title: Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model.
abstract: OBJECTIVE
  Prostate cancer (PCa) is one of the most commonly diagnosed cancers worldwide. Currently available therapies for metastatic PCa are only marginally effective, hence novel treatment modalities are urgently required. Considerable evidence(s) suggest that deregulated activation of oncogenic transcription factor, signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the development and progression of PCa. Thus, agents that can abrogate STAT3 activation could form the basis of novel therapy for PCa patients. In the present study, we analyzed whether the potential anticancer effects of nimbolide (NL), a limonoid triterpene derived from Azadirachta indica, against PCa cell lines and transgenic adenocarcinoma of mouse prostate (TRAMP) model are mediated through the negative regulation of STAT3 pathway.
  
  
  RESULTS
  Data from the in vitro studies indicated that NL could significantly inhibit cell viability, induce apoptosis, and suppress cellular invasion and migration. Interestingly, NL also abrogated STAT3 activation and this effect was found to be mediated via an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Oral administration of NL significantly suppressed the tumor growth and metastasis in TRAMP mouse model without exhibiting any significant adverse effects.
  
  
  METHODS
  The present study demonstrates the critical role of GSH/GSSG imbalance-mediated ROS production contributing to the STAT3 inhibitory and tumor-suppressive effect of NL in PCa.
  
  
  CONCLUSIONS
  Overall, our findings indicate that NL exhibits significant anticancer effects in PCa that may be primarily mediated through the ROS-regulated inhibition of STAT3 signaling cascade.
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: 2 College of Korean Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Kwang Seok
authors.initials: KS
authors.lastname: Ahn
authors.affiliation: 2 College of Korean Medicine, Kyung Hee University , Seoul, Republic of Korea.
authors.forename: Chulwon
authors.initials: C
authors.lastname: Kim
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Muthu K
authors.initials: MK
authors.lastname: Shanmugam
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Kodappully Sivaraman
authors.initials: KS
authors.lastname: Siveen
authors.affiliation: 3 School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University , Perth, Australia .
authors.forename: Frank
authors.initials: F
authors.lastname: Arfuso
authors.affiliation: 4 Department of Anatomy, Venom and Toxin Research Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|5 Department of Microbiology Infectious Diseases Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|6 Department of Physiology, NUS Immunology Programme, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Ramar Perumal
authors.initials: RP
authors.lastname: Samym
authors.affiliation: 7 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research , National Cancer Centre, Singapore, Singapore .
authors.forename: Amudha
authors.initials: A
authors.lastname: Deivasigamanim
authors.affiliation: 6 Department of Physiology, NUS Immunology Programme, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .
authors.forename: Lina Hsiu Kim
authors.initials: LH
authors.lastname: Lim
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|8 Centre for Translational Medicine (CeTM), Cancer Science Institute, National University of Singapore , Singapore, Singapore .
authors.forename: Lingzhi
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|8 Centre for Translational Medicine (CeTM), Cancer Science Institute, National University of Singapore , Singapore, Singapore .
authors.forename: Boon Cher
authors.initials: BC
authors.lastname: Goh
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|8 Centre for Translational Medicine (CeTM), Cancer Science Institute, National University of Singapore , Singapore, Singapore .|9 School of Biomedical Sciences, Curtin University , Perth, Australia .|10 Department of Biological Sciences, University of North Texas , Denton, Texas.
authors.forename: Alan Prem
authors.initials: AP
authors.lastname: Kumar
authors.affiliation: 7 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research , National Cancer Centre, Singapore, Singapore .
authors.forename: Kam Man
authors.initials: KM
authors.lastname: Hui
authors.affiliation: 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore .|9 School of Biomedical Sciences, Curtin University , Perth, Australia .
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D036701:Limonins / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D036701:Limonins; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C042198:nimbolide