiosensitivity. This radiosensitization has been linked to a compromise in the DNA damage response to radiation including the inhibition of cell cycle checkpoint activation and DNA double-strand break repair. With respect to potential clinical application, the expression of ErbB3 seems to predict tumor cells that are resistant to the effects of Hsp90 inhibition on radiosensitivity. Moreover, whereas an increase in tumor cell radiosensitivity was consistently reported, the radiosensitivity of normal fibroblasts was not affected by Hsp90 inhibition, suggesting the potential for tumor-selective radiosensitization. This review summarizes the preclinical data available on Hsp90 inhibition and cellular radiosensitivity. Results generated to date suggest that Hsp90 inhibition can provide a multitarget approach to tumor radiosensitization.
Insights
Inhibiting heat shock protein 90 (Hsp90) can increase tumor cell radiosensitivity by disrupting DNA repair and cell cycle checkpoints. This approach shows promise for tumor-selective radiosensitization, sparing normal cells.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Heat shock protein 90 (Hsp90) is a molecular chaperone regulating critical cellular proteins.
- Hsp90 clients include proteins that confer radioresistance to tumor cells.
- Hsp90 inhibitors are clinically relevant and affect tumor cell stability.
Purpose of the Study:
- To review preclinical data on Hsp90 inhibition and its effects on cellular radiosensitivity.
- To explore the potential of Hsp90 inhibition as a strategy for tumor radiosensitization.
Main Methods:
- Exposure of solid tumor cell lines to Hsp90 inhibitors.
- Assessment of changes in radioresponse-associated proteins.
- Evaluation of DNA damage response, cell cycle checkpoint activation, and DNA double-strand break repair.
- Analysis of ErbB3 expression as a predictive marker.
Main Results:
- Hsp90 inhibition leads to the loss of radioresistance proteins and increased tumor cell radiosensitivity.
- Radiosensitization is associated with impaired DNA damage response and repair.
- ErbB3 expression may predict resistance to Hsp90 inhibition's radiosensitizing effects.
- Normal fibroblast radiosensitivity is unaffected, suggesting tumor selectivity.
Conclusions:
- Hsp90 inhibition offers a multitarget approach to enhance tumor radiosensitivity.
- The potential for tumor-selective radiosensitization warrants further clinical investigation.
- Targeting Hsp90 could be a valuable strategy in cancer radiotherapy.
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