Anticancer Synergy of Myricetin and Doxorubicin in Breast Cancer: Network Pharmacology and In Vitro Evaluation

Abstract

Breast cancer is a major public health problem worldwide, leading to an urgent need for the development of new strategies to improve treatment efficacy and manage drug resistance. Doxorubicin is among the most commonly used chemotherapy drugs and has the disadvantage of being easy resistance and toxicity, which causes limited efficiency. A potentially effective strategy is combining doxorubicin with natural compounds possessing anticancer activity and the ability to modulate drug resistance pathways. Therefore, this study aimed to explore the potential of combining myricetin and doxorubicin as an effective and safe anticancer treatment. A network pharmacology method was used to examine how the two compounds interact at the molecular level, including the target genes, signaling pathways, and possible synergistic effect. Additionally, laboratory (in vitro) tests were performed using MTT assay to evaluate the toxicity of the compounds to both T47D breast cancer and normal Vero cells. Several key parameters, including IC50 values of each compound, as well as the combination index and selectivity index (SI), were analyzed to evaluate the safety against normal cells. The results showed that the combination of myricetin and doxorubicin targeted 19 interconnected genes triggering apoptosis often associated with cancer treatment. Laboratory tests (in vitro) found that myricetin and doxorubicin had moderate anticancer or cytotoxic activity, with IC50 values of 31.936 µg/mL and 27.39 µg/mL, respectively. The combination at concentrations of 7.984 µg/mL myricetin + 3.424 µg/mL doxorubicin, 15.986 µg/mL myricetin + 3.424 µg/mL doxorubicin, and 31.936 µg/mL myricetin + 3.424 µg/mL doxorubicin had a powerful synergistic effect as well as high viability in Vero cells with a value of 168.756 µg/mL. Based on the determined combination concentrations and IC50 values of the compounds, myricetin, and doxorubicin showed potential synergistic activity against breast cancer cells. Breast cancer remains a significant global health challenge, necessitating the development of novel strategies to enhance treatment efficacy and combat drug resistance. Doxorubicin, a common chemotherapeutic drug, has limitations owing to its resistance and toxicity. This study investigated the potential of combining myricetin, a natural compound, with doxorubicin to address these issues. Employing a network pharmacology approach, we first explored the molecular interactions between myricetin and doxorubicin and identified target genes, signaling pathways, and potential synergistic effects. Concurrently, in vitro experiments using the MTT assay assessed the toxicity of the compounds in T47D breast cancer cells and normal Vero cells. The key parameters analyzed included the IC50 values, combination index, and selectivity index to evaluate safety. Our findings revealed that the combination of myricetin and doxorubicin targeted 19 interconnected genes that are frequently associated with apoptosis during cancer treatment. In vitro tests showed that both myricetin and doxorubicin exhibited moderate cytotoxic activity, with IC50 values of 31.936 µg/mL and 27.39 µg/mL, respectively. Specific combinations (e.g., 7.984 µg/mL myricetin + 3.424 µg/mL doxorubicin) demonstrated a powerful synergistic effect against breast cancer cells, while maintaining high viability in normal Vero cells (168.756 µg/mL). These results suggested that the combination of myricetin and doxorubicin offers a promising synergistic approach for breast cancer treatment.