Abstract
Doxorubicin (DOX) is a wide-spectrum antitumor agent, but its clinical application is largely limited by its cardiotoxicity. Therefore, identification of effective agents against DOX-induced cardiotoxicity is of critical importance. The present study aimed to determine the beneficial role of punicalagin (PUN), a polyphenol isolated from pomegranate, in DOX-induced cardiotoxicity in vitro and explored the underlying mechanisms. H9c2 cardiomyocytes were pretreated with different concentrations (50, 100 and 200 μM) of PUN prior to DOX exposure. The results showed that PUN pretreatment significantly increased cell viability, inhibited lactate dehydrogenase (LDH) release and suppressed cell apoptosis induced by DOX. Additionally, PUN pretreatment attenuated the loss of mitochondrial membrane potential and cytochrome c release. Besides, PUN further enhanced the expression of nuclear Nrf2 and HO-1 in DOX-treated H9c2 cells, and the aforementioned beneficial effects of PUN were partially abolished by small interfering RNA (siRNA)-mediated Nrf2 knockdown. Hence, our findings clearly revealed that PUN might be a promising agent for alleviating the cardiotoxicity of DOX, and Nrf2/HO-1 signaling might serve a critical role during this process.
Highlights
Doxorubicin (DOX), an anthracycline antibiotic, is one of the most effective chemotherapeutic agents widely used in the management of a wide spectrum of human neoplasms [1]
Chen et al [4] indicated that PUN reduced oxidative stress and stimulus-induced apoptosis in human placental trophoblasts, and Ding et al [5] reported that PUN protected against ischemia/reperfusion-induced myocardial injury by suppressing cardiomyocyte apoptosis
Cellular apoptosis was assessed by Annexin V/PI double staining, and the results showed that the number of apoptotic cells was notably increased upon DOX stimulation, and PUN concentration-dependently reduced the apoptotic ratio (Figure 2A)
Summary
Doxorubicin (DOX), an anthracycline antibiotic, is one of the most effective chemotherapeutic agents widely used in the management of a wide spectrum of human neoplasms [1]. It is of great necessity to identify effective therapeutic agents against DOX-induced cardiotoxicity. Punicalagin (2,3-hexahydroxydiphenoyl-gallagyl-D-glucose; PUN; Figure 1A), the main ellagitannin polyphenol derived from pomegranate peel or seeds, exhibits a wide range of pharmacological properties. Chen et al [4] indicated that PUN reduced oxidative stress and stimulus-induced apoptosis in human placental trophoblasts, and Ding et al [5] reported that PUN protected against ischemia/reperfusion-induced myocardial injury by suppressing cardiomyocyte apoptosis. The main goal of the present study was to investigate the potential beneficial role of PUN against DOX-induced cardiotoxicity using in vitro cellular model and to elucidate the underlying molecular mechanisms
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