부산대학교 도서관

Pancreatic cancer is amongst the deadliest cancers in the world. It is associated with poor prognosis, is notorious for developing chemoresistance, and very few approved chemotherapeutics are available to treat this disease. The natural compound pancratistatin (PST) has shown to effectively induce cytotoxicity selectively in numerous cancer cell types. However, it is present in only minute quantities in its natural source and many complications have burdened its chemical synthesis. We have overcome these bottlenecks by synthesizing a C-1 acetoxymethyl analogue of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), which we have shown to have similar selective anti-cancer activity to that of PST. In this report, we show JCTH-4 to be a potent chemotherapeutic against pancreatic cancer cells (BxPC-3, PANC-1). It induced apoptosis selectively in BxPC-3 and PANC-1 cells by targeting the mitochondria; it dissipated mitochondrial membrane potential, caused release of apoptogenic factors, and in isolated mitochondria, increased the generation of reactive oxygen species. Furthermore, JCTH-4 selectively induced autophagy in pancreatic cancer cells while normal human fetal fibroblasts were markedly less sensitive to JCTH-4 insult. Altogether, this study outlines JCTH-4 as a potentially safe and effective chemotherapeutic agent in treating notoriously chemoresistant pancreatic cancer. [ABSTRACT FROM AUTHOR]