A marine-derived meroterpenoid inhibits colorectal cancer via PI3K pathway modulation in mice.

Authors

Ming-Qian Han, Ji-Chao Zhang, Ying-Jie Zhao, Yun-Feng Liu, Hua-Jie Zhu, Charles U Pittman, Fei Cao

Published in

Marine life science & technology. Volume 8. Issue 3. Pages 767-782. Epub Mar 05, 2026.

Abstract

Colorectal cancer is among the most leading cancers in China, characterized by activating mutations in PIK3CA or aberrant AKT signaling in approximately 30%-40% of cases. Marine natural products, especially those derived from marine fungi, offer a valuable source of novel phosphatidylinositol 3-kinase (PI3K) inhibitors. In this study, two novel phenylspirodrimane-type meroterpenoids, chloropenoids A and B (1 and 2), along with ten known analogues (3-12), were isolated from the marine-derived fungus Stachybotrys chlorohalonatus. The absolute configurations of 1 and 2 were established by time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculations. Structural optimization via esterification at the C-2' position of 3 generated a series of derivatives (3a-3i), among which derivative 3a displayed potent antiproliferative activity against CT-26 colorectal cancer cells. Mechanistic studies revealed that 3a disrupted mitochondrial membrane potential, induced apoptosis (total apoptosis rate: approximately 32% at 12.50 μM), and induced G1-phase cell cycle arrest. Molecular docking and Western blot assays demonstrated that 3a effectively inhibited PI3K phosphorylation, consequently attenuating the PI3K/AKT/mTOR signaling cascade. In vivo evaluation using a BALB/c mouse xenograft model revealed that intraperitoneal administration of 3a (50 mg/kg/day for 10 days) significantly suppressed tumor growth (Tumor Growth Inhibition = 85.2%) compared with the control group, exhibiting superior efficacy and reduced systemic toxicity compared to the standard chemotherapy drug, 5-fluorouracil. These findings identify compound 3a as a promising candidate for further development as a PI3K inhibitor for colorectal cancer therapy and provide critical mechanistic insights into phenylspirodrimane-based antitumor agents.
The online version contains supplementary material available at https://doi.org/10.1007/s42995-026-00356-7.

PMID:
42668644
Bibliographic data and abstract were imported from PubMed on 30 Aug 2026.

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