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dc.contributor.authorKim, C.
dc.contributor.authorLee, S.
dc.contributor.authorYang, W.
dc.contributor.authorArfuso, Frank
dc.contributor.authorUm, J.
dc.contributor.authorKumar, Alan Prem
dc.contributor.authorBian, J.
dc.contributor.authorSethi, G.
dc.contributor.authorAhn, K.
dc.date.accessioned2018-06-29T12:26:12Z
dc.date.available2018-06-29T12:26:12Z
dc.date.created2018-06-29T12:09:05Z
dc.date.issued2018
dc.identifier.citationKim, C. and Lee, S. and Yang, W. and Arfuso, F. and Um, J. and Kumar, A.P. and Bian, J. et al. 2018. Formononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model. Cancer Letters. 431: pp. 123-141.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/68548
dc.identifier.doi10.1016/j.canlet.2018.05.038
dc.description.abstract

© 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 cell proliferation, survival, metastasis, and angiogenesis. Therefore, agents capable of inhibiting STAT activation can form the basis of novel therapies for MM patients. In the present study, we investigated whether the potential anti-cancer effects of Formononetin (FT), a naturally occurring isoflavone derived from Astragalus membranaceus, Trifolium pratense, Glycyrrhiza glabra, and Pueraria lobata, against MM cell lines and human multiple myeloma xenograft tumors in athymic nu/nu mice model are mediated through the negative regulation of STAT3 and STAT5 pathways. Data from the in vitro studies indicated that FT could significantly inhibit cell viability, and induce apoptosis. Interestingly, FT also suppressed constitutive STAT3 (tyrosine residue 705 and serine residue 727) and STAT5 (tyrosine residue 694/699) activation, which correlated with the suppression of the upstream kinases (JAK1, JAK2, and c-Src) in MM cells, and this effect was found to be mediated via an increased production of reactive oxygen species (ROS) due to GSH/GSSG imbalance. Also, FT abrogated STAT3 and STAT5 DNA binding capacity and nuclear translocation. FT induced cell cycle arrest, downregulated the expression of STAT3-regulated anti-apoptotic, angiogenetic, and proliferative gene products; and this correlated with induction of caspase-3 activation and cleavage of PARP. Intraperitoneal administration of FT significantly suppressed the tumor growth in the multiple myeloma xenograft mouse model without exhibiting any significant adverse effects. Overall, our findings indicate that FT exhibits significant anti-cancer effects in MM that may be primarily mediated through the ROS-regulated inhibition of the STAT3 and STAT5 signaling cascade.

dc.publisherElsevier
dc.titleFormononetin-induced oxidative stress abrogates the activation of STAT3/5 signaling axis and suppresses the tumor growth in multiple myeloma preclinical model
dc.typeJournal Article
dcterms.source.volume431
dcterms.source.startPage123
dcterms.source.endPage141
dcterms.source.issn0304-3835
dcterms.source.titleCancer Letters
curtin.departmentSchool of Pharmacy and Biomedical Sciences
curtin.accessStatusFulltext not available


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