Cardioprotective effects of melatonin and metformin against doxorubicin-induced cardiotoxicity in rats are through preserving mitochondrial function and dynamics.
Doxorubicin (Dox) is widely used in chemotherapy regimens for several malignant conditions. Unfortunately, cumulative and irreversible cardiotoxicity of Dox is the most prominent adverse effect which limits its use. Several pharmacological interventions which exert antioxidant properties, including melatonin and metformin, have demonstrated beneficial effects against various cardiac pathological conditions. However, the exact molecular mechanisms underlying their cardioprotective effects are not completely understood. We hypothesized that treatment with either melatonin or metformin provides cardioprotection against Dox-induced cardiotoxicity through mitochondrial protection. Thirty-two male Wistar rats received 6 doses of either 0.9% normal saline solution (0.9% NSS, n = 8) or Dox (3 mg/kg, i.p., n = 24). The Dox-treated rats (n = 8/group) were co-treated with: 1) Vehicle (0.9% NSS), 2) Melatonin (10 mg/kg/day), and 3) Metformin (250 mg/kg/day) for 30 consecutive days via oral gavage. Following the treatment, left ventricular (LV) function, oxidative stress, inflammation, mitochondrial function, dynamics, biogenesis and bioenergetics, mitophagy, autophagy, and apoptosis were determined. Dox induced excessive oxidative stress, inflammation, autophagy, apoptosis, reduced mitochondrial function, dynamics balance, biogenesis, and bioenergetics leading to LV dysfunction. Treatment with either melatonin or metformin exerted equal measures of cardioprotection via reducing oxidative stress, inflammation, autophagy, apoptosis, and improved mitochondrial function, dynamics balance, biogenesis, and bioenergetics in the Dox-treated rats. Melatonin and metformin exerted both anti-cancer and cardioprotective properties, suggesting they have potential roles in concomitant therapy in cancer patients receiving Dox treatment.
Arinno A
，Maneechote C
，Khuanjing T
，Ongnok B
，Prathumsap N
，Chunchai T
，Arunsak B
，Kerdphoo S
，Shinlapawittayatorn K
，Chattipakorn SC
，Chattipakorn N
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All-trans retinoic acid protects against doxorubicin-induced cardiotoxicity by activating the ERK2 signalling pathway.
Doxorubicin is a powerful antineoplastic agent for treating a wide range of cancers. However, doxorubicin cardiotoxicity of the heart has largely limited its clinical use. All-trans retinoic acid (ATRA) plays an important role in many cardiac biological processes, but its protective effects on doxorubicin-induced cardiotoxicity remain unknown. Here, we studied the effect of ATRA on doxorubicin cardiotoxicity and the underlying mechanisms.
Cellular viability assays, Western blotting and mitochondrial respiration analyses were employed to evaluate the cellular response to ATRA in H9c2 cells and primary cardiomyocytes. Quantitative PCR and gene knockdown were performed to investigate the underlying molecular mechanisms of ATRA's effects on doxorubicin cardiotoxicity.
ATRA significantly inhibited doxorubicin-induced apoptosis in H9c2 cells and primary cardiomyocytes. ATRA was more effective against doxorubicin cardiotoxicity than resveratrol and dexrazoxane. ATRA also suppressed reactive oxygen species generation and restored expression levels of mRNA and proteins in the phase II detoxifying enzyme system: nuclear factor-E2-related factor 2, manganese superoxide dismutase, haem oxygenase-1, and mitochondrial function (mitochondrial membrane integrity, mitochondrial DNA copy numbers and mitochondrial respiration capacity, biogenesis and dynamics). Both a ERK1/2 inhibitor (U0126) and ERK2 siRNA, but not ERK1 siRNA, abolished the protective effect of ATRA against doxorubicin-induced toxicity in H9c2 cells. Remarkably, ATRA did not compromise the anticancer efficacy of doxorubicin in gastric carcinoma cells.
ATRA protected cardiomyocytes against doxorubicin-induced toxicity, by activating the ERK2 pathway, without compromising its anticancer efficacy. Therefore, ATRA is a promising candidate as a cardioprotective agent against doxorubicin cardiotoxicity.
Yang L
，Luo C
，Chen C
，Wang X
，Shi W
，Liu J
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