Clinical development of novel proteasome inhibitors for cancer treatment

Abstract

Background: Emerging evidence demonstrates that targeting the tumor proteasome is a promising strategy for cancer therapy. Objective: This review summarizes recent results from cancer clinical trials using specific proteasome inhibitors or some natural compounds that have proteasome-inhibitory effects. Methods: A literature search was carried out using PubMed. Results about the clinical application of specific proteasome inhibitors and natural products with proteasome-inhibitory activity for cancer prevention or therapy were reviewed. Results/conclusion: Bortezomib, the reversible proteasome inhibitor that first entered clinical trials, has been studied extensively as a single agent and in combination with glucocorticoids, cytotoxic agents, immunomodulatory drugs and radiation as treatment for multiple myeloma and other hematological malignancies. The results in some cases have been impressive. There is less evidence of bortezomib's efficacy in solid tumors. Novel irreversible proteasome inhibitors, NPI-0052 and carfilzomib, have also been developed and clinical trials are underway. Natural products with proteasome-inhibitory effects, such as green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG), soy isoflavone genistein, and the spice turmeric compound curcumin, have been studied alone and in combination with traditional chemotherapy and radiotherapy against various cancers. There is also interest in developing these natural compounds as potential chemopreventive agents.

Keywords::

• clinical trials
• combinational therapy
• hematological malignancies
• natural products
• proteasome inhibitors
• solid tumors

Acknowledgements

This research is partially supported by Karmanos Cancer Institute of Wayne State University (to QP Dou), Department of Defense Breast Cancer Research Program Awards (W81XWH-04-1-0688 and DAMD17-03-1-0175 to QP Dou), National Cancer Institute/NIH (1R01CA120009; 5R03CA112625 to QP Dou), and the National Cancer Institute/NIH Cancer Center Support Grant (to Karmanos Cancer Institute). The authors thank Di Chen, Michael Frezza, and Carol Maconochie for critical reading of the manuscript.