Received for publication December 13, 2005.
Revised April 22, 2006.
Accepted for publication April 24, 2006.

A Boronic-Chalcone Derivative Exhibits Potent Anti-Cancer Activity through Inhibition of the Proteasome

Abstract

Chalcones and their derivatives have been to have potent anticancer activity. However, the exact mechanisms of cytotoxic activity remain to be established. In this study, we have evaluated a series of boronic chalcones for their anticancer activity and mechanisms of action. Among the 8 chalcone derivatives tested, AM114 exhibited most potent growth inhibitory activity with IC₅₀ values of 1.5 µM and 0.6 µM in MTT assay and colony formation assay, respectively. The cytotoxic activity of AM114 was shown to be associated with the accumulation of p53 and p21 proteins and induction of apoptosis. Mechanistic studies showed that AM114 treatment inhibited the chymotrypsin-like activity of the 20S proteasome in vitro, leading to a significant accumulation of ubiquitinated p53 and other cellular proteins in whole cells. In vitro studies showed that AM114 did not significantly disrupt the interaction of p53 and MDM2 protein. Interestingly, AM114 as a single agent was preferentially toxic to cells with wild-type p53 expression, whereas combination of this compound with ionizing radiation (IR) significantly enhanced the cell killing activity of IR in both wild-type p53 and p53-null cells. Taken together, these results indicate that the boronic chalcone derivative AM114 induces significant cytotoxic effect in cancer cells through the inhibition of the cellular proteasome, and provide a rationale for the further development of this class of compounds as novel cancer chemotherapeutic agents.

Key words: Mechanisms of cell killing/apoptosis, Tumor suppressors

This article has been cited by other articles:

				L. Rickardson, M. Wickstrom, R. Larsson, and H. Lovborg Image-Based Screening for the Identification of Novel Proteasome Inhibitors J Biomol Screen, March 1, 2007; 12(2): 203 - 210. [Abstract] [PDF]