Research Abstract

My cancer research originated with the discovery of the anticancer effect of the anti-fungal drug clotrimazole (CLT). I found that CLT has a dual effect on intracellular calcium: it releases clacium from internal stores and closes restorative calcium influx. The resulting partial depletion of internal calcium activates the enzyme PKR, which phosphorylates and thereby inhibits eukaryotic initiation factor 2, the first step in mRNA translation initiation. In this manner, CLT inhibits translation initiation and synthesis of a subset of proteins that includes cyclin D1 and E, and stops cell cycle progression in the G1. My identification of the pharmacophore responsible for this anti-cancer effect of CLT has led to the rational design of analogs that are more potent and less toxic inhibitors of translation initiation.

My laboratory's most recent finding is that the n-3 unsaturated fatty acid EPA as well as thiazoinianones (TZDs) have anti-cancer effects that are mediated by inhibition of translation initiation in a manner almost identical to the effect of CLT. This is potentially important because epidemiological studies have shown that populations eating fish diets rich in EPA exhibit a very low incidence of cnacer, and the TZDs have already been tested in clinical trials for human cancers.

In summary, my cancer research has led to the uncovering of translation initiation as a valid target for anticancer drugs and to the discovery of new inhibitors of translation initiation soon to be tested in humans.