Abstract
Doxorubicin is a valuable antineoplastic drug although its clinical use is greatly hindered by its severe cardiotoxicity with dismal target therapy available. Luteolin is a natural product extracted from vegetables and fruits with a wide range of biological efficacies including anti-oxidative, anti-tumorigenic, and anti-inflammatory properties. This study was designed to examine the possible effect of luteolin on doxorubicin-induced cardiotoxicity, if any, and the mechanism(s) involved with a focus on mitochondrial autophagy. Luteolin application (10 μM) in adult mouse cardiomyocytes overtly improved doxorubicin-induced cardiomyocyte contractile dysfunction including elevated peak shortening amplitude and maximal velocity of shortening/relengthening along with unchanged duration of shortening and relengthening. Luteolin alleviated doxorubicin-induced cardiotoxicity including apoptosis, accumulation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential. Furthermore, luteolin attenuated doxorubicin-induced cardiotoxicity through promoting mitochondrial autophagy in association with facilitating phosphorylation of Drp1 at Ser616, and upregulating TFEB expression. In addition, luteolin treatment partially attenuated low dose doxorubicin-induced elongation of mitochondria. Treatment of Mdivi-1, a Drp1 GTPase inhibitor, negated the protective effect of luteolin on levels of TFEB, LAMP1, and LC3B, as well as loss of mitochondrial membrane potential and cardiomyocyte contractile dysfunction in the face of doxorubicin challenge. Taken together, these findings provide novel insights for the therapeutic efficacy of luteolin against doxorubicin-induced cardiotoxicity possibly through improved mitochondrial autophagy.
Highlights
Doxorubicin is an effective anti-neoplastic chemotherapeutic agent its clinical application has been greatly hindered by its severe and pronounced cardiotoxicity
Our results indicated that doxorubicin significantly promoted mTOR phosphorylation (Ser2448) and inhibited Drp1 phosphorylation (Ser616) without affecting pan protein expression of mTOR and Drp1 in adult mouse cardiomyocytes (AMCMs), the effect of which was overtly attenuated by luteolin (Figures 5D–H)
The salient findings from our study noted that luteolin protected against doxorubicin-induced contractile dysfunction and apoptosis in cardiomyocytes
Summary
Doxorubicin is an effective anti-neoplastic chemotherapeutic agent its clinical application has been greatly hindered by its severe and pronounced cardiotoxicity. Ample clinical and experimental evidence has depicted that doxorubicin triggers cardiac anomalies including tachycardia, myocardial injury and heart failure Extensive efforts have been made toward exploring the mechanisms behind doxorubicin-induced cardiotoxicity including accumulation of reactive oxygen species (ROS), compromised lysosomal function, reduction of ATP production, mitochondrial membrane potential collapse and apoptosis (Octavia et al, 2012; Ma et al, 2017; Guo et al, 2018). Ample evidence has indicated that luteolin offers cardiovascular protection including ischemia/reperfusion and heart failure through alleviating ROS and apoptosis, as well as intracellular Ca2+ dysregulation (Galati et al, 2001; He et al, 2012; Rao et al, 2012; Zhu et al, 2017). Several theories have been proposed for the underlying mechanisms of doxorubicin-induced cardiotoxicity including mitochondrial damage (Marechal et al, 2011; Octavia et al, 2012; Ichikawa et al, 2014), whether luteolin affects doxorubicin-induced cardiotoxicity remains elusive
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