Targeting Aldose Reductase: A Novel Strategy in Treating Endocrine Resistance Using Combination Therapy.

Abstract

Breast cancer is the most commonly diagnosed form of cancer in women. Among breast cancer patients about 2/3 are initially hormone sensitive or estrogen receptor (ER) positive and respond to endocrine therapy. Aromatase inhibitors (AI's) are superior class of hormonal therapeutic agents effectively control ER positive breast cancer in postmenopausal women. Acquired resistance to AI's is expected to be an emerging serious problem in clinics and recent studies have shown that tumors use adaptive signaling mechanisms to overcome AI sensitivity. Thus there is an urgent need for newer treatment modalities. Combination of endocrine and non endocrine agents that block these signaling pathways may prevent or delay the adaptive mechanism and thereby onset of resistance to hormonal therapy. In our study we have found that Fidarestat, an aldose reductase (enzyme which catalyzes the rate limiting step of glucose to fructose or sorbitol formation in polyol pathway) inhibitor effectively re-sensitize letrozole resistant LTLT-Ca breast cancer cells to letrozole. 1µM of fidarestat + 1uM letrozole was found very effective in inducing maximum cell death in LTLT-Ca cells when compared to fidarestat alone. The combination treatment not only restored ER-α levels but also down regulated HER2/MAPK signaling proteins. Aldose reductase siRNA (100nM)- treated MCF-7/Aro and MCF-7 cells upregulated ER-α in western blot and ER-functionality assays. On the other hand in aldose reductase-siRNA- treated LTLT-Ca cells, ER-α levels were down- regulated as in fidarestat treatment. Pretreatment of LTLT-Ca with fidarestat for one week showed reduced proliferation of cells and the effect was maintained until four passages with 1µM letrozole alone. Fidarestat treatment up-regulated E2-mediated transcription in LTLT-Ca cells. In order to enhance the efficacy and targeted delivery of fidarestat in LTLT–Ca cells we have used a nanoparticle-based therapeutic formulation. Folate receptor, highly expressed on epithelial carcinomas, could be a potential molecular target for tumor selective drug delivery. Physcio-chemically well characterized Fidarestat–folate nanoparticles (FFNP's) were prepared to increase the tumor selective intracellular delivery. FFNP's were found superior in exerting cytotoxicity when compared to fidarestat alone. Combination therapy was equally effective in controlling LTLT-Ca cell growth using xenograft model. Taken together, the increased glucose metabolism in LTLT-Ca cells may be critically contributing to chemotherapeutic resistance by increasing drug metabolism and decreasing uptake. Hence targeting aldose reductase in endocrine resistance may be attractive alternative to increase the sensitivity of hormonal therapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 67.