A novel resveratrol analogue, HS-1793, inhibits hypoxia-induced HIF-1α and VEGF expression, and migration in human prostate cancer cells

Kim,Dong   Hwan; Hossain,Mohammad   Akbar; Kim,Min  Young; Kim,Jin-Ah; Yoon,Jeong-Hyun; Suh,Hong   Suk; Kim,Gi-Young; Choi,Yung   Hyun; Chung,Hae   Young; Kim,Nam  Deuk

doi:10.3892/ijo.2013.2116

A novel resveratrol analogue, HS-1793, inhibits hypoxia-induced HIF-1α and VEGF expression, and migration in human prostate cancer cells

Authors:
- Dong Hwan Kim
- Mohammad Akbar Hossain
- Min Young Kim
- Jin-Ah Kim
- Jeong-Hyun Yoon
- Hong Suk Suh
- Gi-Young Kim
- Yung Hyun Choi
- 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 609-735, Republic of Korea, Department of Chemistry and Chemistry Institute for Functional Materials, Pusan National University, Busan 609-735, Republic of Korea, Faculty of Applied Marine Science, Cheju National University, Jeju 690-756, Republic of Korea, Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan 614-052, Republic of Korea
Published online on: October 2, 2013 https://doi.org/10.3892/ijo.2013.2116
Pages: 1915-1924

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Abstract

In many studies, resveratrol has been shown to have a chemopreventive effect in various types of cancer cells. However, the biological activity of resveratrol is limited by its photosensitivity and metabolic instability. This study investigated the effects of a novel analogue of resveratrol, HS-1793, on the expression of HIF-1α and vascular endothelial growth factor (VEGF) in PC-3 human prostate cancer cells. Hypoxic condition induced HIF-1α protein level in PC-3 cells in a time‑dependent manner, and treatment with HS-1793 markedly decreased HIF-1α expression levels. HS-1793 also inhibited VEGF level. Mechanistically, HS-1793 inhibited HIF-1α and VEGF expression through multiple mechanisms. Firstly, HS-1793 inhibited phosphorylation of PI3K and Akt in PC-3 cells. Furthermore, HS-1793 substantially induced HIF-1α protein degradation through the proteasome pathway. Finally, HS-1793 inhibited hypoxia-induced PC-3 cell migration. These data suggest that HS-1793 may inhibit human prostate cancer progression and angiogenesis by inhibiting the expression of HIF-1α and VEGF. Moreover, HS-1793 showed more potent effects than resveratrol on the cytotoxic effects on PC-3 cells. Taken together, these results implied that HS-1793, a novel analogue of resveratrol, may be a new potent chemopreventive agent against human prostate cancer cells.

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1.	Semenza GL: Hypoxia and cancer. Cancer Metastasis Rev. 26:223–224. 2007. View Article : Google Scholar
2.	Harris AL: Hypoxia - a key regulatory factor in tumour growth. Nat Rev Cancer. 2:38–47. 2002. View Article : Google Scholar : PubMed/NCBI
3.	Semenza GL: Regulation of cancer cell metabolism by hypoxia-inducible factor 1. Semin Cancer Biol. 19:12–16. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Baek JH, Jang JE, Kang CM, Chung HY, Kim ND and Kim KW: Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene. 19:4621–4631. 2000. View Article : Google Scholar : PubMed/NCBI
5.	Semenza GL: Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 33:207–214. 2012. View Article : Google Scholar : PubMed/NCBI
6.	Al-Ubaidi FL, Schultz N, Egevad L, Granfors T and Helleday T: Castration therapy of prostate cancer results in downregulation of HIF-1alpha levels. Int J Radiat Oncol Biol Phys. 82:1243–1248. 2012. View Article : Google Scholar : PubMed/NCBI
7.	Marignol L, Rivera-Figueroa K, Lynch T and Hollywood D: Hypoxia, notch signalling, and prostate cancer. Nat Rev Urol. 10:405–413. 2013. View Article : Google Scholar : PubMed/NCBI
8.	Szliszka E, Czuba ZP, Domino M, Mazur B, Zydowicz G and Krol W: Ethanolic extract of propolis (EEP) enhances the apoptosis-inducing potential of TRAIL in cancer cells. Molecules. 14:738–754. 2009. View Article : Google Scholar : PubMed/NCBI
9.	Syed DN, Suh Y, Afaq F and Mukhtar H: Dietary agents for chemoprevention of prostate cancer. Cancer Lett. 265:167–176. 2008. View Article : Google Scholar : PubMed/NCBI
10.	Santos JA, de Carvaho GS, Oliveira V, Raposo NR and da Silva AD: Resveratrol and analogues: a review of antioxidant activity and applications to human health. Recent Pat Food Nutr Agric. 5:144–153. 2013. View Article : Google Scholar : PubMed/NCBI
11.	Benitez DA, Pozo-Guisado E, Alvarez-Barrientos A, Fernandez-Salguero PM and Castellon EA: Mechanisms involved in resveratrol-induced apoptosis and cell cycle arrest in prostate cancer-derived cell lines. J Androl. 28:282–293. 2007. View Article : Google Scholar : PubMed/NCBI
12.	Cao Z, Fang J, Xia C, Shi X and Jiang BH: trans-3,4,5′-Trihydroxystibene inhibits hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in human ovarian cancer cells. Clin Cancer Res. 10:5253–5263. 2004.
13.	Zhang Q, Tang X, Lu QY, Zhang ZF, Brown J and Le AD: Resveratrol inhibits hypoxia-induced accumulation of hypoxiainducible factor-1alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. Mol Cancer Ther. 4:1465–1474. 2005. View Article : Google Scholar : PubMed/NCBI
14.	Park SY, Jeong KJ, Lee J, et al: Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: their inhibition by resveratrol. Cancer Lett. 258:63–69. 2007. View Article : Google Scholar : PubMed/NCBI
15.	Jeong SH, Lee JS, Jeong NY, et al: A novel resveratrol analogue HS-1793 treatment overcomes the resistance conferred by Bcl-2 and is associated with the formation of mature PML nuclear bodies in renal clear cell carcinoma Caki-1 cells. Int J Oncol. 35:1353–1360. 2009.
16.	Ha YM, Chung SW, Song S, Lee H, Suh H and Chung HY: 4-(6-Hydroxy-2-naphthyl)-1,3-bezendiol: a potent, new tyrosinase inhibitor. Biol Pharm Bull. 30:1711–1715. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Jeong SH, Hanh TM, Kim HK, et al: HS-1793, a recently developed resveratrol analogue protects rat heart against hypoxia/reoxygenation injury via attenuating mitochondrial damage. Bioorg Med Chem Lett. 23:4225–4229. 2013. View Article : Google Scholar
18.	Um HJ, Bae JH, Park JW, et al: Differential effects of resveratrol and novel resveratrol derivative, HS-1793, on endoplasmic reticulum stress-mediated apoptosis and Akt inactivation. Int J Oncol. 36:1007–1013. 2010.PubMed/NCBI
19.	Jeong SH, Song IS, Kim HK, et al: An analogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 cells via inhibition of mitochondrial biogenesis gene expression. Mol Cells. 34:357–365. 2012. View Article : Google Scholar : PubMed/NCBI
20.	Kim HJ, Yang KM, Park YS, et al: The novel resveratrol analogue HS-1793 induces apoptosis via the mitochondrial pathway in murine breast cancer cells. Int J Oncol. 41:1628–1634. 2012.PubMed/NCBI
21.	Jeong SH, Jo WS, Song S, et al: A novel resveratrol derivative, HS1793, overcomes the resistance conferred by Bcl-2 in human leukemic U937 cells. Biochem Pharmacol. 77:1337–1347. 2009. View Article : Google Scholar
22.	Jeong MH, Yang KM, Choi YJ, et al: Resveratrol analog, HS-1793 enhance anti-tumor immunity by reducing the CD4⁺CD25⁺ regulatory T cells in FM3A tumor bearing mice. Int Immunopharmacol. 14:328–333. 2012. View Article : Google Scholar : PubMed/NCBI
23.	Choi YJ, Yang KM, Kim SD, et al: Resveratrol analogue HS-1793 induces the modulation of tumor-derived T cells. Exp Ther Med. 3:592–598. 2012.PubMed/NCBI
24.	Jeong NY, Yoon YG, Rho JH, et al: The novel resveratrol analog HS-1793-induced polyploid LNCaP prostate cancer cells are vulnerable to downregulation of Bcl-xL. Int J Oncol. 38:1597–1604. 2011.PubMed/NCBI
25.	Semenza GL: Hypoxia, clonal selection, and the role of HIF-1 in tumor progression. Crit Rev Biochem Mol Biol. 35:71–103. 2000. View Article : Google Scholar : PubMed/NCBI
26.	Semenza G: Signal transduction to hypoxia-inducible factor 1. Biochem Pharmacol. 64:993–998. 2002. View Article : Google Scholar : PubMed/NCBI
27.	Wu H, Liang X, Fang Y, Qin X, Zhang Y and Liu J: Resveratrol inhibits hypoxia-induced metastasis potential enhancement by restricting hypoxia-induced factor-1 alpha expression in colon carcinoma cells. Biomed Pharmacother. 62:613–621. 2008. View Article : Google Scholar
28.	Copple BL, Bustamante JJ, Welch TP, Kim ND and Moon JO: Hypoxia-inducible factor-dependent production of profibrotic mediators by hypoxic hepatocytes. Liver Int. 29:1010–1021. 2009. View Article : Google Scholar : PubMed/NCBI
29.	Yasuda H: Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. Nitric Oxide. 19:205–216. 2008. View Article : Google Scholar
30.	Thorpe JF, Jain S, Marczylo TH, Gescher AJ, Steward WP and Mellon JK: A review of phase III clinical trials of prostate cancer chemoprevention. Ann R Coll Surg Engl. 89:207–211. 2007. View Article : Google Scholar : PubMed/NCBI
31.	Fernandez PL, Hernandez L, Farre X, Campo E and Cardesa A: Alterations of cell cycle-regulatory genes in prostate cancer. Pathobiology. 70:1–10. 2002. View Article : Google Scholar : PubMed/NCBI
32.	Antonarakis ES and Carducci MA: Targeting angiogenesis for the treatment of prostate cancer. Expert Opin Ther Targets. 16:365–376. 2012. View Article : Google Scholar : PubMed/NCBI
33.	Cottart CH, Nivet-Antoine V and Beaudeux JL: Review of recent data on the metabolism, biological effects, and toxicity of resveratrol in humans. Mol Nutr Food Res June. 6:doi: 10.1002/mnfr.201200589. 2013.PubMed/NCBI
34.	Arvelo F and Cotte C: Hypoxia in cancer malignity. Review. Invest Clin. 50:529–546. 2009.(In Spanish).
35.	Mirzoeva S, Kim ND, Chiu K, Franzen CA, Bergan RC and Pelling JC: Inhibition of HIF-1 alpha and VEGF expression by the chemopreventive bioflavonoid apigenin is accompanied by Akt inhibition in human prostate carcinoma PC3-M cells. Mol Carcinog. 47:686–700. 2008. View Article : Google Scholar : PubMed/NCBI
36.	Krishnamachary B, Berg-Dixon S, Kelly B, et al: Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63:1138–1143. 2003.PubMed/NCBI