The mortality and morbidity rates of pancreatic cancer are high because of its extremely invasive and metastatic nature. Its lack of symptoms, late diagnosis and chemo–resistance and the ineffective treatment modalities warrant the development of new chemo–therapeutic agents for pancreatic cancer. Agents from medicinal plants have demonstrated therapeutic benefits in various human cancers. Nimbolide, an active molecule isolated from Azadirachta indica, has been reported to exhibit several medicinal properties. This study assessed the anticancer properties of nimbolide against pancreatic cancer. Our data reveal that nimbolide induces excessive generation of reactive oxygen species (ROS), thereby regulating both apoptosis and autophagy in pancreatic cancer cells. Experiments with the autophagy inhibitors 3-methyladenine and chloroquine diphosphate salt and the apoptosis inhibitor z-VAD-fmk demonstrated that nimbolide-mediated ROS generation inhibited proliferation (through reduced PI3K/AKT/mTOR and ERK signaling) and metastasis (through decreased EMT, invasion, migration and colony forming abilities) via mitochondrial-mediated apoptotic cell death but not via autophagy. In vivo experiments also demonstrated that nimbolide was effective in inhibiting pancreatic cancer growth and metastasis. Overall, our data suggest that nimbolide can serve as a potential chemo–therapeutic agent for pancreatic cancer.

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Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer.