Jingwen Zhang1, Kwang Seok Ahn2, Chulwon Kim2, Muthu K Shanmugam1, Kodappully Sivaraman Siveen1, Frank Arfuso3, Ramar Perumal Samym4,5,6, Amudha Deivasigamanim7, Lina Hsiu Kim Lim6, Lingzhi Wang1,8, Boon Cher Goh1,8, Alan Prem Kumar1,8,9,10, Kam Man Hui7, Gautam Sethi1,9. 1. 1 Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 2. 2 College of Korean Medicine, Kyung Hee University , Seoul, Republic of Korea. 3. 3 School of Biomedical Sciences, CHIRI Biosciences Research Precinct, Curtin University , Perth, Australia . 4. 4 Department of Anatomy, Venom and Toxin Research Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 5. 5 Department of Microbiology Infectious Diseases Programme, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 6. 6 Department of Physiology, NUS Immunology Programme, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore , Singapore, Singapore . 7. 7 Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research , National Cancer Centre, Singapore, Singapore . 8. 8 Centre for Translational Medicine (CeTM), Cancer Science Institute, National University of Singapore , Singapore, Singapore . 9. 9 School of Biomedical Sciences, Curtin University , Perth, Australia . 10. 10 Department of Biological Sciences, University of North Texas , Denton, Texas.
Abstract
AIMS: 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. INNOVATION: 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. CONCLUSION: 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.
AIMS: 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 limonoidtriterpene 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 TRAMPmouse model without exhibiting any significant adverse effects. INNOVATION: 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. CONCLUSION: 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.