2'-Hydroxyflavanone: A novel strategy for targeting breast cancer
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Jyotsana Singhal1,*, Lokesh Nagaprashantha1,*, Shireen Chikara1, Sanjay Awasthi2, David Horne1 and Sharad S. Singhal1
1Department of Molecular Medicine, Beckman Research Institute of City of Hope, Comprehensive Cancer Center and National Medical Center, Duarte, CA 91010, USA
2Department of Medical Oncology, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
*Authors contributed equally to this work
Sharad S. Singhal, email: [email protected]
Keywords: breast cancer, 2'-hydroxyflavanone, RLIP76, VEGF, xenografts
Received: June 22, 2017 Accepted: July 12, 2017 Published: August 24, 2017
Breast cancer is the most common cancer in women that is driven by cross-talk with hormonal and cellular signaling pathways. The natural phytochemicals, due to broad-spectrum anti-inflammatory and anti-cancerous properties, present with novel opportunities for targeting breast cancer. Intake of citrus fruits is known to reduce the risk for incidence of breast cancer. Hence, we tested the efficacy of citrus flavonoid 2'-hydroxyflavanone (2HF) in breast cancer. 2HF inhibited survival, clonogenic ability, cell cycle progression and induced apoptosis in breast cancer cells. 2HF also decreased VEGF levels and inhibited migratory capacity of breast cancer cells. Administration of 2HF led to regression of triple-negative MDA-MB-231 tumors in the mice xenograft model. 2HF decreased the levels of RLIP76 both in vitro studies and in vivo MDA-MB-231 xenograft model of breast cancer. Western blot and histopathological analyses of resected tumors showed a decline in the levels of survival and proliferation markers Ki67, pAkt, survivin, and cell cycle proteins CDK4 and cyclin B1. 2HF treatment led to inhibition of angiogenesis as determined by decreased VEGF levels in vitro and angiogenesis marker CD31 in vivo. 2HF reversed the pro-/anti-apoptotic ratio of BAX/BCL-2 by decreasing anti-apoptotic protein BCL- 2 and increasing pro-apoptotic proteins BAX and BIM in vivo. 2HF also decreased the mesenchymal markers vimentin and fibronectin along with causing a parallel increase in pro-differentiation protein E-cadherin. Collectively, the ability of 2HF to decrease RLIP76, VEGF and regulate critical proliferative, apoptotic and differentiation proteins together provides strong rationale to further develop 2HF based interventions for targeting breast cancer.
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