The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants
© 2021. The Author(s), under exclusive licence to CPS and SIMM..
Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:43 |
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| Enthalten in: |
Acta pharmacologica Sinica - 43(2022), 4 vom: 28. Apr., Seite 1024-1032 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Hong [VerfasserIn] |
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| Links: |
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| Themen: |
Androgen receptor (AR) |
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| Anmerkungen: |
Date Completed 05.04.2022 Date Revised 02.04.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41401-021-00738-w |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM328662674 |
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| 245 | 1 | 4 | |a The novel indomethacin derivative CZ-212-3 exerts antitumor effects on castration-resistant prostate cancer by degrading androgen receptor and its variants |
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| 520 | |a © 2021. The Author(s), under exclusive licence to CPS and SIMM. | ||
| 520 | |a Androgen receptor (AR) serves as a main therapeutic target for prostate cancer (PCa). However, resistance to anti-androgen therapy (SAT) inevitably occurs. Indomethacin is a nonsteroidal anti-inflammatory drug that exhibits activity against prostate cancer. Recently, we designed and synthesized a series of new indomethacin derivatives (CZ compounds) via Pd (II)-catalyzed synthesis of substituted N-benzoylindole. In this study, we evaluated the antitumor effect of these novel indomethacin derivatives in castration-resistant prostate cancer (CRPC). Upon employing CCK-8 cell viability assays and colony formation assays, we found that these derivatives had high efficacy against CRPC tumor growth in vitro. Among these derivatives, CZ-212-3 exhibited the most potent efficacy against CRPC cell survival and on apoptosis induction. Mechanistically, CZ-212-3 significantly suppressed the expression of AR target gene networks by degrading AR and its variants. Consistently, CZ-212-3 significantly inhibited tumor growth in CRPC cell line-based xenograft and PDX models in vivo. Taken together, the data show that the indomethacin derivative CZ-212-3 significantly inhibited CRPC tumor growth by degrading AR and its variants and could be a promising agent for CRPC therapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CZ-212-3 | |
| 650 | 4 | |a androgen receptor (AR) | |
| 650 | 4 | |a castration-resistant prostate cancer (CRPC) | |
| 650 | 4 | |a indomethacin derivatives | |
| 650 | 4 | |a patient-derived xenograft model (PDX) | |
| 650 | 7 | |a Receptors, Androgen |2 NLM | |
| 650 | 7 | |a Indomethacin |2 NLM | |
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| 700 | 1 | |a Cai, Guo-di |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Jiang-He |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Shan-Shu |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Yin-Feng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Ming-Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Xue-Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Lei, Jin-Ping |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Pei-Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, De-Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jun-Jian |e verfasserin |4 aut | |
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