MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner.
MDM2 Inhibition Sensitizes Prostate Cancer Cells to Androgen Ablation and Radiotherapy in a p53-Dependent Manner.
复制标题
DOI：
10.1016/j.neo.2016.01.006
复制
发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Hamstra DA
中科院分区：
文献类型：
--
作者：
Feng FY;Zhang Y;Kothari V;Evans JR;Jackson WC;Chen W;Johnson SB;Luczak C;Wang S;Hamstra DA
目的：小鼠双分钟 2 (MDM2) 表达增加，与 p53 状态无关，与接受放射治疗的前列腺癌男性癌症特异性死亡率增加相关。我们评估了 MI-219（一种 MDM2 小分子抑制剂，其药代动力学优于 nutlin-3），以提高前列腺癌细胞对放疗和雄激素剥夺疗法（高危前列腺癌男性的标准治疗选择）的敏感性。实验设计：使用小鼠异种移植模型在含有不同 p53 功能状态的多种前列腺癌细胞系中体外和体内评估 MI-219 抑制 MDM2 的效果。结果：MI-219 抑制 MDM2 导致剂量和时间依赖性 p53 激活，并以 p53 依赖性方式降低辐射后克隆细胞存活率。从机制上讲，抑制 MDM2 后的放射增敏很大程度上是 p53 依赖性细胞凋亡和 DNA 损伤增加的结果，如膜联蛋白 V 流式细胞术和 γ-H2AX 焦点免疫荧光所证明的那样。同样，MI-219 治疗通过 p53 依赖性细胞凋亡增加来增强抗雄激素治疗的反应。最后，与任何单药或双药治疗相比，放射、雄激素剥夺疗法和 MI-219 三联疗法可减少异种移植肿瘤的生长。结论：用 MI-219 抑制 MDM2 会导致前列腺癌细胞对放射、抗雄激素治疗及其组合产生 p53 依赖性敏感性。这些发现支持 MDM2 小分子抑制剂治疗作为一种治疗强化策略，可改善高危局限性前列腺癌的临床结果。翻译相关性：放疗和雄激素剥夺疗法的结合是高危前列腺癌男性的标准治疗选择。尽管在放疗中加入雄激素剥夺疗法可改善预后，但患有高危前列腺癌的男性在治疗后的前 10 年内仍有很大的疾病复发、进展甚至死亡的风险。我们证明，MI-219（MDM2 抑制剂）治疗可导致前列腺癌细胞在体外和体内对放射和雄激素剥夺疗法敏感。与任何单药或双药治疗相比，MI-219、放疗和雄激素剥夺疗法的三联疗法可显着降低肿瘤生长。这些发现提供的证据表明，抑制 MDM2 是增强放疗和雄激素剥夺疗法疗效的可行方法，从而改善前列腺癌的治疗结果。因此，需要进一步研究以将这些发现转化为临床环境。
PURPOSE: Increased murine double minute 2 (MDM2) expression, independent of p53 status, is associated with increased cancer-specific mortality for men with prostate cancer treated with radiotherapy. We assessed MI-219, a small molecule inhibitor of MDM2 with improved pharmacokinetics over nutlin-3, for sensitization of prostate cancer cells to radiotherapy and androgen deprivation therapy, a standard treatment option for men with high-risk prostate cancer. EXPERIMENTAL DESIGN: The effect of MDM2 inhibition by MI-219 was assessed in vitro and in vivo with mouse xenograft models across multiple prostate cancer cell lines containing varying p53 functional status. RESULTS: MDM2 inhibition by MI-219 resulted in dose- and time-dependent p53 activation and decreased clonogenic cell survival after radiation in a p53-dependent manner. Mechanistically, radiosensitization following inhibition of MDM2 was largely the result of p53-dependent increases in apoptosis and DNA damage as evidenced by Annexin V flow cytometry and γ-H2AX foci immunofluorescence. Similarly, treatment with MI-219 enhanced response to antiandrogen therapy via a p53-dependent increase in apoptotic cell death. Lastly, triple therapy with radiation, androgen deprivation therapy, and MI-219 decreased xenograft tumor growth compared with any single- or double-agent treatment. CONCLUSION: MDM2 inhibition with MI-219 results in p53-dependent sensitization of prostate cancer cells to radiation, antiandrogen therapy, and the combination. These findings support MDM2 small molecule inhibitor therapy as a therapy intensification strategy to improve clinical outcomes in high-risk localized prostate cancer. TRANSLATIONAL RELEVANCE: The combination of radiotherapy and androgen deprivation therapy is a standard treatment option for men with high-risk prostate cancer. Despite improvements in outcomes when androgen deprivation therapy is added to radiation, men with high-risk prostate cancer have significant risk for disease recurrence, progression, and even death within the first 10 years following treatment. We demonstrate that treatment with MI-219 (an inhibitor of MDM2) results in prostate cancer cell sensitization to radiation and androgen deprivation therapy in vitro and in vivo. Triple therapy with MI-219, radiation, and androgen deprivation therapy dramatically decreased tumor growth compared with any single- or double-agent therapy. These findings provide evidence that inhibition of MDM2 is a viable means by which to enhance the efficacy of both radiation and androgen deprivation therapy and thereby improve outcomes in the treatment of prostate cancer. As such, further investigation is warranted to translate these findings to the clinical setting.