Abstract 1687: A novel PKC inhibitor: Inhibition of cell proliferation in cancer cell lines and pharmacokinetics in Sprague-Dawley rats

Abstract

Abstract Background: Cancer treatment by conventional chemotherapy is hindered by toxic side effects and the frequent development of multi-drug resistance by cancer cells. Cytotoxic peptides are a promising class of drugs that avoid the shortcomings of conventional chemotherapy because certain peptides exhibit selective cytotoxicity against a broad spectrum of human cancer cells (Mader J.S. and Hoskin D.W., 2006). Protein kinase C (PKC) is a family of kinases involved in the transduction of signals for cell proliferation, differentiation, angiogenesis, migration and apoptosis. PKC has been implicated in tumorigenesis (Griner E.M. and Kazanietz M.G., 2007). PharmaGap based its anticancer therapy strategy on the use of proprietary computer modelling for the design of novel cytotoxic peptide candidates for select PKC peptides in order to develop novel drugs targeting PKC. Objective: 1) To test novel GAP-107B8 peptide-based PKC inhibitors’ capability to inhibit cell proliferation in various cancer cell lines; and 2) To gather information about the pharmacokinetics of an inhibitor in a rodent model. Methods: Cell proliferation was measured in LS513 colon, A2780cp ovarian, and ES-2 ovarian cancer cell lines after treatment with different peptides (concentrations in the micromolar range) up to 48 hours. Proliferation was measured using CyQuant Assay and data was normalized to untreated controls. Pharmacokinetic data was obtained from a bolus study and from a 2 hour continuous infusion study performed in Sprague-Dawley rats. Single bolus doses ranged from 1.0 to 5.5 mg/kg. Blood sampling was obtained over 120 minutes following administration. Doses for the 2 hour continuous infusion study ranged from 10 to 40 mg/kg. Blood sampling was obtained prior to infusion start, and up to 120 minutes post-infusion. Plasma was used for all subsequent pharmacokinetic analyses. Results: In different screenings, a peptide dose-response inhibition on cell proliferation was observed in all cell lines tested. In one screening study, at the highest peptide concentration after a 48 hour incubation, the peptide decreased proliferation by 67%, 71%, and 28% in LS513, A2780cp, and ES-2 cells respectively. Another screening showed decreased proliferation by 92%, 92%, and 75% in LS513, A2780cp, and ES-2 cells respectively. From the bolus study it was found that the pharmacokinetic profiles of the cytotoxic peptide were similar for all doses and for both genders. Elimination appeared to be biphasic, and plasma half-life values were dose dependent. Exposure, based on AUC0-t, increased in a dose related fashion (pseudo linear) for both genders. Conclusions: Novel PKC inhibitors have been found to inhibit cell proliferation of various cancer cell lines. The first pharmacokinetic data for these novel inhibitors was obtained after a bolus and an infusion study. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1687. doi:10.1158/1538-7445.AM2011-1687