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
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DOI：
10.1002/adtp.202000164
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发表时间：
2021
影响因子：
4.6
通讯作者：
Guang-Fu Yang
中科院分区：
文献类型：
--
作者：
Yuan-Yuan Chen;Hao-Qi Liang;Meng-Ting Liu;Wei Huang;Peng-Fei Yi;Si-Qi Yuan;Long-Can Mei;Ying-Hui Hu;Ya-Ya Cao;Ge-Fei Hao;Dan Zhang;Guang-Fu Yang
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 H2O2 levels 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.
