Mechanistic insights into Telmisartan-enhanced doxorubicin cytotoxicity in cancer cell lines

Background: Telmisartan, an angiotensin II receptor blocker, has shown potential anticancer properties beyond its antihypertensive effects. Recent studies suggest that its combination with doxorubicin may enhance cytotoxicity in cancer cell lines through synergistic mechanisms involving apoptosis modulation and drug resistance attenuation. Aims of the study: The aim of this study is to evaluate the synergistic cytotoxic effects of telmisartan in combination with doxorubicin on A549 lung cancer cell lines and to investigate the underlying mechanisms involved in enhancing apoptosis and reducing drug resistance. Methodology: The study, conducted at Iraq Biotech Company in Basrah (Jan-May 2024), evaluated cytotoxic effects on A549 lung cancer cells across four treatment groups: control, Doxorubicin, Telmisartan, and their combination. Each group was exposed to six concentrations (25-800 μg/mL) for 72 hours. Standard cell culture protocols were followed using RPMI-1640 medium, supplements, and sterilized solutions. Cells were cultured, subcultured, and treated under standard conditions. Viability was assessed using Trypan blue, and cytotoxicity was measured via the MTT assay. Results: The results showed that cell inhibition increased significantly with higher doxorubicin concentrations, with the combined treatment of doxorubicin and telmisartan producing much greater inhibition than either drug alone. The combination reached 86.78% inhibition at 800 mg/ml, showing strong synergy, especially at lower doses where increases exceeded 400%. The IC₅₀ for the combination (72.21 µg/ml) was much lower than for doxorubicin or telmisartan alone, confirming enhanced efficacy. The combination also allowed dose reductions (DRI > 8), improving therapeutic potential and reducing side effects. Overall, combined therapy significantly boosted cytotoxicity and stability compared to single treatments. Conclusions: The combination of Doxorubicin and Telmisartan enhances cytotoxicity against A549 cells due to a synergistic effect. This is supported by reduced IC50 and increased caspase-3 activity, suggesting enhanced apoptosis and potential for dose reduction and lower toxicity.