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The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17?-Hydroxysteroid Dehydrogenase Type 3.

ABSTRACT: The 17?-hydroxysteroid dehydrogenase type 3 (17?-HSD3) enzyme is a potential therapeutic target for hormone-dependent prostate cancer, as it is the key enzyme in the last step of testosterone (T) biosynthesis. A curcumin analog, H10, was optimized for inhibiting T production in LC540 cells that stably overexpressed 17?-HSD3 enzyme (LC540 [17?-HSD3]) (P < 0.01), without affecting progesterone (P) synthesis. H10 downregulated the production of T in the microsomal fraction of rat testes containing the 17?-HSD3 enzyme from 100 to 78.41 ± 7.41%, 51.86 ± 10.03%, and 45.14 ± 8.49% at doses of 10, 20, and 40 ?M, respectively. There were no significant differences among the groups with respect to the protein expression levels of 17?-HSD3, 3?HSD1, CYP17a1, CYP11a1, and STAR, which participate in 17?-HSD3-mediated conversion of androgens to T (P > 0.05). This indicated that H10 only inhibited the enzymatic activity of 17?-HSD3 in vitro. Furthermore, H10 inhibited the adione-stimulated growth of xenografts established from LNCaP cells in nude mice in vivo. We conclude that H10 could serve as an effective inhibitor of 17?-HSD3, which in turn would inhibit the biosynthesis of androgens and progression of prostate cancer.

SUBMITTER: Cheng Y

PROVIDER: S-EPMC7227374 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3.

Cheng Yating Y Yang Yan Y Wu Yinan Y Wang Wencheng W Xiao Lichun L Zhang Yifan Y Tang Jianzhong J Huang Ya-Dong YD Zhang Shu S Xiang Qi Q

Frontiers in pharmacology 20200508

The 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) enzyme is a potential therapeutic target for hormone-dependent prostate cancer, as it is the key enzyme in the last step of testosterone (T) biosynthesis. A curcumin analog, H10, was optimized for inhibiting T production in LC540 cells that stably overexpressed 17β-HSD3 enzyme (LC540 [17β-HSD3]) (P < 0.01), without affecting progesterone (P) synthesis. H10 downregulated the production of T in the microsomal fraction of rat testes containing ...[more]

PMID: 32457626

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Project description:17?-Hydroxysteroid dehydrogenase type 1 (17?-HSD1) catalyzes the reduction of estrone to estradiol, which is the most potent estrogen in humans. Inhibition of 17?-HSD1 and thereby reducing the intracellular estradiol concentration is thus a promising approach for the treatment of estrogen dependent diseases. In the past, several steroidal and non-steroidal inhibitors of 17?-HSD1 have been described but so far there is no cocrystal structure of the latter in complex with 17?-HSD1. However, a distinct knowledge of active site topologies and protein-ligand interactions is a prerequisite for structure-based drug design and optimization. An elegant strategy to enhance this knowledge is to compare inhibition values obtained for one compound toward ortholog proteins from various species, which are highly conserved in sequence and differ only in few residues. In this study the inhibitory potencies of selected members of different non-steroidal inhibitor classes toward marmoset 17?-HSD1 were determined and the data were compared with the values obtained for the human enzyme. A species specific inhibition profile was observed in the class of the (hydroxyphenyl)naphthols. Using a combination of computational methods, including homology modelling, molecular docking, MD simulation, and binding energy calculation, a reasonable model of the three-dimensional structure of marmoset 17?-HSD1 was developed and inhibition data were rationalized on the structural basis. In marmoset 17?-HSD1, residues 190 to 196 form a small ?-helix, which induces conformational changes compared to the human enzyme. The docking poses suggest these conformational changes as determinants for species specificity and energy decomposition analysis highlighted the outstanding role of Asn152 as interaction partner for inhibitor binding. In summary, this strategy of comparing the biological activities of inhibitors toward highly conserved ortholog proteins might be an alternative to laborious x-ray or site-directed mutagenesis experiments in certain cases. Additionally, it facilitates inhibitor design and optimization by offering new information on protein-ligand interactions.

Dataset Information

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17?-Hydroxysteroid Dehydrogenase Type 3.

Publications

The Curcumin Derivative, H10, Suppresses Hormone-Dependent Prostate Cancer by Inhibiting 17β-Hydroxysteroid Dehydrogenase Type 3.

Similar Datasets

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