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Catalase Inhibitors with Dual Pro‐Oxidant Effect as New Therapeutic Agents in Castration‐Resistant Prostate Cancer
Author(s) -
Chen YuanYuan,
Liang HaoQi,
Liu MengTing,
Huang Wei,
Yi PengFei,
Yuan SiQi,
Mei LongCan,
Hu YingHui,
Cao YaYa,
Hao GeFei,
Zhang Dan,
Yang GuangFu
Publication year - 2021
Publication title -
advanced therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
0ISSN - 2366-3987
DOI - 10.1002/adtp.202000164
Subject(s) - du145 , prostate cancer , cancer research , pharmacology , chemistry , catalase , medicine , antioxidant , cancer , lncap , biochemistry
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 (O 2 •− ) and H 2 O 2 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.