Abstract 571: Andrographolide enhances sensitivity to 5-fluorouracil by targeting ferroptosis-related genes in colorectal cancer

Abstract

Abstract Purpose: Despite improvements in response rates from various treatment strategies, the 5-year survival rates for metastatic colorectal cancer (mCRC) remain dismal (~10-15%). One of the primary reasons for CRC therapy failure is development of acquired drug resistance to first line chemotherapies such as 5-fluorouracil (5FU), and nearly half of all mCRC patients are resistant to 5FU-based therapies. These limitations highlight the need for novel treatment strategies that offer improved efficacy and can help overcome acquired chemoresistance and enhance anti-cancer efficacy of conventional chemotherapies. Considering that some naturally-occurring botanicals have chemo-sensitizing properties, we analyzed the potential of andrographolide, a botanical with key biological activities, including anti-inflammatory, antitumorigenic, apoptotic, antiangiogenic and immunomodulatory activities, in reversing chemoresistance in CRC, and also delineated the associated molecular pathways underpinning this activity. Experimental design: We performed a series of in-vitro and in-vivo experiments to investigate the chemo-sensitizing ability of andrographolide in 5-FU resistant (5FUR) CRC cells, xenografts animal models and CRC-derived organoids. Furthermore, we performed gene expression microarrays and other mechanistic studies to explore the molecular mechanisms responsible for its chemo-sensitizing activity. Results: Andrographolide treatment significantly enhanced the efficacy of 5FU in HCT116 5FUR and SW480 5FUR cells, as evidenced by enhanced apoptosis and decreased proliferation rates (p<0.05). In line with our in-vitro findings, treatment with andrographolide also led to significant tumor growth inhibition in a xenograft animal model (p<0.0001). Likewise, in accordance with the results from cell lines and mice xenografts, the combination of 5FU and andrographolide significantly decreased the growth of patient-derived tumor organoids compared to those treated with 5FU alone (p<0.01 for patient 1, p<0.05 for patient 2). Through microarray-based gene expression profiling analysis in 5FU-resistant CRC cells, we identified ferroptosis and WNT signaling as the key cancer associated pathways responsible for andrographolide mediated chemo-sensitization in CRC cells. Taken together, using genome-wide gene expression analysis, we delineated the mechanism underlying the chemo-sensitizing properties of andrographolide and made a case for the potential use of andrographolide for enhancing the therapeutic efficacy of 5FU in CRC. Conclusion: Our data provides first evidence for andrographolide mediated sensitization to 5FU based therapy, through modulation of ferroptosis pathway in CRC. These results highlight the potential adjunctive therapeutic role for andrographolide in combination with conventional chemotherapeutic drug in patients with CRC. Citation Format: Priyanka Sharma, Tadanobu Shimura, Jasjit K Banwait, Ajay Goel. Andrographolide enhances sensitivity to 5-fluorouracil by targeting ferroptosis-related genes in colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 571.