Nimbolide-induced oxidative stress abrogates STAT3 signaling cascade and inhibits tumor growth in transgenic adenocarcinoma of mouse prostate model
MetadataShow full item record
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 Azadirachtaindica, 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.
Showing items related by title, author, creator and subject.
Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical modelKim, C.; Lee, S.; Yang, W.; Arfuso, Frank; Um, J.; Kumar, Alan Prem; Bian, J.; Sethi, G.; Ahn, K. (2018)© 2018 Elsevier B.V. Aberrant reactions of signal transducer and transcriptional activator (STAT) are frequently detected in multiple myeloma (MM) cancers and can upregulate the expression of multiple genes related to ...
Honokiol inhibits signal transducer and activator of transcription-3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP-1Rajendran, P.; Li, F.; Shanmugam, M.; Vali, S.; Abbasi, T.; Kapoor, S.; Ahn, K.; Kumar, Alan Prem; Sethi, G. (2012)The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an ...
Suppression of signal transducer and activator of transcription 3 activation by butein inhibits growth of human hepatocellular carcinoma in vivoRajendran, P.; Ong, T.; Chen, L.; Li, F.; Shanmugam, M.; Vali, S.; Abbasi, T.; Kapoor, S.; Sharma, A.; Kumar, Alan Prem; Hui, K.; Sethi, G. (2011)Purpose: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third cause of global cancer mortality. Increasing evidence suggest that STAT3 is a critical mediator of oncogenic signaling ...