Abstract 1484: Aldose reductase inhibition prevents breast cancer cell growth and restores breast cancer cell hormone dependency

Abstract

Abstract Breast Cancer (BC) is the second leading cause of cancer deaths in the U.S. women. Hormone ablation therapy reduces the risk of cancer recurrence and improves the survival rate of most BC patients. Although BC initially responds to estrogen ablation therapy, as the cancer progresses, the cancer cells become hormone-independent and prone to metastasis, a major cause of mortality in BC patients. The few currently available drugs that restore hormone dependence are only partially effective and prohibitively costly. Hence there is an urgent need for novel therapeutic modalities. We have recently shown that aldose reductase (AR)-catalyzed GSH-lipid aldehyde conjugates such as GS-DHN induces growth factors-, cytokines- and chemokines-mediated signals that activate PKC, PLC and PI3K, which regulate transcription of NF-κB- and AP1-dependent inflammatory markers. Further, AR has been shown to be overexpressed in human breast cancers. We have investigated the efficacy of AR inhibition in preventing BC cells growth and reversing hormone dependency of BC cells. Our results indicate that pharmacological inhibition of AR or siRNA ablation of AR prevents growth factor -induced proliferation of BC cells (MCF-7) in culture. Similar results were observed when MDA-MB-231 and MDA-MB-468 BC cells were used. To further investigate how AR inhibitor prevents BC cell growth, we have examined the role of AR in resensitization of BC cells to letrozole. We found that combination of fidarestat with letrozole was very effective in inducing maximum cell death in LTLT-Ca cells when compared to fidarestat alone. The combination treatment not only restored estrogen receptor-α (ER-α) levels but also down-regulated HER2/MAPK-signaling proteins. Further, AR-siRNA - transfected MCF-7/Aro and MCF-7 cells upregulated ER-α in western blot and ER-functionality assays whereas in LTLT-Ca cells, ER-α levels were down-regulated as in fidarestat treated cells. Targeting the LTLT-Ca cells with PLG-based fidarestat nanoparticles having polyethylene glycol (PEG)-5000 as stabilizer and conjugated with FITC significantly prevented the aromatase activity in BC cells. Thus we have identified a novel role of AR in BC cell growth and estrogen-dependence of hormone insensitive BC cells and suggest the use of AR inhibitors either alone or in combination with letrozole to prevent as well as treat BC. 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 1484.