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

Abstract

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 Arumugam, Rebecca Lopez, Sushmita Nandy, Christina Gutierrez, Jacqueline Parada, Pamela Agullo, Rajkumar Lakshmanaswamy. Anticancer effect of gedunin against pancreatic cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2264. doi:10.1158/1538-7445.AM2013-2264

Biological Activities of Gedunin—A Limonoid from the Meliaceae Family

“…Later, using a similar approach and the LNCaP cell line as well, it was shown that gedunin inhibited Hsp90 activity and Hsp90 clients, including AR [38]. Boopalan et al [39] demonstrated that gedunin inhibited the growth of cancer cells and decreased the expression of Hsp90 and phosphorylation of mTOR and 4EBP. Gedunin also induced autophagy and apoptosis simultaneously by regulating key factors like LC3B, WIPI-1, VMP-1, pJNK, cleavage of caspases, and PARP.…”

Induction of apoptosis in response to improved gedunin by liposomal nano-encapsulation in human non-small-cell lung cancer (NCI-H292) cell line

“…Anti-proliferative effects of gedunin have also been reported in several cancer cells such as colon, prostate, ovarian, pancreatic, breast and cervical. However, anti-proliferative effects of gedunin in lung cancer have not been evaluated so far [7,8]. Since gedunin is poorly soluble (due to hydrophobic nature) in the aqueous extracellular environment which limits its bioavailability and pharmacokinetic profile, we hypothesize that nano-formulations of gedunin may enhance its anti-proliferative and apoptotic effects in lung cancer cells.Therefore, this study was planned to evaluate anti-proliferative and apoptotic effects of gedunin-loaded liposomal nano-particles in human non-small-cell lung cancer (NCI-H292) cell line.…”