Synergistic effects of abietic acid combined with doxorubicin on apoptosis induction in a human colorectal cancer cell line

Cancer is a significant global disease with high mortality and limited therapeutic options. Chemotherapy is a cancer treatment option; however, there are still issues, including severe side effects, inadequate response, and drug resistance. Abietic acid is a natural diterpene with diverse pharmacological properties and can be used for cancer treatment. Therefore, this study aimed to assess the anticancer efficacy of abietic acid in combination with doxorubicin, a highly clinically used chemotherapeutic agent. Biochemical investigations include initial viability assays, combination therapy using isobologram analysis, apoptosis and cell cycle assays, gene expression assay, ELISA analysis of protein expression, DNA fragmentation, and wound healing assays. The data showed that doxorubicin-abietic acid (DOX-AB) is an effective and safe anticancer combination for Caco-2 cells. DOX-AB had a high safety index with minimal cytotoxicity at the combination dose on normal WI-38 fibroblasts cells. DOX-AB significantly decreased the proliferation and viability of Caco-2 cells, with an increase in the apoptosis rate in the late stage and necrosis with cell cycle arrest at the G₂/M phase. Significant changes in the expression of modulators related to apoptosis, inflammation, and epigenetics were observed in gene and protein levels. DOX-AB combination had more efficient anticancer activity than doxorubicin alone. This study suggested that the use of abietic acid in combination with doxorubicin is a promising treatment for colorectal cancer because it enhances doxorubicin activity at relatively low doses with minimal cytotoxicity and overcomes multidrug resistance in tumors; these findings merit further investigation.