Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.
Minnelide Inhibits Androgen Dependent, Castration Resistant Prostate Cancer Growth by Decreasing Expression of Androgen Receptor Full Length and Splice Variants.
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DOI：
10.1002/pros.23298
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Konety B
中科院分区：
文献类型：
--
作者：
Isharwal S;Modi S;Arora N;Uhlrich C 3rd;Giri B;Barlass U;Soubra A;Chugh R;Dehm SM;Dudeja V;Saluja A;Banerjee S;Konety B
前列腺癌每年导致近 30,000 人死亡，是男性癌症相关死亡的第二大原因。几十年来，雄激素剥夺疗法（ADT）一直是前列腺癌治疗的基石。然而，尽管前列腺癌对 ADT 最初有反应，但最终失败并且肿瘤复发，导致去势抵抗性前列腺癌 (CRPC)。雷公藤甲素是一种二萜三环氧化物，十多年来一直在多种癌症中测试其抗肿瘤特性。由于其在水介质中溶解度差，其临床应用受到限制。为了解决这个问题，我们合成了一种水溶性雷公藤内酯醇前药 Minnelide，目前正在针对胃肠道肿瘤的一期临床试验中对其进行评估。在当前的研究中，我们评估了 Minnelide 及其活性化合物雷公藤内酯醇在体外和体内对雄激素依赖性前列腺癌的治疗潜力。用多剂量的雷公藤甲素处理前列腺癌细胞后，通过基于 MTT 的测定来测量细胞活力。使用 caspase 3/7 活性测量细胞凋亡。使用荧光素酶报告基因测定评估雄激素受体（AR）启动子结合活性。为了评价体内效果，将22Rv1细胞植入动物皮下，然后开始用0.21mg/kg Minnelide进行治疗。我们的研究表明，雷公藤甲素治疗可诱导 CRPC 细胞凋亡。雷公藤甲素治疗抑制 AR 转录活性，并在 mRNA 和蛋白质水平降低 AR 及其剪接变体的表达。我们的研究表明，雷公藤内酯醇抑制 Sp1 的核易位，导致其转录活性降低，从而导致前列腺癌细胞中 AR 及其剪接变体的下调。在体内，Minnelide (0.21mg/kg) 在我们的研究终点消退了源自 CRPC 22RV1 的皮下肿瘤。我们的动物研究进一步证实，Minnelide 比标准护理疗法多西他赛和恩杂鲁胺更有效。我们的研究表明，Minnelide 作为 CRPC 的治疗选择非常有效，目前正在进行的临床试验中患者可以耐受的剂量。
With almost 30,000 deaths per year, prostate cancer is the second-leading cause of cancer-related death in men. Androgen Deprivation Therapy (ADT) has been the corner stone of prostate cancer treatment for decades. However, despite an initial response of prostate cancer to ADT, this eventually fails and the tumors recur, resulting in Castration Resistant Prostate Cancer (CRPC). Triptolide, a diterpene triepoxide, has been tested for its anti-tumor properties in a number of cancers for over a decade. Owing to its poor solubility in aqueous medium, its clinical application had been limited. To circumvent this problem, we have synthesized a water-soluble pro-drug of triptolide, Minnelide, that is currently being evaluated in a Phase 1 clinical trial against gastrointestinal tumors. In the current study, we assessed the therapeutic potential of Minnelide and its active compound triptolide against androgen dependent prostate cancer both in vitro as well as in vivo. Cell viability was measured by a MTT based assay after treating prostate cancer cells with multiple doses of triptolide. Apoptotic cell death was measured using a caspase 3/7 activity. Androgen Receptor (AR) promoter-binding activity was evaluated by using luciferase reporter assay. For evaluating the effect in vivo, 22Rv1 cells were implanted subcutaneously in animals, following which, treatment was started with 0.21mg/kg Minnelide. Our study showed that treatment with triptolide induced apoptotic cell death in CRPC cells. Triptolide treatment inhibited AR transcriptional activity and decreased the expression of AR and its splice variants both at the mRNA and the protein level. Our studies show that triptolide inhibits nuclear translocation of Sp1, resulting in its decreased transcriptional activity leading to downregulation of AR and its splice variants in prostate cancer cells. In vivo, Minnelide (0.21mg/kg) regressed subcutaneous tumors derived from CRPC 22RV1 at our study endpoint. Our animal studies further confirmed that Minnelide was more efficacious than the standard of care therapies, Docetaxel and Enzalutamide. Our study indicates that Minnelide is very effective as a therapeutic option against CRPC at a dose that is currently tolerated by patients in the ongoing clinical trials.
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影响因子：
64.5
作者：
Chang KH;Li R;Kuri B;Lotan Y;Roehrborn CG;Liu J;Vessella R;Nelson PS;Kapur P;Guo X;Mirzaei H;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
3.8
作者：
Alsaied, Osama A.;Sangwan, Veena;Jensen, Eric H.
通讯作者：
Jensen, Eric H.
影响因子：
4.8
作者：
Banerjee, Sulagna;Sangwan, Veena;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.
影响因子：
158.5
作者：
Scher, Howard I.;Fizazi, Karim;de Bono, Johann S.
通讯作者：
de Bono, Johann S.