Mechanism of neem limonoids-induced cell death in cancer: Role of oxidative phosphorylation

Publication date: January 2016
Source:Free Radical Biology and Medicine, Volume 90
Author(s): Neelu Yadav, Sandeep Kumar, Rahul Kumar, Pragya Srivastava, Leimin Sun, Peter Rapali, Timothy Marlowe, Andrea Schneider, Joseph R. Inigo, Jordan O'Malley, Ramesh Londonkar, Raghu Gogada, Ajay K. Chaudhary, Nagendra Yadava, Dhyan Chandra
We have previously reported that neem limonoids (neem) induce multiple cancer cell death pathways. Here we dissect the underlying mechanisms of neem-induced apoptotic cell death in cancer. We observed that neem-induced caspase activation does not require Bax/Bak channel-mediated mitochondrial outer membrane permeabilization, permeability transition pore, and mitochondrial fragmentation. Neem enhanced mitochondrial DNA and mitochondrial biomass. While oxidative phosphorylation (OXPHOS) Complex-I activity was decreased, the activities of other OXPHOS complexes including Complex-II and -IV were unaltered. Increased reactive oxygen species (ROS) levels were associated with an increase in mitochondrial biomass and apoptosis upon neem exposure. Complex-I deficiency due to the loss of Ndufa1-encoded MWFE protein inhibited neem-induced caspase activation and apoptosis, but cell death induction was enhanced. Complex II-deficiency due to the loss of succinate dehydrogenase complex subunit C (SDHC) robustly decreased caspase activation, apoptosis, and cell death. Additionally, the ablation of Complexes-I, -III, -IV, and -V together did not inhibit caspase activation. Together, we demonstrate that neem limonoids target OXPHOS system to induce cancer cell death, which does not require upregulation or activation of proapoptotic Bcl-2 family proteins.



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