Nimbolide inhibits androgen independent prostate cancer cells survival and proliferation by modulating multiple pro-survival signaling pathways

Background: Prostate cancer is the most prominent cancer in men, experiencing a relapse in disease often express high serum TNF-alpha levels. It has been correlated with increased cell survival and proliferation of prostate cancer cells. Previous studies reported that nimbolide, a terpenoid derived from the leaves and flowers of neem tree inhibits cancer growth through selective modulation of cell signaling pathways linked to inflammation, survival, proliferation, angiogenesis and metastasis. Methods: The present study aimed to examine the effect of nimbolide at 1 and 2 mu M concentrations on TNF-alpha/TNFR1 mediated signaling molecules involved in cell survival and proliferation in PC-3 cell line via NF-kB and MAPK pathways by real time PCR and western blot. Protein and compound interaction were performed by Molecular docking analysis. Results: Our results indicate that nimbolide treatment suppressed expression of TNF-alpha, SODD, Grb2, SOS mRNA and modulated TNF-alpha/TNFR1 regulated NF-kB and MAPK signaling molecules in PC-3 cells. Additional molecular dynamics simulation studies confirmed the stability of nimbolide and signaling molecules binding interactions. Binding pose analysis revealed the significance of hydrogen bond interactions for effective stabilization of virtual ligand protein complexes. Conclusion: Nimbolide inhibited prostate cancer cell survival and proliferation via NF-kB and MAPK pathways. (C) 2016 Elsevier Masson SAS. All rights reserved.