Marine-Derived Yaequinolone Derivative CHNQD-02792 Suppresses Colorectal Cancer Cell Proliferation and Induces Apoptosis via MAPK Pathway Modulation.

Abstract

Colorectal cancer is currently the third most common malignancy, and the toxic side effects of clinical therapeutic drugs often influence treatment outcomes. Marine-derived quinolone alkaloids exhibit various biological activities and are particularly notable for their antitumor properties. Compounds 1-13 were semi-synthesized based on 4'-desmethoxyyaequinolone J1, which is a 4-phenyl derivative of the natural quinolone alkaloid yaequinolone J1 and was isolated from Penicillium sp. FKI-2140. This study is the first to investigate the antitumor activity of 1-13 in colorectal cancer cells through proliferation, clonality, apoptosis, cell cycle, and MAPK signaling pathway. Cytotoxicity screening against seven colorectal cancer cell lines revealed that CHNQD-02792 (13) had the most sensitivity to HT-29 cells (IC₅₀ = 4.5 μM), far exceeding positive control 5-fluorouracil (IC₅₀ = 15.58 μM). The plate cloning assay revealed that CHNQD-02792 completely inhibited the growth of HT-29 cells at the concentration of 9 μM. CHNQD-02792 (4.5 μM) inhibited CDK1 expression and triggered G2/M phase arrest in HT-29 cells. Mechanistic analysis revealed that CHNQD-02792 induced apoptosis by suppressing the anti-apoptotic protein Bcl-2 and upregulating the pro-apoptotic proteins Caspase-3 and Bax. Furthermore, CHNQD-02792 inhibited ERK and JNK phosphorylation and thus highlighted its regulatory role in MAPK signaling. These findings suggest that CHNQD-02792 exerts cytotoxic effects on HT-29 cells via dual mechanisms: inducing G2/M arrest and apoptosis while regulating MAPK signaling through ERK/JNK dephosphorylation. This study demonstrates the dual targeting of CHNQD-02792 against tumor cell proliferation and survival pathways, providing a foundation for further development of anti-colorectal cancer drugs.