<i>In vitro</i> cytotoxicity of liposomal stearyl triphenyl phosphonium is influenced by mitochondrial bioenergetics

Stearyl triphenyl phosphonium (STPP) has previously been utilized to prepare mitochondriotropic liposomes for improved drug delivery to mitochondria. Additionally, liposomal STPP has shown higher toxicity toward drug-resistant tumor cells compared to non-drug-resistant tumor cells. The differential toxicity is hypothesized to be due to the differences in mitochondrial bioenergetics between drug-resistant and non-drug-resistant cells. This study aimed to further test the hypothesis by using drug-resistant and non-drug-resistant cell lines from ovarian, lung, uterine and breast carcinomas. Mitochondrial function was assessed by JC-1 dye accumulation and by measurement of oxygen consumption rate. Liposomal STPP cytotoxicity was then assessed using a metabolic assay. The drug-resistant ovarian, lung and uterine carcinoma cell lines showed higher mitochondrial activity compared to their non-drug-resistant counterparts while there was no difference in mitochondrial activity between drug-resistant and non-drug-resistant breast carcinoma cell lines. Consistent with the hypothesis of the study, liposomal STPP showed greater toxicity to the drug-resistant ovarian and uterine carcinoma cell lines compared to the non-drug-resistant cell lines and no difference in toxicity between drug-resistant and non-drug-resistant breast carcinoma cell lines. While liposomal STPP was more toxic toward the non-drug-resistant cell line in the case of lung carcinoma, the effect is likely due to the use of altered growth conditions for the non-drug-resistant cell line that were needed to allow testing by the assays used in the study. Collectively, the results suggest the potential for exploiting mitochondrial bioenergetic differences to target drug-resistant and non-drug-resistant tumor cell populations in a variety of tumor types.