Abstract
Introduction: The triphenyl phosphonium residue is a well-documented mitochondriotropic that has been shown to improve the accumulation of biomolecules in mitochondria. Stearyl triphenyl phosphonium (STPP) modified liposomes have been shown to facilitate the selective accumulation of various biomolecules in mitochondria resulting in improved effect in-vitro and in-vivo. More recently, STPP was reported to have higher toxicity towards a drug resistant ovarian cancer cell line compare to a non-drug resistant cell line. The purpose of this study was to further investigate STPP toxicity using multiple drug resistant and non-drug resistant cell lines. Methods: STPP was incorporated into phosphatidylcholine cholesterol liposomes using the thin film hydration method. Mean particle size and zeta potential was measured using dynamic light scattering. The 5,5,6,6′-tetrachloro-1,1′,3,3′ tetraethylbenzimi-dazoylcarbocyanine iodide (JC-1) dye accumulation assay was used as an indicator of mitochondrial membrane potential in the tested cell lines. Cytotoxicity of the preparations towards different cell lines was determined using light microscopy and the CellTiter 96® AQueous One Solution Cell Proliferation assay. Results: The JC-1 accumulation assay confirmed that the drug-resistant cell lines had significantly higher dye accumulation than the non-drug resistant cell lines. Higher cytotoxicity of STPP towards drug resistant cell line was seen when incorporated into liposomes but not when dissolved in dimethyl sulfoxide (DMSO). STPP showed a comparable toxicity profile to the known oxidative phosphorylation uncoupler carbonyl cyanide p-trifluoro-methoxyphenyl hydrazone (FCCP). Discussion: Taken together, the data suggest that higher STPP toxicity in the drug-resistant cell lines is influenced by the presence of liposomal lipids and that STPP acts in a way similar to an oxidative phosphorylation uncoupler and is therefore more toxic to the drug-resistant cells that rely on a higher mitochondrial membrane potential to maintain their viability.
Highlights
Recent advances in cancer research have resulted in the addition of molecular targeted and immune-therapy approaches to the traditional chemotherapeutic approaches to cancer therapy [1, 2]
We explored the use of mitochondriotropic liposomes to deliver paclitaxel in order to test the hypothesis that paclitaxel resistance could be bypassed in drug resistant tumor cells by increasing the accumulation of paclitaxel in mitochondria [5]
JC-1 is well known to accumulate in mitochondria of cells that have a high mitochondrial membrane potential and reach a high enough concentration in the mitochondrial network to result in the dimerization of the dye molecules [16–18]
Summary
Recent advances in cancer research have resulted in the addition of molecular targeted and immune-therapy approaches to the traditional chemotherapeutic approaches to cancer therapy [1, 2]. Despite these recent advances, effective cancer therapy remains challenging. We explored the use of mitochondriotropic liposomes to deliver paclitaxel in order to test the hypothesis that paclitaxel resistance could be bypassed in drug resistant tumor cells by increasing the accumulation of paclitaxel in mitochondria [5]. The mitochondriotropic liposomes were prepared with stearyl triphenyl phosphonium (STPP). The triphenyl phosphonium ligand is well established as a mitochondria specific targeting ligand and its conjugation to a stearyl chain allows incorporation into liposomes in a
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