HS-1793, a resveratrol analogue, downregulates the expression of hypoxia-induced HIF-1 and VEGF and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model

Kim,Dong Hwan; Sung,Bokyung; Kim,Jin-Ah; Kang,Yong Jung; Hwang,Seong Yeon; Hwang,Na-Lam; Suh,Hongsuk; Choi,Yung Hyun; Im,Eunok; Chung,Hae Young; Kim,Nam Deuk

doi:10.3892/ijo.2017.4058

HS-1793, a resveratrol analogue, downregulates the expression of hypoxia-induced HIF-1 and VEGF and inhibits tumor growth of human breast cancer cells in a nude mouse xenograft model

Authors:
- Dong Hwan Kim
- Bokyung Sung
- Jin-Ah Kim
- Yong Jung Kang
- Seong Yeon Hwang
- Na-Lam Hwang
- Hongsuk Suh
- Yung Hyun Choi
- Eunok Im
- Hae Young Chung
- Nam Deuk Kim
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Affiliations: Department of Pharmacy, Molecular Inflammation Research Center for Aging Intervention, Pusan National University, Busan 46241, Republic of Korea, Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 46241, Republic of Korea, Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 47340, Republic of Korea
Published online on: June 27, 2017 https://doi.org/10.3892/ijo.2017.4058
Pages: 715-723

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Abstract

A synthetic analogue of resveratrol, 4-(6-hydroxy-2-naphtyl)-1,3-benzenediol (HS-1793), with improved photosensitivity and stability profiles, has been recently reported to exert anticancer activity on various cancer cells. However, the molecular mechanism of action and in vivo efficacy of HS-1793 in breast cancer cells have not been fully investigated. In the present study, we evaluated the effect of HS-1793 on hypoxia-inducible factor-1α (HIF-1α), which drives angiogenesis and the growth of solid tumors, in addition to the in vivo therapeutic effects of HS-1793 on breast cancer cells. HS-1793 was found to inhibit hypoxia (1.0% oxygen)-induced HIF-1α expression at the protein level, and its inhibitory effect was more potent than that of resveratrol in MCF-7 and MDA-MB-231 breast cancer cells. Furthermore, HS-1793 reduced the secretion and mRNA expression of vascular endothelial growth factor (VEGF), a key mediator of HIF-1-driven angiogenesis, without affecting cell viability. To evaluate the anticancer effects of HS-1793 in vivo, triple-negative MDA-MB-231 breast cancer xenografts were established in nude mice. HS-1793 significantly suppressed the growth of breast cancer tumor xenografts, without any apparent toxicity. Additionally, decreases in Ki-67, a proliferation index marker, and CD31, a biomarker of microvessel density, were observed in the tumor tissue. Expression of HIF-1 and VEGF was also downregulated in xenograft tumors treated with HS-1793. These in vivo results reinforce the improved anticancer activity of HS-1793 when compared with that of resveratrol. Overall, the present study suggests that the synthetic resveratrol analogue HS-1793 is a potent antitumor agent that inhibits tumor growth via the regulation of HIF-1, and demonstrates significant therapeutic potential for solid cancers.

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