Chang Taihao, Lian Zhenpeng, Ma Shenfei, Liang Zhengxin, Ma Xudong, Wen Xiaodong, Wang Yanming, Liu Ranlu
Department of Urology, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, China.
Department of Urology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.
Prostate. 2023 Apr;83(5):470-486. doi: 10.1002/pros.24479. Epub 2022 Dec 28.
Like DNA methylation, histone modifications are considered important processes for epigenetic alterations in gene function, and abnormally high expression of histone deacetylases (HDACs) plays a key role in many human diseases. In addition to regulating the acetylation levels of histone and non-histone proteins and gene transcription, HDAC inhibitors as antitumor drugs can also affect the DNA damage repair (DDR) pathway in tumor cells. Prostate cancer (PCa) is one of the most heritable malignancies in which DDR pathway defects can be detected in a considerable proportion of cases. Such defects are more prevalent in castration-resistant prostate cancer (CRPC) and are highly enriched in metastatic lesions. There is currently evidence that DDR pathway-deficient PCa is associated with high-risk biological behaviors and response sensitivity to platinum-based chemotherapy. Platinum-based drugs have been used in multiple clinical trials as monotherapy or in combination with other chemotherapeutic agents for the treatment of CRPC.
This study evaluated the combined anticancer effect of (cisplatin) CDDP and the HDAC inhibitors vorinostat (SAHA) on three androgen-dependent cell lines PC-3, DU-145, and C4-2B in vitro. The efficacy and safety of SAHA combined with CDDP in the treatment of CRPC were further verified through animal experiments.
The combination of the two drugs increases cytotoxic effects by increasing DNA damage. Our results showed that the SAHA could not only reduce the expression of homologous recombinant repair proteins BRCA2, BRCA1, PARP1, and RAD51, but also decrease enzymes that Reduce the key enzymes of GSH biosynthesis, GSS and GCLC, and GSTP1 which can catalyze the binding of GSH to cisplatin. The intracellular GSH level also decreased with the increase of SAHA concentration, at the same time, the content of intracellular Pt element.
The combination of CDDP and SAHA can produce synergistic anticancer effects in androgen-independent PCa cells in vitro and in vivo. Our results open up a new avenue for the effective treatment of CRPC. To optimize the chemotherapy regimen for patients with advanced PCa, it is necessary to further study the molecular mechanism of platinum drugs, HDAC inhibitors, and their combined action.
与DNA甲基化一样，组蛋白修饰被认为是基因功能表观遗传改变的重要过程，组蛋白去乙酰化酶（HDACs）的异常高表达在许多人类疾病中起关键作用。HDAC抑制剂作为抗肿瘤药物，除了调节组蛋白和非组蛋白的乙酰化水平以及基因转录外，还可影响肿瘤细胞中的DNA损伤修复（DDR）途径。前列腺癌（PCa）是最具遗传性的恶性肿瘤之一，在相当比例的病例中可检测到DDR途径缺陷。这种缺陷在去势抵抗性前列腺癌（CRPC）中更为普遍，并且在转移病灶中高度富集。目前有证据表明，DDR途径缺陷的PCa与高风险生物学行为以及对铂类化疗的反应敏感性相关。铂类药物已在多项临床试验中作为单一疗法或与其他化疗药物联合用于治疗CRPC。
本研究评估了顺铂（CDDP）与HDAC抑制剂伏立诺他（SAHA）在体外对三种雄激素依赖性细胞系PC-3、DU-145和C4-2B的联合抗癌作用。通过动物实验进一步验证了SAHA联合CDDP治疗CRPC的疗效和安全性。
两种药物联合使用通过增加DNA损伤增强细胞毒性作用。我们的结果表明，SAHA不仅可以降低同源重组修复蛋白BRCA2、BRCA1、PARP1和RAD51的表达，还可以降低谷胱甘肽生物合成的关键酶GSS和GCLC以及可催化谷胱甘肽与顺铂结合的GSTP1的表达。随着SAHA浓度的增加，细胞内谷胱甘肽水平也降低，同时细胞内铂元素含量降低。
CDDP与SAHA联合使用在体外和体内均可在雄激素非依赖性PCa细胞中产生协同抗癌作用。我们的结果为CRPC的有效治疗开辟了一条新途径。为优化晚期PCa患者的化疗方案，有必要进一步研究铂类药物、HDAC抑制剂及其联合作用的分子机制。
