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 cofactors 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 versus glycolysis), morphology, and dynamics. The concomitant effects of Taxol on mitochondrial ATP and reactive oxygen species 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 the following: A549 (non-small-cell lung epithelial cancer cell line), A549-ρ⁰ (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a noncancer 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 affects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and oxidative phosphorylation, fragmentation of the mitochondrial network, and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Noncancer cells, which are oxidative, do not show these changes.