No abstract

Chalcones and their derivatives have been shown 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 eight chalcone derivatives tested, 3,5-bis-(4-boronic acid-benzylidene)-1-methyl-piperidin-4-one (AM114) exhibited most potent growth inhibitory activity with IC 50 values of 1.5 and 0.6 M in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide 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 murine double minute 2 protein. It is noteworthy that 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. 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.Chalcones and their derivatives are a group of compounds reported to exhibit promising anticancer activity. These compounds are precursors of flavonoids and isoflavonoids, which are abundant in edible plants. The chemical structure of chalcones (1,3-diphenyl-2-propen-1-

Despite recent advances in our understanding of the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. One of the oldest and most effective strategies for developing new chemotherapeutics is the isolation and evaluation of chemicals of natural origin. The importance of natural products for drug discovery has been impressive: One has to only look at the number of clinically active drugs that are used in cancer therapy to see how many are either natural products or are based on natural products. It is also apparent that materials from natural sources are excellent probes (indicators) for cellular targets that, when modulated, may have a deleterious effect upon the survival or proliferation of tumor cells. And the search goes on. Sesquiterpenes are a class of naturally occurring molecules that have demonstrated therapeutic potential in decreasing the progression of cancer. These molecules are 15-carbon isoprenoid compounds that are typically found in plants and marine life. Although this class of compounds has frequently provided encouraging leads for chemotherapeutics, they have not been evaluated as potential anticancer agents. In this review, we provide a current overview of sesquiterpenoids that have potential as anticancer agents.