Synergistic Potential of Argentatins A and B to Improve 5-Fluorouracil Cytotoxicity in Colorectal Cancer Cell Models

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second most common cause of cancer-related death in both men and women. Although a number of treatments are available to combat this malignancy, the antimetabolite 5-fluorouracil has been the cornerstone of therapy since its synthesis in the 1950s. Unfortunately, the prolonged use of 5-fluorouracil can lead to chemoresistance, which has prompted research into combination regimens to improve efficacy and quality of life and reduce resistance. Here, we evaluated the synergistic potential of two compounds isolated from guayule, and argentatins A and B, alone and in combination with 5-fluorouracil in a panel of colorectal cancer cell lines. Cell viability assays showed that the combination treatment (argentatin A with 5 fluorouracil) significantly enhanced cytotoxicity, especially in RKO, where the analysis using the Bliss independence model indicated a remarkable synergistic effect with the lowest doses of both compounds. In contrast to the combination with argentatin B, in which the additive effect was only found in the HCT-116 cell line. Finally, immunocytometric analysis revealed that combination treatments induced higher rates of apoptosis than single-agent treatments. Collectively, our findings indicate that argentatins A and B may enhance the anti-tumour effects of 5-fluorouracil and may represent a promising strategy to improve the efficacy of anticancer therapies based on this antimetabolite.