1. HSP90/LSD1 dual inhibitors against prostate cancer as well as patient-derived colorectal organoids.
- Author
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Tang DW, Chen IC, Chou PY, Lai MJ, Liu ZY, Tsai KK, Cheng LH, Zhao JX, Cho EC, Chang HH, Lin TE, Hsu KC, Chen MC, and Liou JP
- Subjects
- Animals, Humans, Male, Apoptosis drug effects, Cell Line, Tumor, Dose-Response Relationship, Drug, Molecular Structure, Structure-Activity Relationship, Zebrafish, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents chemical synthesis, Cell Proliferation drug effects, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Colorectal Neoplasms metabolism, Drug Screening Assays, Antitumor, Histone Demethylases antagonists & inhibitors, Histone Demethylases metabolism, HSP90 Heat-Shock Proteins antagonists & inhibitors, HSP90 Heat-Shock Proteins metabolism, Organoids drug effects, Organoids pathology, Prostatic Neoplasms drug therapy, Prostatic Neoplasms pathology
- Abstract
The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI
50 values of 0.24 and 0.30 μM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 μM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jing-Ping Liou reports financial support was provided by National Science and Technology, Taiwan. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Masson SAS.)- Published
- 2024
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