Natural product myricetin is a pan-KDM4 inhibitor which with poly lactic-co-glycolic acid formulation effectively
Jai-Shin Liu1,2, Wei-Kai Fang1,3, Shan-Min Yang1
1Institute of Molecular and Cellular Biology and Department of Life Sciences, National Tsing-Hua University, Hsinchu, 30013, Taiwan.
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.
Insights
Myricetin, a natural compound, effectively inhibits KDM4 demethylase activity and reduces castration-resistant prostate cancer (CRPC) cell growth. Combining PLGA-encapsulated myricetin with enzalutamide shows promising antitumor effects in CRPC models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Castration-resistant prostate cancer (CRPC) remains a challenge due to sustained androgen receptor (AR) signaling.
- KDM4A-KDM4C demethylases are key AR coactivators and therapeutic targets in prostate cancer.
- Overcoming resistance mediated by AR mutations/alterations in CRPC is critical.
Purpose of the Study:
- To identify natural products inhibiting KDM4 demethylase activity.
- To evaluate the therapeutic potential of myricetin in CRPC.
- To assess the efficacy of combining myricetin with enzalutamide for CRPC treatment.
Main Methods:
- Structure-based screening identified myricetin as a KDM4 inhibitor.
- Inhibition kinetics and cytotoxic effects of myricetin on prostate cancer cells were evaluated.
- Combined effects of myricetin and enzalutamide were assessed in vitro and in vivo using PLGA-encapsulated myricetin.
Main Results:
- Myricetin potently inhibited KDM4 demethylase activity, reducing proliferation in androgen-dependent and CRPC cells.
- A synergistic cytotoxic effect was observed for myricetin combined with enzalutamide.
- PLGA-myricetin and enzalutamide combination demonstrated superior antitumor activity in a CRPC xenograft model.
Conclusions:
- Myricetin acts as a pan-KDM4 inhibitor with significant cytotoxicity against CRPC cells.
- PLGA-encapsulated myricetin combined with enzalutamide represents a potentially effective therapeutic strategy for CRPC.
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