title: Nimbolide inhibits androgen independent prostate cancer cells survival and proliferation by modulating multiple pro-survival signaling pathways.
abstract: BACKGROUND
  Prostate cancer is the most prominent cancer in men, experiencing a relapse in disease often express high serum TNF-α 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 2μM concentrations on TNF-α/TNFR1 mediated signaling molecules involved in cell survival and proliferation in PC-3 cell line via NF-κB 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-α, SODD, Grb2, SOS mRNA and modulated TNF-α/TNFR1 regulated NF-κB 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.
  
  
  CONCLUSIONS
  Nimbolide inhibited prostate cancer cell survival and proliferation via NF-κB and MAPK pathways.
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
authors.forename: P Raja
authors.initials: PR
authors.lastname: Singh
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
authors.forename: E Sugantha
authors.initials: ES
authors.lastname: Priya
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
authors.forename: S
authors.initials: S
authors.lastname: Balakrishnan
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
authors.forename: R
authors.initials: R
authors.lastname: Arunkumar
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India.
authors.forename: G
authors.initials: G
authors.lastname: Sharmila
authors.affiliation: PG & Research Department of Biotechnology & Bioinformatics, Holy Cross College, Tiruchirapalli, 620 002, India.
authors.forename: M
authors.initials: M
authors.lastname: Rajalakshmi
authors.affiliation: Department of Endocrinology, Dr. ALM. Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai, 600 113, India. Electronic address: j_arunakaran@hotmail.com.
authors.forename: J
authors.initials: J
authors.lastname: Arunakaran
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D036701:Limonins / Q000737:chemistry / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D062105:Molecular Docking Simulation; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D036701:Limonins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; C042198:nimbolide
keywords: Cell survival and proliferation; Docking; NF-κB and MAPK pathway; Nimbolide; Prostate cancer; TNF-α; TNFR1