Abstract A171: Cytotoxicity of novel substituted purine derivatives against liver cancer cells

Abstract

Abstract Cytotoxic purine and purine nucleoside analogs (PNA) are widely used in cancer treatment (1). In this study, three newly synthesized substituted purine derivatives, AUM18, AUM23 and AUM32* were evaluated for their cytotoxicities by Sulforhodamine B (SRB) assay initially on Hct116 (colon), T47D (breast), and Huh7 (liver) human carcinoma cell lines (2). The IC50 values for the cell lines analyzed were ∼2.0µM for AUM18, ∼0.5µM for AUM23 and ∼5nM for AUM32. The growth inhibitory effects that we observed with these PNAs were comparable to those of the known anticancer agents Camptothecin (IC50 ∼ 10 nM) and 5-Fluorouracil (IC50 ∼10µM). Subsequently, the cytotoxicity of each molecule was tested on the HCC cell line panel composed of Huh7, HepG2, Hep3B, Mahlavu, PLC, SkHep1, Focus, SNU-182 and SNU-475 cells. The IC50 values were again in micromolar varying between 0.1 to 10 µM range. However, we did not observe significant cytotoxic effect on SNU-182 cells with AUM18 PNA and on SNU-475 with AUM32. The differential inhibition that we observe, can be considered as an indication of the specificity of these inhibitors against their target. They might interfere with the activity of certain kinases rather than acting as a multi-kinase inhibitor. Furthermore, we evaluated the protein kinase activity inhibition potential of these novel purine analogs. Therefore, the kinase assay based on the detection of the amount of ATP in the reaction mixture through bioluminescence was performed with Huh7 and Mahlavu cells. Cells incubated with these novel kinase inhibitor candidates and Staurosporine (STS), a multi-kinase inhibitor used as positive control (4). The relative light units that we observed with novel PNAs were comparable to that of STS. Based on our observations, the newly synthesized PNAs, AUM18, AUM23 and AUM32 can be identified as protein kinase inhibitor candidates which must be further analyzed at the molecular level. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A171.