Radioprotective Effects of Mitochondria-Targeted Antioxidant SkQR1

Abstract

We show here that mitochondria-targeted antioxidant composed of plastoquinone conjugated through hydrocarbon linker with cationic rhodamine 19 (SkQR1) protected against nuclear DNA damage induced by gamma radiation in K562 erythroleukemia cells. We also demonstrate that SkQR1 prevented the early (1 h postirradiation) accumulation of phosphorylated histone H2AX (γ-H2AX) an indicator of DNA double-strand break formation, as well as the radiation-induced increase in chromosomal aberrations. These data suggested that nuclear DNA damage induced by gamma radiation may be mediated by mitochondrial reactive oxygen species (ROS) production. We show that SkQR1 suppressed delayed accumulation of ROS 32 h after irradiation probably by inhibiting mitochondrial ROS-induced ROS release mechanisms. This suggests that mitochondria-targeted antioxidants may protect cells from the late consequences of radiation exposure related to delayed oxidative stress. We have previously reported that SkQRl is the substrate of multidrug resistance pump P-glycoproten (Pgp 170) and selectively protects Pgp 170-negative cells against oxidative stress. In line with this finding, we demonstrate here that SkQR1 did not protect Pgp170-positive K562 subline against DNA damage induced by gamma radiation. The selective radioprotection of normal Pgp 170-negative cells by mitochondria-targeted antioxidants could be a promising strategy to increase the efficiency of radiotherapy for multidrug-resistant tumors.

Mitochondria-Targeted Triphenylphosphonium-Based Compounds: Syntheses, Mechanisms of Action, and Therapeutic and Diagnostic Applications

“…509 Another mitochondria-targeted quinone, SkQR1, was reported to be the substrate of multidrug resistance pump P-glycoprotein (Pgp 170) and to selectively protect Pgp 170-negative cells against oxidative stress. 510 Conversely, SkQR1 did not protect Pgp170-positive K562 subline against DNA damage induced by gamma radiation. The selective radioprotection of normal Pgp 170-negative cells by mitochondria-targeted antioxidants could be a promising strategy to increase the efficiency of radiotherapy for multidrug-resistant tumors.…”

Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR

“…Several reports have shown that delayed production of ROS from mitochondria is observed in human hepatocellular carcinoma HLE cells [10,11], HeLa cells [12,13], human umbilical vein endothelial cells (HUVECs) [14], human leukemic cells K562 cells [15,16], HL60 cells [16], normal human foreskin fibroblast BJ-hTERT cells [17], and Chinese hamster ovary cells [18] after exposure to ionizing radiation. Moreover, it has been reported that the antitumor genotoxic drugs cisplatin- [19] and doxorubicin- [20] induced ROS release from mitochondria is linked to tumor apoptosis.…”

Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model

“…While the role of mitochondrial alterations in RIHD are not yet known, studies in other organ systems have shown a clear contribution of mitochondria to normal tissue radiation injury. Hence, mitochondrially-targeted antioxidants and antioxidant enzyme mimetics serve as radiation protectors and mitigators (11, 12). To determine whether POLY-MVA could slow down or reverse the adverse effects of radiation in the heart, the current study was designed to start POLY-MVA administration at 18 weeks after local heart irradiation, a time point at which manifestations of RIHD have become apparent.…”

“…Studies in organ systems other than the heart have shown a clear contribution of mitochondria to normal tissue radiation injury (11, 12). Radiation-induced heart injury in rodent models has been shown to be associated with mitochondrial dysfunction (13, 14).…”