Abstract B250: Evaluation of anticancer efficacy of 6-propionylpterin characterized from native isolate Bacillus subtilis.

In this context the present study is aimed at purifying a pteridine derivative and studying its apoptotic effect on a cancer cell line. 6-propionyl pterin have been purified from a native strain of Bacillus subtilis and administered via intra peritoneal injection to DLA induced mice. During the course of the experiment reduction in angiogenesis was visualized. Earlier report (Kim et.al., 2011) clearly suggested that sepiapterin, a precursor of tetrahydrobiopterin inhibits VEGF-A induced HUVEC proliferation and adhesion through down-regulation of VEGFR-2 downstream signaling pathways, independently of NO synthesis and this supported the present finding. Based on our preconceived view that administration of 6-pp enhances the activity of iNOS, thereby enhanced production of nitric oxide (NO), an attempt was made to check the pathway of NO induced apoptosis. The expression of iNOS, p53, caspase 3, and mdm2 gene were checked by RT PCR. But only mdm2 gene expression alone was upregulated. p53 downregulation might be due to Mdm2 which block its transcriptional activity, favours its nuclear export and stimulates its degradation (Chene, 2003). Caspase 3 activation does not participate in Mdm2 induced apoptosis as determined by the protein levels or poly (ADP-ribose) polymerase fragmentation (Dilla et al., 2000). The report of Wolf et al., 1999 strongly suggests that caspase 3 is the primary activator of apoptotic DNA fragmentation. This is inconsistent with our present finding wherein there was absence of DNA fragmentation in apoptotic cells and also expression of caspase 3 was absent. Thus overall mechanism may be initiated by expression of Mdm2 which inturn inhibited p53 expression. Mdm2 might have down regulated Bcl2 followed by a cascade of Caspase 2 and Cyt-c expression. Cyt-c activation might have regulated Caspase -7 and ROCK protein. ROCK is responsible for cell shrinking and membrane blebbing and finally leading to apoptosis. Caspase 3 activation does not participate in Mdm2 induced apoptosis and hence DNA fragmentation is not found. This study was done to evaluate the efficacy of the compound as anticancer agent and whether it induces apoptosis or not. Mechanism of action of drug was predicted from the results obtained. To derive the exact mechanism further study on the signaling proteins has to be performed. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B250. Citation Format: S D. Nisshanthini, R. Sukirtha, S. Achiraman, M. Palaniswamy, Angayarkanni Jayaraman. Evaluation of anticancer efficacy of 6-propionylpterin characterized from native isolate Bacillus subtilis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B250.