Doxorubicin-induced oxidative stress: The protective effect of nicorandil on HL-1 cardiomyocytes

Abstract

The primary cardiotoxic action of doxorubicin when used as antitumor drug is attributed to the generation of reactive oxygen species (ROS) therefore effective cardioprotection therapies are needed. In this sense, the antianginal drug nicorandil has been shown to be effective in cardioprotection from ischemic conditions but the underlying molecular mechanism to cope with doxorubicin-induced ROS is unclear. Our in vitro study using the HL-1 cardiomyocyte cell line derived from mouse atria reveals that the endogenous nitric oxide (NO) production was stimulated by nicorandil and arrested by NO synthase inhibition. Moreover, while the NO synthase activity was inhibited by doxorubicin-induced ROS, the NO synthase inhibition did not affect doxorubicin-induced ROS. The inhibition of NO synthase activity by doxorubicin was totally prevented by preincubation with nicorandil. Nicorandil also concentration-dependently (10 to 100 μM) decreased doxorubicin-induced ROS and the effect was antagonized by 5-hydroxydecanoate. The inhibition profile of doxorubicin-induced ROS by nicorandil was unaltered when an L-arginine derivative or a protein kinase G inhibitor was present. Preincubation with pinacidil mimicked the effect of nicorandil and the protection was eliminated by glibenclamide. Quantitative colocalization of fluorescence indicated that the mitochondrion was the target organelle of nicorandil and the observed response was a decrease in the mitochondrial inner membrane potential. Interference with H+ movement across the mitochondrial inner membrane, leading to depolarization, also protected from doxorubicin-induced ROS. The data indicate that activation of the mitochondrial ATP-sensitive K+ channel by nicorandil causing mitochondrial depolarization, without participation of the NO donor activity, was responsible for inhibition of the mitochondrial NADPH oxidase that is the main contributor to ROS production in cardiomyocytes. Impairment of the cytosolic Ca2+ signal induced by caffeine and the increase in lipid peroxidation, both of which are indicators of doxorubicin-induced oxidative stress, were also prevented by nicorandil.

Native myocardial T1 time can predict development of subsequent anthracycline‐induced cardiomyopathy

“…One hypothesis includes the involvement of radical oxygen species, which are known to play a key role in anthracycline‐mediated cardiotoxicity and which affect mitochondrial function and increase lipid peroxidation …”

“…One hypothesis includes the involvement of radical oxygen species, which are known to play a key role in anthracyclinemediated cardiotoxicity and which affect mitochondrial function and increase lipid peroxidation. 30 Native T1 time is increased in case of myocardial oedema or inflammation and decreased by iron overload such as in haemochromatosis or in case of lipid deposition as in Fabry disease. 31 While it is unlikely that a temporary myocardial iron overload is triggered by anthracyclines, they may lead to an increase of intracellular lipid contents affecting native myocardial T1 times.…”

Nicorandil alleviates apoptosis in diabetic cardiomyopathy through PI3K/Akt pathway

“…11,12 Recent studies show that nicorandil can reduce the level of reactive oxygen species(ROS) in endothelial cells and regulate the PI3K/Akt pathway. [13][14][15] However, whether it can alleviate cardiomyocyte apoptosis in diabetic cardiomyopathy has not been reported yet.…”

Oxidation-Triggerable Liposome Incorporating Poly(Hydroxyethyl Acrylate-co-Allyl methyl sulfide) as an Anticancer Carrier of Doxorubicin

“…If the oxidation-sensitive liposomes are taken up by the cancer cell and tumor cell, P(HEA-AMS) chains would be oxidized and the liposomes would be able to destabilized, leading to the promoted release of their payload because the intracellular space of the cancer cell and tumor cell is in a high ROS level [37,38]. It is also known that oxygen free radicals are formed by DOX within the cancer cell and tumor cell and they peroxidize the cellular membrane lipids and exterminate the cancer cell and tumor cell [39][40][41]. The oxidation-sensitive liposomes would also be destabilized by the oxygen free radicals produced by DOX.…”