Abstract 660: Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines

Abstract

Abstract PURPOSE: Triple negative breast cancer (TNBC) is the most aggressive and fatal form of breast cancer. TNBC has no effective therapies since it is not driven by the estrogen (ER), progesterone (PR), and human epidermal growth factor type 2 (Her2/Neu) receptors for which there are targeted drugs. Human epidermal growth factor receptors (EGFR) are overexpressed in 92% of TNBC cases, however, anti-EGFR therapies are ineffective. Monomeric G-proteins that regulate cell proliferation, angiogenesis, migration and apoptosis operate downstream of EGFR and other signal transduction pathways. Polyisoprenylated methylated protein methyl esterase (PMPMEase) metabolizes monomeric G-proteins, allowing them to function properly. PMPMEase is overexpressed in many cancers and may serve as a biomarker and target for cancer therapy. We have synthesized polyisoprenylated cysteinyl amide inhibitors that may inhibit PMPMEase and/or disrupt polyisoprenylated protein function. We hypothesize that the PCAIs will promote anti-tumorigenic effects, inducing apoptosis, while inhibiting cell survival, proliferation, migration, and invasion. The purpose of this study was to test the effectiveness of PCAIs against the biological hallmarks of TNBC. METHODS: Four TNBC cell lines were treated with the PCAIs and analyzed for their effects on cell survival, viability, F-actin organization, cell migration and apoptosis. RESULTS: Treatment of TNBC cells with the PCAIs resulted in a concentration-dependent death of the TNBC cells with EC50 values ranging from 2.13 to 2.78 μM for NSL-BA-040 and NSL-BA-055 in media containing 5% FBS. AO/EB staining revealed early apoptosis at 1 μM. NSL-RD-036 inhibited MDA-MB-231 cell migration by 71% (163±10.7 cells in control versus 47±6.9 in treated (±SEM, N = 3). PCAIs induced complete disruption of F-actin filament organization at 2 μM in MDA-MB-468 cells. CONCLUSION: The PCAIs’ ability to induce apoptosis, and inhibit cell migration by disrupting F-actin filaments suggest that their potential therapeutic value could involve the inhibition of TNBC tumor growth, metastasis, and angiogenesis, which are all essential hallmarks for breast cancer progression. The PCAIs may ultimately fill the targeted therapy void in TNBC therapy. Citation Format: Olufisayo O. Salako, Rosemary A. Poku, Augustine T. Nkembo, Typhon Mazu, Hernan Flores-Rozas, Nazarius S. Lamango. Polyisoprenylated cysteinyl amide inhibitors exhibit anti-tumor effects in human breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2015-660