ORIGINAL RESEARCH article
Front. Pharmacol.
Sec. Pharmacology of Anti-Cancer Drugs
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1576673
original article-basic 8-Nitrotryptanthrin inhibits colorectal cancer progression via TGF-β/SMAD and PI3K/AKT/mTOR pathways
Provisionally accepted
- 1Xuzhou Medical University, Xuzhou, Jiangsu Province, China
- 2Chinese Academy of Sciences (CAS), Beijing, China
- 3Jiangsu Normal University, Xuzhou, Jiangsu Province, China
- 4Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, Beijing Municipality, China
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Objective: To investigate the anticancer effects and underlying mechanisms of 8nitrotryptanthrin (8-Nitrotryp) against colorectal cancer (CRC).Methods: The effects of 8-Nitrotryp on proliferation, colony formation, and migration were evaluated in HCT116 and SW480 cells, with comparisons to its parent compound, tryptanthrin (Tryp). Mitochondrial membrane potential (MMP) was assessed using JC-1 staining, and early apoptosis was analyzed by flow cytometry.Proteomic analysis and Western blotting were employed to examine the modulation of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway and transforming growth factor-β (TGF-β)/Sma-and Mad-related proteins (SMAD) signaling pathways, as well as epithelial-mesenchymal transition (EMT).Results: 8-Nitrotryp significantly inhibited proliferation of HCT116 (IC₅₀ = 0.81-1.08 μM; P < 0.001) and SW480 cells (IC₅₀ = 0.76-1.59 μM; P < 0.001), suppressed colony formation of HCT116 (P < 0.001 at 1 μM) and of SW480 cells (P < 0.001 at 2 μM), and inhibited migration in a dose-dependent manner (0.5-2 μM), demonstrating greater potency than Tryp. It also suppressed MMP and induced early apoptosis in HCT116 (P < 0.001 at 1 μM) and SW480 cells (P < 0.001 at 0.5 μM). Proteomic analysis and Western blotting revealed that 8-Nitrotryp downregulated PI3K expression, inhibited phosphorylation of AKT and mTOR, and reduced TGF-β1-induced SMAD2 phosphorylation. Additionally, 8-Nitrotryp suppressed the EMT process. Conclusion: 8-Nitrotryp inhibits CRC progression by modulating the TGFβ/SMAD and PI3K/AKT/mTOR pathways, highlighting its potential as a multi-target therapeutic agent for CRC, warranting further investigation. Novelty and Impact: CRC is a global health challenge with limited treatments for advanced stages. This study provides the first evidence of 8-Nitrotryp's antitumor efficacy in CRC, demonstrating its dual inhibitory activity on the TGF-β/SMAD and PI3K/AKT/mTOR pathways. Compared to Tryp, 8-Nitrotryp exhibits markedly enhanced potency, with lower IC₅₀ values due to the introduction of a nitro group.Furthermore, the suppression of EMT is mechanistically linked to TGF-β/SMAD pathway inhibition. These findings suggest 8-Nitrotryp's potential as a novel therapeutic for CRC.
Keywords: Colorectal Neoplasms, 8-Nitrotryptanthrin, Signal Transduction, Transforming Growth Factor beta, Phosphatidylinositol 3-Kinases
Received: 14 Feb 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Sun, Cong, Zhao, Fan, Guo and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Mingquan Guo, Chinese Academy of Sciences (CAS), Beijing, China
Zheng-Guo Zhang, Xuzhou Medical University, Xuzhou, 221004, Jiangsu Province, China
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