Abstract
Background: Castration-resistant prostate cancer (CRPC) with sustained androgen receptor (AR) signaling remains a critical clinical challenge, despite androgen depletion therapy. The Jumonji C-containing histone lysine demethylase family 4 (KDM4) members, KDM4A‒KDM4C, serve as critical coactivators of AR to promote tumor growth in prostate cancer and are candidate therapeutic targets to overcome AR mutations/alterations-mediated resistance in CRPC. Methods: In this study, using a structure-based approach, we identified a natural product, myricetin, able to block the demethylation of histone 3 lysine 9 trimethylation by KDM4 members and evaluated its effects on CRPC. A structure-based screening was employed to search for a natural product that inhibited KDM4B. Inhibition kinetics of myricetin was determined. The cytotoxic effect of myricetin on various prostate cancer cells was evaluated. The combined effect of myricetin with enzalutamide, a second-generation AR inhibitor toward C4-2B, a CRPC cell line, was assessed. To improve bioavailability, myricetin encapsulated by poly lactic-co-glycolic acid (PLGA), the US food and drug administration (FDA)-approved material as drug carriers, was synthesized and its antitumor activity alone or with enzalutamide was evaluated using in vivo C4-2B xenografts. Results: Myricetin was identified as a potent α-ketoglutarate-type inhibitor that blocks the demethylation activity by KDM4s and significantly reduced the proliferation of both androgen-dependent (LNCaP) and androgen-independent CRPC (CWR22Rv1 and C4-2B). A synergistic cytotoxic effect toward C4-2B was detected for the combination of myricetin and enzalutamide. PLGA-myricetin, enzalutamide, and the combined treatment showed significantly greater antitumor activity than that of the control group in the C4-2B xenograft model. Tumor growth was significantly lower for the combination treatment than for enzalutamide or myricetin treatment alone. Conclusions: These results suggest that myricetin is a pan-KDM4 inhibitor and exhibited potent cell cytotoxicity toward CRPC cells. Importantly, the combination of PLGA-encapsulated myricetin with enzalutamide is potentially effective for CRPC.
Original language | English |
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Article number | 29 |
Pages (from-to) | 29 |
Journal | Journal of Biomedical Science |
Volume | 29 |
Issue number | 1 |
DOIs | |
Publication status | Published - May 9 2022 |
Keywords
- Castration-resistant prostate cancer
- Enzalutamide
- Histone lysine demethylase family 4 (KDM4)
- Myricetin
- Poly lactic-co-glycolic acid (PLGA)
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Molecular Biology
- Clinical Biochemistry
- Cell Biology
- Biochemistry, medical
- Pharmacology (medical)
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Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer
Liu, J.-S. (Creator), Fang, W.-K. (Creator), Yang, S.-M. (Creator), Wu, M.-C. (Creator), Chen, T.-J. (Creator), Chen, C.-M. (Creator), Lin, T.-Y. (Creator), Liu, K.-L. (Creator), Wu, C.-M. (Creator), Chen, Y.-C. (Creator), Chuu, C.-P. (Creator), Wang, L.-Y. (Creator), Hsieh, H.-P. (Creator), Kung, H.-J. (Creator) & Wang, W.-C. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.c.5987016.v1, https://springernature.figshare.com/collections/Natural_product_myricetin_is_a_pan-KDM4_inhibitor_which_with_poly_lactic-co-glycolic_acid_formulation_effectively_targets_castration-resistant_prostate_cancer/5987016/1
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Additional file 1 of Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively targets castration-resistant prostate cancer
Liu, J.-S. (Creator), Fang, W.-K. (Creator), Yang, S.-M. (Creator), Wu, M.-C. (Creator), Chen, T.-J. (Creator), Chen, C.-M. (Creator), Lin, T.-Y. (Creator), Liu, K.-L. (Creator), Wu, C.-M. (Creator), Chen, Y.-C. (Creator), Chuu, C.-P. (Creator), Wang, L.-Y. (Creator), Hsieh, H.-P. (Creator), Kung, H.-J. (Creator) & Wang, W.-C. (Creator), Figshare, 2022
DOI: 10.6084/m9.figshare.19736397.v1, https://springernature.figshare.com/articles/journal_contribution/Additional_file_1_of_Natural_product_myricetin_is_a_pan-KDM4_inhibitor_which_with_poly_lactic-co-glycolic_acid_formulation_effectively_targets_castration-resistant_prostate_cancer/19736397/1
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