We demonstrate that DRE has the potential to induce apoptosis and autophagy in human pancreatic cancer cells with no significant effect on noncancerous cells. This will provide a basis on which further research in cancer treatment through DRE can be executed.

The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.

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.

No abstract