Bortezomib In Cancer Research Articles

Proteasome Inhibitor Bortezomib: A Double-Edged Sword in Cancer Therapy

A steady flow of reports suggests that proteasome inhibitor bortezomib promotes tumor cell death by degradation of key proteins. Therefore, bortezomib has been gaining intense attention as an anti-neoplastic agent, being the first proteasome inhibitor drug to be used in multiple myeloma´s treatment. However, new evidences point to the adverse effects of bortezomib leading to the poor outcome in both hematological and solid tumors. Despite its therapeutic effects, deciphering the molecular mechanisms of bortezomib action as well as the mechanism(s) of resistance to bortezomib in cancer remains a problem to be conquered.

Incidence and Risk of Cardiotoxicity Associated with Bortezomib in the Treatment of Cancer: A Systematic Review and Meta-Analysis

BackgroundWe conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients.MethodsDatabases from PubMed, Web of Science and abstracts presented at ASCO meeting up to July 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies.ResultsA total of 5718 patients with a variety of malignancies from 25 clinical trials were included in our analysis. The incidence of all-grade and high-grade cardiotoxicity associated with bortezomib was 3.8% (95%CI: 2.6–5.6%) and 2.3% (1.6–3.5%), with a mortality of 3.0% (1.4–6.5%). Patients treated with bortezomib did not significantly increase the risk of all-grade (OR 1.15, 95%CI: 0.82–1.62, p = 0.41) and high-grade (OR 1.13, 95%CI: 0.58–2.24, p = 0.72) cardiotoxicity compared with patients treated with control medication. Sub-group analysis showed that the incidence of cardiotoxicity varied with tumor types, treatment regimens and phases of trials. No evidence of publication bias was observed.ConclusionsThe use of bortezomib does not significantly increase the risk of cardiotoxicity compared to control patients. Further studies are recommended to investigate this association and risk differences among different tumor types, treatment regimens and phases of trials.

Phosphorylation of signal transducer and activator of transcription 1 reduces bortezomib-mediated apoptosis in cancer cells

The potent and selective proteasome inhibitor bortezomib has shown remarkable antitumor activity and is now entering clinical trials for several cancers. However, the molecular mechanisms by which bortezomib induces cytotoxicity in ovarian cancer cells still remain unclear. In this study, we show that bortezomib induced apoptosis, which was demonstrated by the downregulation of antiapoptotic molecules (Bcl-2, Bcl-XL, p-Bad, and p-AKT) and the upregulation of proapoptotic proteins (p21, p27, and cleaved-Bid) in ovarian cancer cell lines. Moreover, bortezomib stimulates Janus kinase (JAK) phosphorylation and activates heat-shock transcription factor-1 (HSF-1) and heat-shock protein 70 (HSP70), ultimately leading to signal transducer and activator of transcription 1 (STAT1) phosphorylation. Phosphorylated STAT1 partially counteracted apoptosis induced by bortezomib in cancer cells. These findings suggest that the antitumor activity of bortezomib in ovarian cancer can be improved by inhibiting bortezomib-induced STAT1 phosphorylation. This effect can be achieved by STAT1 knockdown, HSP70 knockdown, JAK inhibition, or the addition of cisplatin, one of the most commonly used anticancer drugs. These results provide the first evidence that STAT1 phosphorylation can play a role in bortezomib resistance by exerting antiapoptotic effects. They also suggest the possibility to abolish or reduce bortezomib chemoresistance in ovarian cancer by the addition of cisplatin or JAK inhibitors.