Abstract 607: Andrographis and aronia berry extract synergistically exhibit anticancer effects in colorectal cancer by activating the p-YAP/PUMA signaling pathway

Abstract Background: Colorectal cancer (CRC) is the third leading cause of cancer-related mortality worldwide, posing a persistent global health challenge. Despite advancements in current therapeutic strategies, the emergence of resistance highlights the urgent need for novel treatment approaches to overcome their limited efficacy. Among these, natural products have emerged as a promising resource due to their high efficacy, low toxicity, and potential for integration into dietary regimens. The antioxidant and anti-inflammatory properties of Andrographis (Andro) and Aronia berry extract (ABE) counteract cancer by neutralizing free radicals, reducing inflammation, and enhancing immune function. Herein, we hypothesize that their combined treatment may synergistically regulate multiple oncogenic pathways, leading to enhanced anti-cancer effects in CRC. Methods: The synergistic anticancer effects and mechanisms of Andro and ABE in CRC were evaluated through a combination of functional assays and genome-wide transcriptomic profiling. Clonogenic, cell viability, flow cytometry, and transwell migration assays were employed to assess their impact on cell proliferation, apoptosis, and metastatic potential. Transcriptomic analysis was performed to identify the key signaling pathways modulated by the combination treatment. Finally, these findings were validated using CRC patient-derived 3D organoids (PDOs). Results: The combined treatment with Andro and ABE exhibited synergistic anti-tumor effects in CRC cells by suppressing cell viability, proliferation, migration, and invasion. Transcriptomic profiling revealed a significant upregulation of PUMA expression (Andro vs. Control, log2Foldchange [FC]: 1.29, P = 0.01; ABE vs. Control, log2FC: 1.08, P = 0.001), which was associated with modulation of the Hippo-YAP pathway (Fold enrichment: 5.06, P = 0.0009). Mechanistically, Andro, and ABE synergistically promote YAP phosphorylation (p-YAP), which in turn enhances PUMA expression, thereby driving apoptosis in CRC cells, as confirmed by western blot, qRT-PCR, and flow cytometry analyses. These findings were validated in PDOs, which showed reduced size and number, and increased p-YAP activation and PUMA expression, underscoring the therapeutic potential of the combination treatment. Conclusion: In summary, our research provides strong evidence that the combination of Andro and ABE could be a potent and safe integrative approach for CRC treatment. The synergistic activation of the p-YAP/PUMA signaling pathway by these natural products induces apoptosis in CRC cells, offering a promising new direction for cancer treatment. Citation Format: Kainan Wang, Yuan Li, Caiming Xu, Ajay Goel. Andrographis and aronia berry extract synergistically exhibit anticancer effects in colorectal cancer by activating the p-YAP/PUMA 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 607.