Abstract 5007: A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma cells

Abstract

Abstract The monomeric GTP-ase, Ras, is mutated in over 30% of cancers where it promotes uncontrolled proliferation of cancer cells. Ras signaling is one of many pathophysiological pathways implicated in hepatocellular carcinoma that results in cell survival, differentiation, proliferation, and angiogenesis. Ras is bound to the cytoplasmic face of the plasma membrane where it relays intracellular signals. Polyisoprenylated cysteinyl amide inhibitors (PCAIs) effectively disrupt the functions of polyisoprenylated proteins such as Ras. Many hepatocellular carcinomas (HCCs) have dysregulated Ras signaling. However, the effects of PCAIs on hepatocellular carcinoma (HCC) are unknown. The aim of this study was to investigate the effect of a novel PCAI, NSL-BA-055, on HCC. Concentrations of NSL-BA-055 ranging from 0 to 10 μM were used for experimentation. Effects on proliferation of BNL CL.2 (non-tumorigenic mouse hepatocytes) and BNL 1ME A.7R.1 (mouse HCC cells derived from BNL CL.2 hepatocytes) were analyzed. Next, the effects of NSL-BA-055 on Akt protein expression, a downstream component of Ras signaling, were examined by western blotting. NSL-BA-055 significantly inhibited the proliferation of BNL 1ME A. 7R.1 HCC cells, but not the non-tumorigenic BNL CL.2 hepatocytes. Also, concentrations of the NSL-BA-055 compound as low as 4 μM significantly inhibited the proliferation of BNL 1ME A.7R.1 HCC cells. Western blotting revealed that NSL-BA-055 inhibited Akt protein expression at 4μM. Therefore PCAIs such as NSL-BA-055 is a novel class of agents that selectively inhibit the proliferation of HCC cells, but not normal hepatocytes. This effect may be via inhibition of Akt, a downstream intermediate of Ras signaling. Consequently, NSL-BA-055 is a novel candidate agent for HCC therapy. Note: This abstract was not presented at the meeting. Citation Format: Michelle K. Naidoo, Nazarius Lamango, Olorunseun O. Ogunwobi. A novel polyisoprenylated cysteinyl amide inhibitor, NSL-BA-055, selectively inhibits proliferation of hepatocellular carcinoma cells. [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 5007. doi:10.1158/1538-7445.AM2015-5007