Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.

Abstract

Mitochondrial oxygen consumption, dynamics and morphology play roles in the occurrence, development and drug resistance of cancer; thus they are main targets for many anticancer drugs. Increased mitochondrial oxygen consumption and impaired oxygen delivery creates hypoxia, which influences the balance of metabolic co-factors for biogenesis, disease progression and response to therapeutics. We therefore investigated the effects of Taxol, a well-known anticancer drug, on mitochondrial respiration (principally via a measure of oxidative phosphorylation (OXPHOS) versus glycolysis), morphology and dynamics. The concomitant effects of Taxol on mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, mitochondrial membrane potential, radical-induced formation of carbonyl groups, mitochondrial release of cytochrome c, as well as cell cycle were investigated. Cells used in this study include: A549 (non-small cell lung epithelial cancer cell line), A549-ρ⁰ (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as PC3 (prostate cancer) and HepG2 (hepatocellular carcinoma); these cell lines are known to have disparate metabolic profiles. Using a multitude of fluorescence-based measurements, we show that Taxol, even at a low dose, still adversely effects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and OXPHOS, fragmentation of the mitochondrial network and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Non-cancer cells, which are oxidative, do not show these changes.