Abstract
The radiation-induced damage to mitochondrial oxidative respiratory chain could lead to generating of superoxide anions (O2−) and secondary reactive oxygen species (ROS), which are the major resources of continuous ROS production after radiation. Scavenging radiation-induced ROS effectively can help mitochondria to maintain their physiological function and relief cells from oxidative stress. Dihydropyridines (DHPs) are biomimetic hydrogen sources that could protect cells against radiation damage. In this study, we designed and synthetized three novel mitochondrial-targeted dihydropyridines (Mito-DHPs) that utilize the mitochondrial membrane potential to enter the organelle and scavenge ROS. MitoTracker confirmed Mito-DHPs accumulation in mitochondria, and the DCFH-DA assay demonstrated effective ROS scavenging activity. In addition, the γ-H2AX and comet assay demonstrated the ability of Mito-DHPs to protect against both radiation and ROS-induced DNA strand breaks. Furthermore, Mito-DHP1 proved to be non-toxic and displayed significant radioprotection activity (p < 0.05) in vitro. Mito-DHPs are therefore promising antioxidants that could penetrate the membrane of mitochondria, scavenge excessive ROS, and protect cells against radiation-induced oxidative damage.
Highlights
Radiation technology is increasingly applied in physical and medical fields such as nuclear energy and radiotherapy, which is still a dominating way for cancer treatment [1]
Intracellular reactive oxygen species (ROS) attack enzymes involved in oxidative phosphorylation and the electron transport chain (ETC) in mitochondria [31]
Peroxidation of mitochondria membrane lipids disrupts enzyme activity aanndd pprroommootteess lleeaakkaaggee ooffOO22−− ffrroomm tthhee ETC, which is subsequently converted to H2OO22 oorr hhyyddrrooxxyyll rraaddiiccaallss tthhrroouugghh tthhee FFeennttoonn rreeaaccttiioonn aass seconddaarryy free radicals, leadingg totooxoidxaidtiavteivsetresstsreasnsd adnadmadgaemtoagneuclteoarnDuNclAear[32D].NLAeve[l3s2o].f sLeecovneldsaroyf RsOeScoindmarityocRhoOnSdrina amreitoincchroenadserdiaaaftreeriinrrcaredaiasetidona,fctearusirinragdwiaitdioen-r,acnaguisnignganwdidper-rsaisntgenintgoxainddatpiveerssitsrteesnst[1o6x]i.dative stress [16]
Summary
Radiation technology is increasingly applied in physical and medical fields such as nuclear energy and radiotherapy, which is still a dominating way for cancer treatment [1]. Radiation-induced damage is a tremendous potential threat to human body. It is necessary to develop substances that protect cells and tissues against radiation-induced injury. Radiation-induced damage can be divided into direct and indirect damage [8]. The intracellular ROS burst was mostly ascribed to radiation-induced mitochondria damage [9]. Mitochondria are responsible for cellular oxidative respiration through the process of oxidative phosphorylation [10,11], where the potential damaging free radical superoxide anion was constantly produced [12,13]. TThheeyy hhaavvee exxceelllleenntt antioxxiddaanntt prooppeerrttiieess aanndd ROS scavenggiinngg abilitiees [14]. Despite their ppoowweerrffuul ffrreeee--rraaddiiccaal ssccaavvenging capabilities, DHPs cannot be accumulated to mitochondria largely wwiitthhout tthhe ppoossitive cchharged lliippophilic structure. TThheese nnoovvel ccationic compounds were able to use the membrane potential, which is critical for ATTP synthesis and maintaining mitochondrial function, to cross the mitochondrial membrane in order ttoo scavennggee RROOSS aanndd pprrootteeccttaaggaaiinnssttrraaddiiaattiioonn--iinndduucceeddmmiittoocchhoonnddrriiaallooxxiiddaattiivveeddaammaaggee
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