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<p>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 (<b>1</b> and <b>2</b>), along with ten known analogues (<b>3</b>–<b>12</b>), were isolated from the marine-derived fungus <i>Stachybotrys chlorohalonatus</i>. The absolute configurations of <b>1</b> and <b>2</b> were established by time-dependent density functional theory electronic circular dichroism (TDDFT-ECD) calculations. Structural optimization via esterification at the C-2′ position of <b>3</b> generated a series of derivatives (<b>3a</b>–<b>3i</b>), among which derivative <b>3a</b> displayed potent antiproliferative activity against CT-26 colorectal cancer cells. Mechanistic studies revealed that <b>3a</b> disrupted mitochondrial membrane potential, induced apoptosis (total apoptosis rate: approximately 32% at 12.50&#xa0;μM), and induced G1-phase cell cycle arrest. Molecular docking and Western blot assays demonstrated that <b>3a</b> 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 <b>3a</b> (50&#xa0;mg/kg/day for 10&#xa0;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 <b>3a</b> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月5日

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

摘要

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.