Abstract
This study aimed to examine the effect of lipid emulsion on the cardiotoxicity induced by doxorubicin in H9c2 rat cardiomyoblasts and elucidates the associated cellular mechanism. The effects of lipid emulsion on cell viability, Bax, cleaved caspase-8, cleaved capase-3, Bcl-XL, apoptosis, reactive oxygen species (ROS), malondialdehyde, superoxide dismutase (SOD), catalase and mitochondrial membrane potential induced by doxorubicin were examined. Treatment with doxorubicin decreased cell viability, whereas pretreatment with lipid emulsion reduced the effect of doxorubicin by increasing cell viability. Lipid emulsion also suppressed the increased expression of cleaved caspase-3, cleaved caspase-8, and Bax induced by doxorubicin. Moreover, pretreatment with lipid emulsion decreased the increased Bax/Bcl-XL ratio induced by doxorubicin. Doxorubicin-induced late apoptosis was reduced by treatment with lipid emulsion. In addition, pretreatment with lipid emulsion prior to doxorubicin enhanced glycogen synthase kinase-3β phosphorylation. The increased malondialdehyde and ROS levels by doxorubicin were reduced by lipid emulsion pretreatment. Furthermore, lipid emulsion attenuated the reduced SOD and catalase activity and the decreased mitochondrial membrane potential induced by doxorubicin. Taken together, these results suggest that lipid emulsion attenuates doxorubicin-induced late apoptosis, which appears to be associated with the inhibition of oxidative stress induced by doxorubicin.
Highlights
Doxorubicin, an anticancer drug extracted from Streptomyces peucetius var Caesius, has been shown to be highly effective against various human malignancies [1]
H9c2 cells were treated with different concentrations of doxorubicin (10−6 M, 3 × 10−6 M and 10−5 M for 24 h), and dose-dependent decreases in cell viability of 52.84 ± 6.81%, 45.93 ± 5.59%, and 24.24 ± 3.95%, respectively, were observed compared with the cell viability of control cells (Figure 1A)
The major findings of this in vitro study are as follows: (1) Lipid emulsion inhibited the cell viability reduction induced by doxorubicin; (2) lipid emulsion inhibited the late apoptosis induced by doxorubicin; and (3) lipid emulsion inhibited the increased reactive oxygen species (ROS) and MDA induced by doxorubicin, whereas lipid emulsion pretreatment reversed the decreased superoxide dismutase (SOD) and catalase activity and the reduced membrane potential (MMP) induced by doxorubicin
Summary
Doxorubicin, an anticancer drug extracted from Streptomyces peucetius var Caesius, has been shown to be highly effective against various human malignancies [1]. Its successful use in clinical cancer treatment has been limited due to its association with cardiotoxicity. Complex mechanisms underlie doxorubicin-induced cardiotoxicity, one of which is associated with reactive oxygen species (ROS)-induced apoptosis in mitochondria, which leads to congestive heart failure [2,3,4]. Many reports have shown that doxorubicin accumulates in cardiomyocyte mitochondria at a concentration one hundred times higher than that in the extracellular space [5,6]. Lipid emulsion, which was originally developed for parenteral nutrition, is used clinically as drug delivery vehicles (for example, propofol and etomidate) that do not induce severe side effects [7]. Lipid emulsion is effective at treating systemic toxicity induced by local anesthetics and other drugs with high lipid solubility [8]
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