Preclinical evaluation of the proteasome inhibitor bortezomib in cancer therapy |
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Authors: | Email author" target="_blank">Mario?BoccadoroEmail author Gareth?Morgan Jamie?Cavenagh |
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Institution: | (1) Section of Hematology, University of Torino, Torino, Italy;(2) Royal Marsden Hospital, Surrey, UK;(3) Department of Haematology, St. Bartholomew's Hospital, London, UK |
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Abstract: | Bortezomib is a highly selective, reversible inhibitor of the 26S proteasome that is indicated for single-agent use in the
treatment of patients with multiple myeloma who have received at least 2 prior therapies and are progressing on their most
recent therapy. Clinical investigations have been completed or are under way to evaluate the safety and efficacy of bortezomib
alone or in combination with chemotherapy in multiple myeloma, both at relapse and presentation, as well as in other cancer
types. The antiproliferative, proapoptotic, antiangiogenic, and antitumor activities of bortezomib result from proteasome
inhibition and depend on the altered degradation of a host of regulatory proteins. Exposure to bortezomib has been shown to
stabilize p21, p27, and p53, as well as the proapoptotic Bid and Bax proteins, caveolin-1, and inhibitor κB-α, which prevents
activation of nuclear factor κB-induced cell survival pathways. Bortezomib also promoted the activation of the proapoptotic
c-Jun-NH2 terminal kinase, as well as the endoplasmic reticulum stress response. The anticancer effects of bortezomib as a single agent
have been demonstrated in xenograft models of multiple myeloma, adult T-cell leukemia, lung, breast, prostate, pancreatic,
head and neck, and colon cancer, and in melanoma. In these preclinical in vivo studies, bortezomib treatment resulted in decreased tumor growth, angiogenesis, and metastasis, as well as increased survival
and tumor apoptosis. In several in vitro and/or in vivo cancer models, bortezomib has also been shown to enhance the antitumor properties of several antineoplastic treatments. Importantly,
bortezomib was generally well tolerated and did not appear to produce additive toxicities when combined with other therapies
in the dosing regimens used in these preclinical in vivo investigations. These findings provide a rationale for further clinical trials using bortezomib alone or in combination regimens
with chemotherapy, radiation therapy, immunotherapy, or novel agents in patients with hematologic malignancies or solid tumors. |
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