Catalase Inhibitors with Dual Pro-Oxidant Effect as New Therapeutic Agents in Castration-Resistant Prostate Cancer
Catalase Inhibitors with Dual Pro-Oxidant Effect as New Therapeutic Agents in Castration-Resistant Prostate Cancer
复制标题
具有双重促氧化作用的过氧化氢酶抑制剂作为去势抵抗性前列腺癌的新治疗药物
DOI：
10.1002/adtp.202000164
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发表时间：
2020-12-16
影响因子：
4.6
通讯作者：
Yang，Guang-Fu
中科院分区：
文献类型：
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作者：
Chen，Yuan-Yuan;Liang，Hao-Qi;Yang，Guang-Fu
如果内分泌治疗失败，几乎所有晚期前列腺癌(PCA)患者最终都会进展为无法治愈的去势抵抗前列腺癌(CRPC)。因此，识别潜在的细胞靶点对于开发新的有效的CRPC治疗方法至关重要。通过对抗癌药物ATN-224在CRPC DU145细胞中分子机制的研究，抗氧化酶过氧化氢酶(CAT)被认为是CRPC治疗的有效靶点，通过抑制CAT来调节细胞内的氧化还原状态在CRPC治疗中具有很大的潜力。经过系统的设计和合成，苯甲醛缩氨基硫脲衍生物BT-1在DU145细胞中被证明是有效的CAT抑制剂。这种抑制作用导致DU145细胞超氧阴离子自由基(O2·−)和H_2O_2水平显著升高。最后，BT-1的双重抗氧化作用被证明可以导致DU145细胞的凋亡和细胞周期停滞，从而有效地减少CRPC肿瘤。
Almost all patients with advanced prostate cancer (PCa) will eventually progress to incurable castration‐resistant PCa (CRPC) if endocrine therapy fails. Therefore, identifying potential cellular targets is critical for the development of novel and effective treatments for CRPC. Based on the investigation of the molecular mechanism of ATN‐224, an anticancer drug in clinical trials, in CRPC DU145 cells, the antioxidant enzyme catalase (CAT) has been recognized as an actionable CRPC therapeutic target, and the modulation of intracellular redox state through CAT inhibition has great potential for CRPC treatment. After systematic design and synthesis, the benzaldehyde thiosemicarbazone derivative BT‐1 is shown to be effective CAT inhibitor in DU145 cells. This inhibition induces the significant increase of both superoxides (O2•−) and H2O2levels in DU145 cells. Finally, the dual pro‐oxidant effect of BT‐1 is demonstrated to lead to apoptosis as well as cell‐cycle arrest in DU145 cells, effectively reducing CRPC tumors.