Flavonoid genistein protects bone marrow sinusoidal blood vessels from damage by methotrexate therapy in rats

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dc.contributor.authorHassanshahi, M.
dc.contributor.authorSu, Y.W.
dc.contributor.authorKhabbazi, S.
dc.contributor.authorFan, C.M.
dc.contributor.authorChen, K.M.
dc.contributor.authorWang, J.F.
dc.contributor.authorQian, A.
dc.contributor.authorHowe, P.R.
dc.contributor.authorYan, D.W.
dc.contributor.authorZhou, H.D.
dc.contributor.authorXian, C.J.
dc.date.issued2019
dc.description.abstractCancer chemotherapy can cause significant damage to the bone marrow (BM) microvascular (sinusoidal) system. Investigations must now address whether and how BM sinusoidal endothelial cells (SECs) can be protected during chemotherapy. Herein we examined the potential protective effects of genistein, a soy-derived flavonoid, against BM sinusoidal damage caused by treatment with methotrexate (MTX). The groups of young adult rats were gavaged daily with genistein (20 mg/kg) or placebo. After 1 week, rats also received daily injections of MTX (0.75 mg/kg) or saline for 5 days and were killed after a further 4 days. Histological analyses showed that BM sinusoids were markedly dilated ( p < 0.001) in the MTX-alone group but were unaffected or less dilated in the genistein+MTX group. In control rats, genistein significantly enhanced expression of vascular endothelial growth factor (VEGF; p < 0.01), particularly in osteoblasts, and angiogenesis marker CD31 ( p < 0.001) in bone. In MTX-treated rats, genistein suppressed MTX-induced apoptosis of BM SECs ( p < 0.001 vs MTX alone group) and tended to increase expression of CD31 and VEGF ( p < 0.05). Our in vitro studies showed that genistein in certain concentrations protected cultured SECs from MTX cytotoxic effects. Genistein enhanced tube formation of cultured SECs, which is associated with its ability to induce expression of endothelial nitric oxide synthase and production of nitric oxide. These data suggest that genistein can protect BM sinusoids during MTX therapy, which is associated, at least partially, with its indirect effect of promoting VEGF expression in osteoblasts and its direct effect of enhancing nitric oxide production in SECs.
dc.description.statementofresponsibilityMohammadhossein Hassanshahi, Yu‐Wen Su, Samira Khabbazi, Chia‐Ming Fan, Ke‐Ming Chen, Ju‐Fang Wang, Airong Qian, Peter R. Howe, De‐Wen Yan, Hou‐De Zhou, Cory J. Xian
dc.identifier.citationJournal of Cellular Physiology, 2019; 234(7):11276-11286
dc.identifier.doi10.1002/jcp.27785
dc.identifier.issn0021-9541
dc.identifier.issn1097-4652
dc.identifier.orcidHassanshahi, M. [0000-0002-4097-8527]
dc.identifier.orcidKhabbazi, S. [0000-0002-5410-795X]
dc.identifier.orcidHowe, P.R. [0000-0001-6546-7742]
dc.identifier.orcidXian, C.J. [0000-0002-8467-2845]
dc.identifier.urihttp://hdl.handle.net/2440/119545
dc.language.isoen
dc.publisherWiley Online Library
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/508046
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/508047
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1010752
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1127396
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1042105
dc.rights© 2018 Wiley Periodicals, Inc.
dc.source.urihttps://doi.org/10.1002/jcp.27785
dc.subjectangiogenesis
dc.subjectapoptosis
dc.subjectbone marrow sinusoidal endothelial cells (BM SECs)
dc.subjectgenistein
dc.titleFlavonoid genistein protects bone marrow sinusoidal blood vessels from damage by methotrexate therapy in rats
dc.typeJournal article
pubs.publication-statusPublished

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