Antiandrogenic Activity of Resveratrol Analogs in Prostate Cancer LNCaP Cells

Iguchi, Kazuhiro; Toyama, Tomoaki; Ito, Tetsuro; Shakui, Toshinobu; Usui, Shigeyuki; Oyama, Masayoshi; Iinuma, Munekazu; Hirano, Kazuyuki

doi:10.2164/jandrol.112.016782

Cited by 29 publications

(16 citation statements)

References 21 publications

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“…Therefore, clinical trials in human gliomas are urgently required. Currently, analogs of Res with improved bioviability are being developed as potential anticancer agents, and clinical trials of Res against some other cancers are being conducted (54,55). It is expected that Res will provide at least an adjuvant for currently available combined therapy against malignant gliomas.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways

Wang¹,

Dai

et al. 2015

International Journal of Oncology

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Abstract. Resveratrol (Res), a natural polyphenolic compound, has anticancer activity in a variety of cancers. In the present study, the antitumor effect and underlying molecular mechanism of Res on rat C6 glioma growth was studied. The results demonstrated that Res inhibited glioma cell proliferation, arrested cell cycle in S phase and induced apoptosis in vitro. Res also suppressed intracranial C6 tumor growth in vivo and prolonged survival in a fraction of the rats bearing intracranial gliomas. Res significantltly downregulated the specific miRs, including miR-21, miR-30a-5p and miR-19, which have been identified as oncomiRs in our previous studies, and altered the expression of their targeting and crucial genes for glioma formation and progression such as p53, PTEN, EGFR, STAT3, COX-2, NF-κB and PI3K/AKT/mTOR pathway. Therefore, the anti-glioma effect of Res, at least in part, is through the regulation of oncogenic miRNAs. The effect of Res on noncoding RNAs should be studied further. Res is a potential multi-targeting drug for the treatment of gliomas. IntroductionMalignant gliomas are the most common and highly aggressive primary brain tumors. Even using multiple modalities of treatment, including maximal safe resection, radiotherapy, and chemotherapy, the prognosis of patients with malignant gliomas remains dismal (1,2). Therefore, novel therapeutic strategies and drugs for treatment of malignant gliomas are urgently required.A large number of chemopreventive and chemotherapeutic agents have been discovered from natural products and provided promising approaches to treat and prevent cancer (3,4). Res (3,5,4'-trihydroxy-trans-stilbene), a naturally polyphenolic compound, has been identified in the skin of red grapes, peanuts and various food products. It has a variety of important biological effects such as suppression of platelet aggregation, anti-inflammatory, anti-oxidant, and vasorelaxant activities (5-7). Res also exhibits antitumor properties by blocking the three stages of carcinogenesis, initiation, promotion and progression (8). Res has exerted anticancer effects against prostate, breast, leukemia and other epithelial cancer cells. There are some reports on the studies of the treatment of gliomas with Res (9-12) but the molecular mechanism of its antitumorigenic or chemopreventive activities is complex and not fully understood.The objective of the present study was to investigate the anti-proliferative effect of Res on glioma cells using both in vitro and in vivo models. It is well known that small non-coding regulatory RNAs -microRNAs (miRs) are found to be dysregulated in almost all types of cancers and play important roles in cancer development and progression (13)(14)(15)(16)(17). Recent studies have demonstrated that miRs can be regulated by natural agents such as curcumin and Res resulting in suppression of tumor growth, drug resistance and metastasis (18-21). Our previous studies have confirmed that specific miRs, including miR-21, miR19 and miR-30a-5p are upregulated in GBMs with significa...

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Section: Discussionmentioning

confidence: 99%

Resveratrol inhibits glioma cell growth via targeting oncogenic microRNAs and multiple signaling pathways

Wang¹,

Dai

et al. 2015

International Journal of Oncology

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“…The 3,5-dihydroxyl groups of resveratrol are required for direct interaction with CBR1 (14). Furthermore, the transcriptional activity of androgen receptor is inhibited by resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not by 3,5-dimethoxy-4′-hydroxy-trans-stilbene (40). In contrast, the 4′-hydroxyl group of resveratrol is required for enhancing the transcriptional activity of estrogen receptor a (41).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Reduces the Hypoxia-Induced Resistance to Doxorubicin in Breast Cancer Cells

Mitani

Ito

Harada

et al. 2014

J Nutr Sci Vitaminol

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Summary Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is known to enhance the cytotoxicity of the anticancer drug doxorubicin. On the other hand, breast cancer MCF-7 cells acquire resistance to doxorubicin under hypoxic conditions. In this study, we investigated the effect of resveratrol on hypoxia-induced resistance to doxorubicin in MCF-7 cells. Resveratrol and its derivative 3,5-dihydroxy-4′-methoxy-trans-stilbene, but not 3,5-dimethoxy-4′-hydroxy-trans-stilbene, cancelled hypoxia-induced resistance to doxorubicin at a concentration of 10 mm. Carbonyl reductase 1 (CBR1) catalyzes the conversion of doxorubicin to its metabolite doxorubicinol, which is much less effective than doxorubicin. Hypoxia increased the expression of CBR1 at both mRNA and protein levels, and knockdown of CBR1 inhibited hypoxia-induced resistance to doxorubicin in MCF-7 cells. Knockdown of hypoxiainducible factor (HIF)-1a repressed the hypoxia-induced expression of CBR1. Resveratrol repressed the expression of HIF-1a protein, but not HIF-1a mRNA, and decreased hypoxiaactivated HIF-1 activity. Resveratrol repressed the hypoxia-induced expression of CBR1 at both mRNA and protein levels. Likewise, 3,5-dihydroxy-4′-methoxy-trans-stilbene decreased the hypoxia-induced expression of CBR1 protein, but not 3,5-dimethoxy-4′-hydroxy-transstilbene. Furthermore, resveratrol decreased the expression of HIF-1a protein even in the presence of the proteasome inhibitor MG132 in hypoxia. Theses results indicate that in MCF-7 cells, HIF-1a-increased CBR1 expression plays an important role in hypoxia-induced resistance to doxorubicin and that resveratrol and 3,5-dihydroxy-4′-methoxy-trans-stilbene decrease CBR1 expression by decreasing HIF-1a protein expression, perhaps through a proteasome-independent pathway, and consequently repress hypoxia-induced resistance to doxorubicin.

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“…This effect was accompanied by a decrease of β-tubulin, a marker of metastatic melanoma cells. The increased anti-androgenic activity brought by a methoxy group on the C-4' of resveratrol and its analogs provided a more potent inhibition against prostate cancer cell LNCaP proliferation (31). In earlier studies about anti-androgen transcription, resveratrol was used at a concentration of 50 μM or higher, whereas in this study, the analogs were used at a concentration of 10 μM or less.…”

Section: Intrinsic Pathway Of Apoptosismentioning

confidence: 95%