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J Cell Physiol. 2019 Jul;234(7):11276-11286. doi: 10.1002/jcp.27785. Epub 2018 Nov 22.

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

Author information

1
School of Pharmacy and Medical Sciences, and UniSA Cancer Research Institute, University of South Australia, Adelaide, South Australia, Australia.
2
Institute of Orthopaedics, Lanzhou General Hospital of CPLA, Lanzhou, China.
3
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, Gansu, China.
4
Laboratory for Bone Metabolism, Key Laboratory for Space Bioscience and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, Shaanxi, China.
5
Institute for Resilient Regions, University of Southern Queensland, Springfield, Queensland, Australia.
6
Clinical Nutrition Research Centre, University of Newcastle, Callaghan, New South Wales, Australia.
7
Department of Endocrinology, The First Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong, China.
8
Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

Cancer 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.

KEYWORDS:

angiogenesis; apoptosis; bone marrow sinusoidal endothelial cells (BM SECs); genistein

PMID:
30565680
DOI:
10.1002/jcp.27785

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