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Abstract

Most of the currently available drugs to treat breast cancer (BC) have major limitations in long-term use because of significant toxicities or adverse effects associated with these drugs. Published studies have established that resveratrol (Res), possesses antioxidant, anti-inflammatory and anticancer activities. Unfortunately, however, the available evidence supports the conclusion that its potency in preventing or treating BC is relatively modest at best. We hypothesize that this problem can be successfully addressed through synthesis of Res analogs with appropriate structural modifications. We have synthesized a series of novel compounds that resemble the basic Res skeleton but contain some structural modifications with different pharmacophoric groups. We evaluated these compounds for their cytotoxicities against several BC cell lines. We demonstrate that one of the synthesized compounds 4-(E) {(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) has significantly higher potency than Res in inhibiting the growth of all BC cell lines that we tested. Moreover, TIMBD did not have any detectable detrimental effect on the growth of normal (non-neoplastic) human breast cells and other cell types of the brain. Additionally, increased oxidative stress has been suggested to contribute to development of breast tumors and many other diseases. Our preliminary results suggest that TIMBD also functions to decrease levels of oxidative stress, induce mRNA and protein expression levels of antioxidant defense genes such as NQO1, SOD3 and Nrf2 in normal (non-neoplastic) breast cell lines as well as in human SVGA astrocytes but not in BC cells. Our results thus suggest that TIMBD is not only cytotoxic towards BC cells but can also help to protect normal cells against increased oxidative burden. Thus, chemotherapeutic agents that have the potential of specifically killing, or inhibiting the growth of, BC cells with relatively minimal toxicity towards normal cells, would be expected to have a significant therapeutic advantage in selectively targeting BCs.

Biography

Email: bhath@umkc.edu