Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition

Abstract

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.

Deoxyelephantopin Induces Reactive Oxygen Species-Mediated Apoptosis and Autophagy in Human Osteosarcoma Cells

“…7E, 7F), which revealed that the DET-induced autophagy was ROS-dependent. Since autophagy can play both positive and negative roles in tumor cell growth [19, 20], the autophagy inhibitor, chloroquine, was also used in MTT assays to elucidate its role. Nevertheless, autophagy inhibition did not alter the decrease in cell viability (Fig.…”

Pancreatic Cancer: Current Status and Challenges

“…Furthermore, there are currently no published results for clinical trials investigating capsaicin or EGCG in PanCA patients. New studies of natural products, have begun exploring the anti-cancer properties of plant extracts and compounds such as Nexrutine® (Nx), sulforaphane, and Nimbolide in PanCA [103–108]. All three of these natural products have been demonstrated to have clinical potential as they exhibit strong anti-cancer effects in vitro [104–108].…”

“…New studies of natural products, have begun exploring the anti-cancer properties of plant extracts and compounds such as Nexrutine® (Nx), sulforaphane, and Nimbolide in PanCA [103–108]. All three of these natural products have been demonstrated to have clinical potential as they exhibit strong anti-cancer effects in vitro [104–108]. In addition, Nimbolide and sulforaphane have been demonstrated to strongly reduce the size to PanCA xenografts in athymic mice [107, 108].…”

“…All three of these natural products have been demonstrated to have clinical potential as they exhibit strong anti-cancer effects in vitro [104–108]. In addition, Nimbolide and sulforaphane have been demonstrated to strongly reduce the size to PanCA xenografts in athymic mice [107, 108]. Though Nx has not been studied under this type of pre-clinical setting, results thus far indicate that Nx has strong potential for clinical use [103–105].…”

Pancreatic cancer: from bench to bedside

“…FDA granted necuparanib treatment of pancreatic cancer, which is derived from the unfractionated heparin; it is designed to significantly reduce the anticoagulant activity while preserving antitumor properties related. In herbal medicine (29), India Melia lactone can induce cancer cell death, led to the colony size and number of pancreatic cancer cells decreased by 80%, at the same time, does not damage the normal healthy cells. The researchers Mazur (30) found that a BET family protein inhibitor-JQ1 can inhibit the development of PDAC mice by inhibiting the activity of MYC and inflammatory signals.…”