CPA-7 influences immune profile and elicits anti-prostate cancer effects by inhibiting activated STAT3.
CPA-7 influences immune profile and elicits anti-prostate cancer effects by inhibiting activated STAT3.
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CPA-7 通过抑制激活的 STAT3 影响免疫特征并引发抗前列腺癌作用
DOI：
10.1186/s12885-016-2488-6
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发表时间：
2016-07-19
期刊：
影响因子：
3.8
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Liang M;Zhan F;Zhao J;Li Q;Wuyang J;Mu G;Li D;Zhang Y;Huang X
背景基于铂的化疗正在成为去势抵抗性前列腺癌的一线治疗方法。在铂 (IV) 基化合物家族中，一种名为 CPA-7 的成员可抑制多种癌细胞系的生长。然而，CPA-7 在体内如何以及在多大程度上引发其抗前列腺癌作用尚不清楚。方法在本研究中，我们首先评估了合成的 CPA-7 在前列腺癌模型以及正常小鼠中的潜在毒性。接下来，我们利用细胞计数法评估了CPA-7对前列腺癌细胞生长的体外影响，并通过Kaplan-Meier法计算了CPA-7治疗期间荷瘤小鼠的肿瘤大小和累积存活率。然后，我们通过协同使用蛋白质印迹、IHC 和萤火虫荧光素酶报告基因测定来测量 STAT3（CPA-7 的靶标之一）的激活形式的表达水平及其 CPA-7 处理后的转录活性。最后，通过流式细胞术评估 CPA-7 对肿瘤引流淋巴结和脾脏中免疫细胞运输的影响。结果 CPA-7 治疗在体外显着抑制前列腺癌细胞的生长，在小鼠体内也能延长生存期并降低复发率。这些治疗效果至少部分归因于前列腺肿瘤组织以及肿瘤细胞侵袭周围区域中 STAT3 的功能性缺失。 CPA-7 治疗还导致脾脏和肿瘤浸润淋巴结中调节性 T 细胞水平降低，细胞毒性 T 细胞和 T 辅助细胞水平增加。这种对免疫细胞运输的有利作用可能是针对复发性前列腺癌的遗忘性免疫反应的原因。结论CPA-7是一种有前途的新型前列腺癌治疗剂，它既能抑制肿瘤细胞增殖，又能刺激抗肿瘤免疫。它有潜力作为难治性前列腺癌的一线治疗和/或佐剂。
BackgroundPlatinum-based chemotherapy is emerging as the first line of treatment for castration resistant prostate cancer. Among the family of platinum (IV)-based compounds, a member known as CPA-7 inhibits the growth of multiple cancer cell lines. However, how and to what extent CPA-7 elicits its anti-prostate cancer effects in vivo is largely unknown.MethodsIn this study, we firstly assessed the potential toxicity of the synthesized CPA-7 in a prostate cancer model as well as in normal mice. Next, we evaluated the in vitro effects of CPA-7 on the growth of prostate cancer cells using cell counting assay, and calculated the tumor sizes and cumulative survival rate of the tumor bearing mice by Kaplan-Meier method during CPA-7 treatment. Then we measured the expression level of the activated form of STAT3 (one targets of CPA-7) and its transcriptive activity post CPA-7 treatment by synergistically using western blot, IHC, and firefly luciferase reporter assays. Finally, effects of CPA-7 on immune cell trafficking in the tumor draining lymph nodes and in the spleens are evaluated with flow cytometry.ResultsTreatment with CPA-7 significantly inhibited growth of prostate cancer cells in vitro, and also in mice resulting in a prolonged survival and a decreased recurrence rate. These therapeutic effects are due, at least in part, to functional depletion of STAT3 in prostate tumor tissue as well as in the surrounding areas of tumor cell invasion. CPA-7 treatment also resulted in a reduced level of regulatory T cells and increased levels of cytotoxic T and T helper cells in the spleen and in tumor infiltrating lymph nodes. This favorable effect on immune cell trafficking may account for the amnestic immune response against recurrent prostate cancer.ConclusionsCPA-7 is a promising new therapeutic agent for prostate cancer that both inhibits tumor cell proliferation and stimulates anti-tumor immunity. It has potential as first line treatment and/or as an adjuvant for refractory prostate cancer.