Nimbolide-Induced Oxidative Stress Abrogates STAT3 Signaling Cascade and Inhibits Tumor Growth in Transgenic Adenocarcinoma of Mouse Prostate Model.

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.

• Authors: Jingwen Zhang, Kwang Seok Ahn, Chulwon Kim, Muthu K Shanmugam, Kodappully Sivaraman Siveen, Frank Arfuso, Ramar Perumal Samym, Amudha Deivasigamanim, Lina Hsiu Kim Lim, Lingzhi Wang, Boon Cher Goh, Alan Prem Kumar, Kam Man Hui, Gautam Sethi
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 24 Issue 11 Pg. 575-89 (Apr 10 2016) ISSN: 1557-7716 [Electronic] United States
• PMID: 26649526 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Limonins
• Reactive Oxygen Species
• STAT3 Transcription Factor
• Stat3 protein, mouse
• nimbolide

Topics

• Adenocarcinoma (drug therapy, pathology)
• Animals
• Antineoplastic Agents (administration & dosage, pharmacology)
• Cell Proliferation (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Drug Screening Assays, Antitumor
• Humans
• Limonins (administration & dosage, pharmacology)
• Male
• Mice
• Mice, Transgenic
• Neoplasms, Experimental (drug therapy, pathology)
• Oxidative Stress (drug effects)
• Prostatic Neoplasms (drug therapy, pathology)
• Reactive Oxygen Species (metabolism)
• STAT3 Transcription Factor (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)