The Prophylactic Effect of Pinocembrin Against Doxorubicin-Induced Cardiotoxicity in an In Vitro H9c2 Cell Model

Abstract

Background The clinical use of Doxorubicin (Dox) is significantly limited by its dose-dependent cardiotoxic side effect. Accumulative evidence suggests that the use of flavonoids, such as the antioxidative Pinocembrin (Pin), could be effective in the prevention of Dox-induced cardiotoxicity. Accordingly, we investigated the ability of pinocembrin (Pin) to attenuate Dox-induced cardiotoxicity in an in vitro H9c2 cardiomyoblast model. Methodology The cardioprotective potential of Pin was established in H9c2 cells. Here, cells were treated with Dox (2μM), Dox (2μM) + Pin (1μM), and Dox (2μM) + Dexrazoxane (20μM) for 6 days. Thereafter, the safe co-administration of Pin with Dox, in a cancer environment, was investigated in MCF-7 breast cancer cells subjected to the same experimental conditions. Untreated cells served as the control. Subsequently, Pin’s ability to attenuate Dox-mediated oxidative stress, impaired mitochondrial bioenergetics and potential, as well as aggravated apoptosis was quantified using biochemical assays. Results The results demonstrated that co-treatment with Pin mitigates Dox-induced oxidative stress by alleviating the antioxidant enzyme activity of the H9c2 cells. Pin further reduced the rate of apoptosis and necrosis inferred by Dox by improving mitochondrial bioenergetics. Interestingly, Pin did not decrease the efficacy of Dox but, rather increased the rate of apoptosis and necrosis in Dox-treated MCF-7 cells. Conclusion The findings presented in this study showed, for the first time, that Pin attenuates Dox-induced cardiotoxicity without reducing its chemotherapeutic effect. We propose that additional studies, using in vivo models, should be conducted to further investigate Pin as a suitable candidate in the prevention of the cardiovascular dysfunction inferred by Dox administration.

Wogonin reduces cardiomyocyte apoptosis from mitochondrial release of cytochrome c to improve doxorubicin‑induced cardiotoxicity

“…A large number of pro-apoptotic factors such as cytochrome c enter the cytoplasm from mitochondria, activate the caspase pathway, initiate the endogenous apoptosis pathway and finally lead to cardiomyocyte death (33). Other studies also found that DOX can cause abnormal mitochondrial morphology and structure, lipid deposition and irregular arrangement of myofilaments, accompanied by myofilament breakage and dissolution (4,10). This indicates that mitochondrial function serves an important role in DOX induced heart injury.…”

“…At present, dexrazoxane is the only anthracycline anti-tumor drug cardioprotective agent approved by the FDA (USA), but it is rarely used clinically in China due to its high price and lack of popularity ( 9 , 10 ). Therefore, it is urgent to find a more effective protective drug to protect the heart from the damage of anthracycline anti-tumor drugs.…”

The Implication of Low Dose Dimethyl Sulfoxide on Mitochondrial Function and Oxidative Damage in Cultured Cardiac and Cancer Cells

“…Both H9c2 and MCF-7 cells are widely used to investigate the therapeutic potential of drugs against oxidative stress mechanisms [ 14 , 22 , 23 , 24 , 25 , 26 ]. In the current study, these cells were exposed to DMSO doses, ranging from 0.001 to 3.7% for 6 days, before assessing endpoints such as cell viability, ROS production, efficiency of the mitochondrial respiratory capacity, changes in mitochondrial membrane potential, as well as markers of early and late apoptosis.…”

Chlorogenic Acid Enhances Doxorubicin-Mediated Cytotoxic Effect in Osteosarcoma Cells

“…Therefore, increasing Doxo efficacy should go hand-in-hand with reducing side effects, expressly cardiotoxicity. In order to address the combination impact on Doxo-induced toxicity in cardiac cells, we employed embryonic rat cardiac tissue-derived H9c2 cells as a suitable in vitro model to study the anthracycline-mediated effects [39][40][41][42]. More in detail, 200 µM CGA and 0.1 µM Doxo were supplemented alone and in combination to the growing media of H9c2 and MG-63 cells for 48 h. Interestingly, whilst combination treatment further reduced the cell number and increased the percentage of PI-positive cells in MG-63 compared with Doxo alone, this trend was completely reverted in H9c2 cells (Figure 6).…”