Abstract 2264: Anticancer effect of gedunin against pancreatic cancer cell lines

Pancreatic cancer is 4th leading cause of cancer related deaths. It is highly aggressive and resistant to most chemotherapeutic treatments. Unfortunately, treatment options for pancreatic cancer are limited, leading to a poor prognosis and high mortality rates. The development of resistance to chemotherapeutic agents is a major obstacle to the treatment of cancer. Current therapies often target a single oncogenic protein; due to genetic plasticity/instability, pancreatic cancer cells are able to circumvent the drug effects. This type of resistance may be avoided, if multiple cancer signaling pathways are targeted simultaneously with a single therapeutic agent. Thus, novel therapeutic approaches are needed to treat pancreatic cancer. Natural products have been shown to play an important role as anticancer agents. Neem (Azadirachta indica) tree is known for its medicinal values. All parts of the tree including leaves, flowers, seeds, fruits, roots and bark are known to possess a wide range of medicinal properties. Neem leaf extracts, which are non-toxic and non-mutagenic, have been shown to possess anti-inflammatory, antioxidant, anticarcinogenic, and potent immuno-stimulant activities in many cancer cells. We have demonstrated that ethanolic fraction of neem leaves has potent anticancer effect against mammary carcinogenesis. Gedunin is a tetraterpinoid isolated from neem leaves. Gedunin has been established as a potent inhibitor of heat shock protein 90 (Hsp90). The family of 90 kDa heat shock proteins (Hsp90) has emerged as a novel drug target that mediates multiple signaling nodes to combat cancer. In the current study, we investigated the anticancer effect of gedunin against pancreatic cancer cell lines. Our preliminary data clearly demonstrates that gedunin inhibits the growth of pancreatic cancer cell lines. We also explored the molecular mechanism underlying the anti-cancer effect of gedunin on pancreatic cancer cells. As expected gedunin decreased the expression of Hsp90. Gedunin treatment also decreased the phosphorylation of mTOR, 4EBP. Furthermore, gedunin also induced autophagy and apoptosis simultaneously by regulating key factors involved in these processes like LC3B, WIPI-1, VMP-1, pJNK, cleavage of caspases and PARP. Overall, our preliminary results strongly suggest that gedunin could be a potential anticancer compound for the treatment of pancreatic cancer. Citation Format: Thiyagarajan Boopalan, Anirudh Chaudhary, Sowmiya Murali, Arunkumar