Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways.
Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways.
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DOI：
10.1038/s41598-021-01697-2
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发表时间：
2021-11-15
影响因子：
4.6
通讯作者：
Oya M
中科院分区：
文献类型：
--
作者：
Hongo H;Kosaka T;Suzuki Y;Mikami S;Fukada J;Oya M
卡巴西紫杉醇(CBZ)被批准用于治疗耐多西他赛的去势耐药前列腺癌(CRPC)。然而，它对CRPC的疗效有限，而且还没有有效的治疗方法来治疗CBZ耐药的CRPC。本研究探讨卡氮紫杉醇后治疗慢性前列腺癌的最佳治疗方案。本研究使用卡马西平敏感的PC3细胞和卡马西平抗性的PC3CR细胞。我们进行了电子药物筛选，寻找可以对PC3CR细胞的基因表达特征进行重新编程的候选药物。在异种移植小鼠模型上测试了该药物组合的体内效应。我们确定依托泊苷(VP16)是治疗卡马西平耐药CRPC的有前景的候选药物。WST实验表明，VP16对PC3CR细胞有明显的抗肿瘤作用。PC3CR细胞拓扑异构酶IIα(TOP2A)的表达明显高于PC3细胞。在癌症基因组图谱前列腺癌队列中，TOP2A的高表达是一个不良的预后因素。在弗雷德·哈钦森癌症研究中心的数据集中，暴露于多西紫杉醇的组织和转移性肿瘤有较高的TOP2A表达。此外，VP16显著抑制了这两种细胞系产生的肿瘤的生长。基于这些发现，基于VP16的化疗可能是CBZ后CPRC的最佳治疗方案。
Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.
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影响因子：
30.8
作者：
通讯作者：
--
影响因子：
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作者：
Kosaka T;Hongo H;Miyazaki Y;Nishimoto K;Miyajima A;Oya M
通讯作者：
Oya M
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64.5
作者：
Cancer Genome Atlas Research Network
通讯作者：
Cancer Genome Atlas Research Network
影响因子：
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作者：
PedersenBjergaard, J;BrondumNielsen, K;Johansson, B
通讯作者：
Johansson, B
影响因子：
3.8
作者：
Hornhardt, Sabine;Roessler, Ute;Gomolka, Maria
通讯作者：
Gomolka, Maria