Abstract
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the hallmarks of doxorubicin-induced cardiotoxicity (DICT) is the cascade of mitophagy deficiency-mitochondrial oxidative injury-apoptosis, while so far, there is no preventive strategy for alleviating DICT by targeting this molecular mechanism. Excitedly, based on our previous drug screen in DICT zebrafish model, harpagoside (HAR) showed dramatic anti-DICT efficacy superior to dexrazoxane (DXZ) only cardioprotectant approved by FDA. Therefore, its pharmacological effects and molecular mechanism on DICT mouse and rat cardiomyocytes were further discussed. In vivo, HAR significantly improved cardiac function and myocardial structural lesions with concomitant of diminished mitochondrial oxidative damage and recovered mitophagy flux. In parallel, HAR protected mitophagy and mitochondria homeostasis, and repressed apoptosis in vitro. Intriguingly, both nutlin-3 (agonist of p53) and Parkin siRNA reversed these protective effects of HAR. Additional data, including fluorescence colocalization of Parkin and MitoTracker and mt-Keima for the detection of mitophagy flux and coimmunoprecipitation of p53 and Parkin, showed that HAR promoted Parkin translocation to mitochondria and substantially restored Parkin-mediated mitophagy by inhibiting the binding of p53 and Parkin. Importantly, the results of the cell viability demonstrated that cardioprotective effect of HAR did not interfere with anticancer effect of DOX on MCF-7 and HepG2 cells. Our research documented p53-Parkin-mediated cascade of mitophagy deficiency-mitochondrial dyshomeostasis-apoptosis as a pathogenic mechanism and druggable pathway and HAR as a cardioprotection on DICT by acting on novel interaction between p53 and Parkin.
Highlights
Anthracycline quinone doxorubicin is a potent and broadspectrum chemotherapeutic agent isolated from Streptomyces peucetius in 1967 and has been widely used for the treatment of numerous solid tumours and leukaemias (Blum and Carter, 1974)
We further evaluated the cardioprotective effect of HAR in doxorubicin-induced cardiotoxicity (DICT) mouse model
The impact of HAR and DOX on the cardiac function of mice were evaluated by echocardiography detection of left ventricular internal diameter at end-diastole (LVID; d), left ventricular internal diameter at endsystole (LVID; s), left ventricular anterior wall at end-diastole (LVAW; d), left ventricular anterior wall at end-systole (LVAW; s), left ventricular posterior wall at end-diastole (LVPW; d) and left ventricular posterior wall at end-systole (LVPW; s)
Summary
Anthracycline quinone doxorubicin is a potent and broadspectrum chemotherapeutic agent isolated from Streptomyces peucetius in 1967 and has been widely used for the treatment of numerous solid tumours and leukaemias (Blum and Carter, 1974). Mitophagy, a mitochondrial quality control mechanism that selectively removes damaged and unwanted mitochondria to maintain a healthy and functional mitochondrial population, has become one of the most promising therapeutic targets for the treatment of DICT (Catanzaro et al, 2019; Wang et al, 2019; Xiao et al, 2020). PTEN-inducible putative kinase 1 (PINK1)/ Parkinson juvenile disease protein 2 (Parkin)-mediated mitophagy is the most established mechanism of this process. When mitochondria are depolarized or damaged, Pink accumulates at mitochondrial outer membrane and phosphorylates mitofusin (Mfn2) as Parkin’s receptor which subsequently can recruit Parkin. A number of studies reported that DOX impedes Parkin-mediated mitophagy, resulting in the accumulation of damaged mitochondria and decline in cardiac function (Hoshino et al, 2013; Bartlett et al, 2017; Koleini and Kardami, 2017)
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