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Updated: Aug 15, 2026
Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
Published on: January 20, 2023
Antimyeloma activity of heat shock protein-90 inhibition
Constantine S Mitsiades1, Nicholas S Mitsiades, Ciaran J McMullan
1Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana Farber Cancer Institute, Harvard Medical School, Boston MA 02115, USA. constantine_mitsiades@dfci.harvard.edu
Abstract:
We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.
Insights
Multiple myeloma (MM) responds to HSP90 inhibitors, even without typical HSP90 client proteins. These inhibitors induce apoptosis and sensitize MM cells to other treatments, expanding therapeutic options.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multiple myeloma (MM) is a hematologic malignancy with limited treatment options.
- HSP90 inhibitors are effective in tumors dependent on known HSP90 client proteins.
- The role of HSP90 in MM, independent of these traditional clients, is not well understood.
Purpose of the Study:
- To investigate the efficacy of HSP90 inhibitors in multiple myeloma.
- To determine the molecular mechanisms underlying HSP90 inhibition in MM.
- To explore the potential of HSP90 inhibitors in combination therapy for MM.
Main Methods:
- In vitro studies using MM cell lines.
- In vivo orthotopic mouse model of MM.
- Analysis of signaling pathways including IGF-1R, IL-6R, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK.
- Assessment of downstream effectors such as proteasome, telomerase, and HIF-1alpha.
Main Results:
- HSP90 inhibitors demonstrate significant anti-myeloma activity in vitro and in vivo.
- HSP90 inhibition effectively suppresses multiple signaling pathways (IGF-1R, IL-6R, NF-kappaB, Akt, MAPK) and downstream targets in MM cells.
- This suppression leads to pleiotropic proapoptotic effects and abrogates protective signals from bone marrow stromal cells.
- HSP90 inhibitors sensitize MM cells to chemotherapy and bortezomib.
Conclusions:
- HSP90 is a viable therapeutic target in multiple myeloma, irrespective of traditional client protein dependence.
- HSP90 inhibition offers a novel strategy to overcome resistance mechanisms and enhance the efficacy of existing MM therapies.
- Targeting HSP90 has broader implications for treating various cancers by modulating tumor-specific client protein constellations.
