Antiandrogen Therapy with Hydroxyflutamide or Androgen Receptor Degradation Enhancer ASC-J9 Enhances BCG Efficacy to Better Suppress Bladder Cancer Progression.
Antiandrogen Therapy with Hydroxyflutamide or Androgen Receptor Degradation Enhancer ASC-J9 Enhances BCG Efficacy to Better Suppress Bladder Cancer Progression.
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DOI：
10.1158/1535-7163.mct-14-1055-t
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发表时间：
2015-11
影响因子：
5.7
通讯作者：
Chang C
中科院分区：
文献类型：
--
作者：
Shang Z;Li Y;Zhang M;Tian J;Han R;Shyr CR;Messing E;Yeh S;Niu Y;Chang C
近年来的研究表明雄激素受体（AR）可能在影响膀胱癌（BCa）进展中发挥重要作用，但其临床应用尚不清楚。在这里，我们开发了一种新的联合治疗卡介苗（BCG）和AR降解增强剂ASC-J9®或抗雄激素羟氟他胺（HF），以更好地抑制BCa的进展。机制分析表明，ASC-J9通过增加单核/巨噬细胞的募集，通过增加整合素-α5β1的表达和IL-6的释放，促进BCG对BCa细胞的附着/内化，从而增强了BCG抑制BCa细胞增殖的功效。这些结果可能通过增加TNF-α释放而增强bcg诱导的BCa细胞死亡。有趣的是，我们还发现ASC-J9®处理可以直接促进BCG诱导的HMGB1释放，从而增强BCG抑制BCa细胞生长的细胞毒作用。在bbn诱导的BCa小鼠模型中，ASC-J9®可以增强BCG的疗效，更好地抑制BCa的进展。总之，这些结果表明，新开发的卡介苗和asc - j9联合治疗可能成为一种更好地抑制BCa进展的新疗法。
Recent studies suggested that the androgen receptor (AR) might play important roles to influence the bladder cancer (BCa) progression, yet its clinical application remains unclear. Here we developed a new combined therapy with Bacillus Calmette-Guérin (BCG) and the AR degradation enhancer ASC-J9® or anti-androgen hydroxyflutamide (HF) to better suppress the BCa progression. Mechanism dissection revealed that ASC-J9® treatment enhanced BCG efficacy to suppress BCa cell proliferation via increasing the recruitment of monocytes/macrophages that involved the promotion of BCG attachment/internalization to the BCa cells through increased integrin-α5β1 expression and IL-6 release. Such consequences might then enhance BCG-induced BCa cell death via increased TNF-α release. Interestingly, we also found ASC-J9® treatment could directly promote BCG-induced HMGB1 release to enhance the BCG cytotoxic effects for the suppression of BCa cell growth. In vivo approaches also concluded that ASC-J9® could enhance the BCG efficacy to better suppress the BCa progression in BBN-induced BCa mouse models. Together, these results suggest that the newly developed therapy combining BCG plusASC-J9® may become a novel therapy to better suppress BCa progress.