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Targeting adenocarcinoma and enzalutamide‑resistant prostate cancer using the novel anti‑androgen inhibitor ADA‑308.

ABSTRACT: Prostate cancer (PCa) is the leading cause of cancer‑related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA‑308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA‑308 has emerged as a promising candidate, demonstrating potent inhibition of AR‑sensitive adenocarcinoma as well as ENZ‑resistant PCa cell lines. The results of the study revealed that ADA‑308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro. Furthermore, ADA‑308 demonstrated notable efficacy in vivo, with a robust antitumor response in ENZ‑resistant models. These findings establish the role of ADA‑308 as a potent AR inhibitor that overcomes resistance to AR‑targeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.

SUBMITTER: Nouruzi S

PROVIDER: S-EPMC11332584 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature

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Targeting adenocarcinoma and enzalutamide‑resistant prostate cancer using the novel anti‑androgen inhibitor ADA‑308.

Nouruzi Shaghayegh S Johnson Fraser F Kumar Sahil S Sivak Olena O Tabrizian Nakisa N Koistinaho Milla M Muona Anu A Zoubeidi Amina A

Oncology reports 20240812 4

Prostate cancer (PCa) is the leading cause of cancer‑related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA‑308 was evaluated through <i>in vitro</i> assessments of AR activity and cell proliferation, alongside <i>in vivo</i> studies. ADA‑308 has emerged as a p ...[more]

PMID: 39129317

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Project description:Histone deacetylase inhibitors (HDACIs) can disrupt the viability of prostate cancer (PCa) cells through modulation of the cytosolic androgen receptor (AR) chaperone protein heat shock protein 90 (HSP90). However, toxicities associated with their pleiotropic effects could contribute to the ineffectiveness of HDACIs in PCa treatment. We designed hybrid molecules containing partial chemical scaffolds of enzalutamide and suberoylanilide hydroxamic acid (SAHA), with weakened intrinsic pan-HDACI activities, to target HSP90 and AR in enzalutamide-resistant PCa cells. The potency of the new molecules, compounds 2-75 [4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluoro-N-(7-(hydroxyamino)-7-oxoheptyl)benzamide] and 1005 [(E)-3-(4-(3-(4-cyano-3-(trifluoromethyl)phenyl)-5,5-dimethyl-4-oxo-2-thioxoimidazolidin-1-yl)-2-fluorophenyl)-N-hydroxyacrylamide], as inhibitors of nuclear and cytosolic histone deacetylases was substantially lower than that of SAHA in cell-free and in situ assays. Compounds 2-75 and 1005 antagonized gene activation by androgen without inducing chromatin association of AR. Enzalutamide had no effect on the levels of AR or HSP90, whereas the hybrid compounds induced degradation of both AR and HSP90, similar to (compound 1005) or more potently than (compound 2-75) SAHA. Similar to SAHA, compounds 2-75 and 1005 decreased the level of HSP90 and induced acetylation in a predicted approximately 55 kDa HSP90 fragment. Compared with SAHA, compound 2-75 induced greater hyperacetylation of the HDAC6 substrate α-tubulin. In contrast with SAHA, neither hybrid molecule caused substantial hyperacetylation of histones H3 and H4. Compounds 2-75 and 1005 induced p21 and caused loss of viability in the enzalutamide-resistant C4-2 cells, with efficacies that were comparable to or better than SAHA. The results suggest the potential of the new compounds as prototype antitumor drugs that would downregulate HSP90 and AR in enzalutamide-resistant PCa cells with weakened effects on nuclear HDACI targets.

Dataset Information

Targeting adenocarcinoma and enzalutamide‑resistant prostate cancer using the novel anti‑androgen inhibitor ADA‑308.

Publications

Targeting adenocarcinoma and enzalutamide‑resistant prostate cancer using the novel anti‑androgen inhibitor ADA‑308.

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