Pancreatic Cancer’s (PC’s) 5-year survival rate of only 6.7% indicate the need to improve treatment modalities. Despite decades of research, current chemotherapy and radiation therapy regimens offer minimal or no help. It is critical to develop new agents for the effective management of PC. Given that Kras mutations initiate and maintain PC, inhibition of this pathway is widely considered a therapeutic target of exceptional importance. Our laboratory is currently exploring the chemotherapeutic efficacy of a novel Chemically-Modified Curcumin (CMC2.24) as a potential chemotherapeutic agent for PC. Preliminary studies have shown that CMC2.24 has higher bioavailability than curcumin, as shown in pharmacokinetic studies in rats, and inhibits PC growth in vitro and in vivo. However, the exact mechanism on how CMC2.24 reduces cell growth remains unidentified. The objective of this work was to determine the mechanism of CMC2.24 in PC. Using human PC MIA PaCa-2 and Panc-1 cell lines and pancreatic acinar explants from Kras mutant mice, we explored the effects of CMC2.24 on Ras activation, ERK phosphorylation, mitochondrial reactive oxygen species, mitochondrial ATP production, and intrinsic apoptosis. In human PC MIA PaCa-2 cells CMC2.24 inhibited Ras activation by 90% (p<0.05). This was confirmed in primary acinar explants isolated from Kras mutant mice in which CMC treatment reduced Ras activation by 70%, compared to control. Furthermore, CMC 2.24 treatment reduced the phosphorylation MEK, ERK and c-Raf, down-stream pathway of Ras, both in vitro and in vivo. The effect of CMC2.24 on ERK phosphorylation was confirmed by Immunofluorescence, showing a significant decrease in ERK phosphorylation (47.8%; p<0.05). Moreover, CMC2.24 treatment enhanced the levels of superoxide anion in mitochondria by 200% (p<0.02), decreased ATP levels in a concentration-dependent manner (p<0.05), and induced intrinsic apoptosis, as shown by the increase in caspase 9 and Parp cleavage downstream of cytochrome C cytosolic release. In conclusion, our results indicate that the Ras pathway is a key molecular target for CMC2.24 and that CMC induces apoptosis in PC cells through the intrinsic pathway.

This research was supported by the Stony Brook Cancer Center and a URECA Summer Grant.

Citation Format: Naveen Mallangada, Gerardo G. Mackenzie. A novel curcumin derivative inhibits active ras and its downstream pathway in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1182. doi:10.1158/1538-7445.AM2017-1182