Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer (Retracted article. See vol. 78, pg. 5475, 2018)
Antitumor and antimetastatic activities of docetaxel are enhanced by genistein through regulation of osteoprotegerin/receptor activator of nuclear factor-κB (RANK)/RANK ligand/MMP-9 signaling in prostate cancer (Retracted article. See vol. 78, pg. 5475, 2018)
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DOI：
10.1158/0008-5472.can-05-3752
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发表时间：
2006-05-01
期刊：
影响因子：
11.2
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Li, Yiwei;Kucuk, Omer;Sarkar, Fazlul H.
骨转移在晚期前列腺癌中非常常见。多西他赛已被证明可以改善转移性前列腺癌患者的生存率。然而，多西他赛治疗与一定程度的毒性相关。从大豆中提取的染料木黄酮被发现可以抑制癌细胞的生长而没有毒性。我们最近报道染料木黄酮可以增强化疗药物的抗肿瘤活性，在体外和体内。然而，染料木黄酮这种新作用的分子机制尚未完全阐明。在这项研究中，我们发现，金雀异黄素显着增强多西他赛在文化和严重联合免疫缺陷（SCID）-人实验性前列腺癌骨转移模型的抗肿瘤，抗侵袭和抗转移活性。我们进一步进行了微阵列分析、实时逆转录-PCR、Western印迹分析、小干扰RNA和cDNA转染、基质金属蛋白酶-9（MMP-9）活性测定和侵袭测定。我们发现，骨保护素（OPG）的表达被金雀异黄素诱导和多西他赛抑制，而金雀异黄素显着下调核因子-κ B受体激活因子（RANK）配体（RANKL）的表达和分泌，并抑制破骨细胞的形成。Genistein可下调多西他赛诱导的MMP-9的表达和活性，抑制PC-3细胞的侵袭能力。这些结果表明，在SCID-人实验性骨转移模型中观察到的染料木素增强多西紫杉醇的抗肿瘤活性可能是通过调节OPG/RANK/RANKL/MMP-9信号传导介导的，从而抑制骨吸收和前列腺癌骨转移。从这些结果中，我们得出结论，染料木素可能是一个有前途的无毒剂，以改善与多西他赛转移性前列腺癌的治疗结果。
Bone metastasis is very common in advanced prostate cancer. Docetaxel has been shown to improve survival in patients with metastatic prostate cancer. However, treatment with docetaxel is associated with a certain degree of toxicity. Genistein, derived from soybeans, has been found to inhibit cancer cell growth without toxicity. We have recently reported that genistein could potentiated the antitumor activity of chemotherapeutic agents both in vitro and in vivo. However, the molecular mechanism of this novel effect of genistein has not been fully elucidated. In this study, we found that genistein significantly potentiated the antitumor, anti-invasive, and antimetastatic activities of docetaxel both in culture and in severe combined immunodeficient (SCID)-human model of experimental prostate cancer bone metastasis. We further conducted microarray analysis, real-time reverse transcription-PCR, Western blot analysis, small interfering RNA and cDNA transfection, matrix metalloproteinase-9 (MMP-9) activity assay, and invasion assay. We found that the expression of osteoprotegerin (OPG) was induced by genistein and inhibited by docetaxel, whereas genistein significantly down-regulated the expression and secretion of receptor activator of nuclear factor-kappa B (RANK) ligand (RANKL) and inhibited osteoclast formation. Moreover, genistein down-regulated the expression and activity of MMP-9, which was induced by docetaxel treatment, and inhibited invasion of PC-3 cells. These results suggest that the observed potentiation of antitumor activity of docetaxel by genistein in the SCID-human model of experimental bone metastasis could be mediated by regulation of OPG/RANK/RANKL/MMP-9 signaling, resulting in the inhibition of osteoclastic bone resorption and prostate cancer bone metastasis. From these results, we conclude that genistein could be a promising nontoxic agent to improve the treatment outcome of metastatic prostate cancer with docetaxel.