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Proteasome Inhibitors in the Clinical Setting

Benefits and Strategies to Overcome Multiple Myeloma Resistance to Proteasome Inhibitors

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Abstract

The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341), a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and other malignancies.

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Acknowledgements

This study was supported in part by the Myeloma Foundation of America and the Pastore Foundation. Mohamad A. Hussein has received a research grant from Millennium Pharmaceuticals, Inc. The other authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. The Cleveland Clinic Foundation, Taussig Cancer Center, Center for Hematology and Oncology Molecular Therapeutics, Cleveland, Ohio, USA

    Venugopalan Cheriyath & Barbara S. Jacobs

  2. Division of Malignant Hematology, Department of Interdisciplinary Oncology, USF College of Medicine, and the H. Lee Moffitt Cancer and Research Institute, Tampa, Florida, USA

    Venugopalan Cheriyath &  Mohamad A. Hussein

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  1. Venugopalan Cheriyath
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Cheriyath, V., Jacobs, B.S. & Hussein, M.A. Proteasome Inhibitors in the Clinical Setting. Drugs R D 8, 1–12 (2007). https://doi.org/10.2165/00126839-200708010-00001

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