Nimbolide reduces CD44 positive cell population and induces mitochondrial apoptosis in pancreatic cancer cells

• Published in: Cancer letters 2018-01, Vol.413, p.82-93
• Main Authors: Kumar, Sandeep, Inigo, Joseph R., Kumar, Rahul, Chaudhary, Ajay K., O'Malley, Jordan, Balachandar, Srimmitha, Wang, Jianmin, Attwood, Kristopher, Yadav, Neelu, Hochwald, Steven, Wang, Xinjiang, Chandra, Dhyan
• Format: Article
• Language: English
• Subjects: Adenocarcinoma; Antineoplastic Agents, Phytogenic - pharmacology; Antitumor agents; Apoptosis; Apoptosis - drug effects; Cancer stem cells; Cancer therapies; Carcinoma, Pancreatic Ductal - drug therapy; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Caspase Inhibitors - pharmacology; CD44 antigen; Cell death; Cell Line, Tumor; Cell Movement - drug effects; Cells; Chemotherapy; Curcumin; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; Disease; Dose-Response Relationship, Drug; Gemcitabine; Growth factors; Humans; Hyaluronan Receptors - metabolism; Immunoglobulins; Kinases; Life sciences; Limonins - pharmacology; Medical treatment; Metastasis; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mutant p53; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nimbolide; p53 Protein; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Penicillin; Reactive oxygen species; Reactive Oxygen Species - metabolism; Thyroid cancer; Time Factors; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2017.10.029

Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive disease and current treatment regimens fail to effectively cure PDAC. Development of resistance to current therapy is one of the key reasons for this outcome. Nimbolide (NL), a triterpenoid obtained from Azadirachta indica, exhibits anticancer properties in various cancer including PDAC cells. However, the underlying mechanism of this anticancer agent in PDAC cells remains undefined. We show that NL exerts a higher level of apoptotic cell death compared to the first-line agent gemcitabine for PDAC, as well as other anticancer agents including sorafenib and curcumin. The anticancer efficacy of NL was further evidenced by a reduction in the CD44+ as well as cancer stem-like cell (CSC) population, as it causes decreased sphere formation. Mechanistically, the anticancer efficacy of NL associates with reduced mutant p53 as well as increased mitochondrial activity in the form of increased mitochondrial reactive oxygen species and mitochondrial mass. Together, this study highlights the therapeutic potential of NL in mutant p53 expressing pancreatic cancer. •Nimbolide is a more effective caspase activator compared to gemcitabine.•Nimbolide treatment depletes CD44+ population in pancreatic cancer cells.•Nimbolide-induced apoptosis associates with increased mitochondrial activity.•Reduced levels of mutant p53 may contribute to anticancer effects of nimbolide.