Abstract 715: Synthesis of potent anticancer genistein derivatives to cure estrogen receptor-related breast cancers
Authors: Marik Radharani , Alu Madan , Anchoori Ravi , Umbricht Christopher , Khan Saeed 
Published: February 2011

Abstract: Background: Estrogen Receptor (ER) is a major target for the treatment of breast cancer as estrogens act to stimulate the growth of estrogen-dependent tumors. Estrogens exert their physiological action through ER (ERα and ERβ). Both of them are expressed in normal breast tissue and several other tissues. In many breast cancers, an up-regulation of ERα expression as well as down-regulation of ERβ expression was observed by several groups. Studies also showed that high ERβ levels are associated with a reduced breast cancer risk.

Genistein is a soy isoflavone with a structure similar to estrogen, can mimic and antagonize the estrogen effects in tissues, which could allow it to act as chemo-preventive agent in breast cancer. It has been noted that Genistein is an effective anticancer agent in breast cancer cell lines, but only at supraphysiological concentrations. We synthesized several structurally modified Genistein derivatives, to enhance its antiproliferative effects and to minimize its alpha-estrogenic effects.

Methods: We first synthesized 7 Genistein derivatives (MA-6, MA-8, MA-11, MA-19, MA-20, MA-21 and MA-22) in which Genistein was linked to aliphatic side-chains or heterocyclic triazole moieties that precluded standard agonist binding-induced conformational changes in the ERα receptor pocket. Then we investigated the biochemical effects of these substituted genistein derivatives in the three ER positive breast cancer cell lines (MCF7, 21PT and T47D). Effects were compared to those seen with the parent compound genistein.

Results: 1) Three derivatives (MA-6, MA-8 and MA-19) showed growth inhibitory activity at 5-15 times lower concentrations than the parent Genistein, as assessed by 50% inhibitory concentrations (IC50) in all the 3 breast cancer cell lines. They also induced apoptosis in the breast cancer cell lines as it was reported earlier by Genistein.

2) Treatment with these 3 genistein derivatives in the above low IC50 concentrations, resulted in a decrease of ERα levels and an increase in ERβ levels, at similar levels compared to Genistein itself. These effects were accompanied by the expected changes in gene expression of presenilin-2 and psoriasin, downstream genes of ERα and ERβ signaling respectively.

3) The observed increase of ER β /ER α ratio after MA8, MA6 and MA19 treatments also reached to similar levels achieved by Genistein, explain their high and better potency as anticancer drugs.

Conclusion: Modified Genistein derivatives MA6, MA8 and MA19 reduce proliferation & ERα levels and induce ERβ levels in all the 3 estrogen positive breast cancer cell lines. These effects are seen at 5-15 times lower IC50 concentrations than the parent drug Genistein. ERβ level enhancement by the genistein derivatives may also be associated with a reduced breast cancer risk by the modulation of growth. These new drugs may therefore be much better chemopreventive agents than Genistein itself.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 715.