Abstract 602: Synergistic anti-tumor effects of andrographis and lactoferrin in colorectal cancer via modulation of AXIN2/Wnt/E-cadherin signaling pathway

Abstract Background: Colorectal cancer (CRC) is one of the most common malignancies worldwide and 20-25% of patients experience metastatic colorectal cancer (mCRC) at initial diagnosis. However, the high mortality rates associated with mCRC are largely due to the inadequate efficacy of current treatments and the development of acquired resistance to conventional chemotherapy. Recent studies have indicated that Lactoferrin is frequently used as a drug transport carrier, enhancing drug absorption. Natural compounds like Andrographis offer cost-effective, multi-targeted treatments for tumors. Therefore, we hypothesize that Lactoferrin might serve as a transport carrier for Andrographis, improving its bioabsorption and in offering a more pronounced anticancer activity in CRC. Methods: We conducted a series of in-vitro and in-vivo experiments to evaluate the synergistic anticancer effects of Lactoferrin and Andrographis in CRC. Furthermore, we performed a genomewide transcriptomic analysis to identified specific growth-signaling pathways targeted by the combined treatment and subsequently validated these findings in cell lines and patient-derived 3D organoids. Results: The combined treatment with Lactoferrin and Andrographis exhibited excellent synergistic anti-tumor potential, affecting cell viability, proliferation, migration, and invasion in CRC cells. In CRC, metastasis commonly occurs through the epithelial-mesenchymal transition. This combination treatment exerted the most pronounced effects on β-catenin responsive transcription and E-cadherin promoter activity. Mechanistically, transcriptomic analysis revealed that the combined treatment resulted in the inhibition of AXIN2 which resulted in E-cadherin-mediated inhibition of Wnt signaling ([FC]: 3.46, P < 0.005). Additionally, we observed that the expression levels of AXIN2 were significantly higher in cancer vs. normal tissues (P < 0.005) in the TCGA dataset. Finally, in 3D organoid models, the combined treatment exhibited superior anti-cancer activity, significantly reducing both the number and size of organoids (P < 0.05). These findings highlight the therapeutic potential of targeting the AXIN2/Wnt/E-cadherin axis with Lactoferrin and Andrographis in CRC. Conclusion: We present evidence that the synergistic anticancer effects of Lactoferrin and Andrographis in CRC are mediated through the AXIN2/Wnt/E-cadherin axis, highlighting their potential as a therapeutic strategy. Citation Format: Yuan Li, Caiming Xu, Takayuki Noma, Ajay Goel. Synergistic anti-tumor effects of andrographis and lactoferrin in colorectal cancer via modulation of AXIN2/Wnt/E-cadherin signaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 602.