Cisplatin is one of the most clinically effective anticancer agents and improves survival rate. this gain in cancer survivorship has also produced a growing cohort of patients with increased cardiovascular complications secondary to cardiotoxicity cisplatin-induced. However, as current cancer therapy-related cardiovascular disease remains limited in the scope of available cisplatin treatments, it is a current effort to find effective adjuvant drugs to attenuate cisplatin-induced cardiotoxicity [28].
Chinese herbal medicine has been broadly accepted as a safe and effective medication for the treatment of various ailments. The co-administration of different herbs often appeared in the form of prescriptions to potentiate the pharmacological activities of one herb and regulate the overall bias of the body in traditional Chinese medicine. Hence, attention has been focused on identifying compounds of natural origin in preventing cisplatin-induced cardiotoxicity strategies. TG is one of the bioactive components derived from the Chinese herb “Citrus peel”, which has been used for the treatment of cardiovascular and cerebrovascular diseases such as chest obstruction syndrome in the clinic for decades [29, 30]. Hesperidin, TG, and their derivatives have been confirmed the beneficial effects in the treatment of heart failure and cardiac remodeling, myocardial ischemia and infarction, and hypertension [31–33]. In heart disease, TG had been found to exhibit antihypertensive effects and alleviate ventricular dysfunction and remodeling in hypertensive rats [21]. TG also could protect the heart against cardiac in streptozotocin-induced diabetic rats. [34] Simultaneously, studies have shown that TG possesses anti-cancer properties and displays selective cytotoxicity towards cancerous cells, but not normal cells. Thus, we hypothesize that TG might have the potential as an effective drug for treating cisplatin-induced cardiotoxicity. To our knowledge, the present study first investigated the effect of TG on cisplatin-induced myocardial dysfunction.
In the present study, a pharmacology approach was applied to predict and elucidate the potential molecular mechanisms of action of TG active substances on cardiovascular complications and found that TG protected cisplatin-treated cardiomyocytes from apoptosis via an AMPK-dependent mechanism and mitochondrial dysfunction. The effect was also confirmed in heart tissues from cisplatin-induced mice, which showed increased activity of cardiac myocytes, a decreased tendency toward apoptosis, and significantly improved cardiac insufficiency compared with the mice that did not receive TG.
Considering the potential cardiotoxicity of cisplatin, the present study was conducted to understand its cytotoxic effects and their amelioration by TG using H9c2 cells. Observations of the present study indicated that cisplatin resulted in a concentration and time-dependent inhibition of H9c2 cell growth in vitro. TG protected H9c2 cells upon stimulation with cisplatin in a concentration-dependent manner with notable levels of increase achieved at as low as 1.25 µM. Exposure of H9c2 cells to TG prior (5µM) to cisplatin produced more beneficial effects on cell viability whereas the administration of individual drugs TG exposure inhibition of cardiomyocyte proliferation and survival. The phenomenon of a high dose adaptive response to hormones increased the resistance of the cell to evoked stress [35]. Both activations of AMPK and mitochondrion membrane potential and apoptosis may explain the observed biphasic responses of TG and cisplatin.
AMPK is a highly conserved regulator of cellular energy metabolism that plays an important role in regulating cell survival, apoptosis, and regulation of energy metabolism in the body [36–38]. Cardiomyocyte apoptosis is a major pathogenic mechanism underlying CDDP-induced injury. Thus, maintaining cardiomyocyte homeostasis to inhibit apoptosis may effectively minimize cardiac injury. In cardiomyocytes, consistent evidence has indicated that an activated AMPK signal pathway regulates fatty acid oxidation and enhances glucose uptake, and inhibits apoptosis [39, 40]. As discussed in the study, AMPK phosphorylates ACC, resulting in the inhibition of ACC activity, which in turn leads to a decrease in malonyl CoA content and increased fatty acid oxidation. While regulation of the Glut4 distribution plays a role in glucose homeostasis maintenance and following stimulation with activation of AMPK, glucose uptake in the myocardium occurs through the translocation of GLUT4 to the cell membrane [41].
Myocardial cells have high mitochondrial density and mitochondria play a central role, even deciding the fate of the cell. In the intrinsic apoptosis pathway, cisplatin could trigger the opening of mitochondrial permeability transition, resulting in the loss of mitochondrial membrane potential, the number of mitochondrial per cell decreased, the release of cytochrome C, and eventually leading to the apoptosis of cardiomyocytes [42]. Thus, observations of the present study revealed that TG pre-treatment reversed cisplatin-mediated cell proliferation inhibition and contributed to protecting cells against cisplatin-induced cell death, suggesting that TG has the potential to combat cisplatin-mediated toxicity.
Our research indicated that when TG was added to cultured cardiomyocytes, increased TG-dependent AMPK activation and its downstream effect on ACC phosphorylation, GLUT4 translocation, and suppressed p38 MAPK phosphorylation [43–45]. In addition, AMPK phosphorylation was able to inhibit mitochondrial-injured endogenous apoptosis signal conduction pathway, thereby modifying cisplatin-induced apoptosis in which the mitochondrial permeability transition pore (PTP) opens resulting in mitochondrial membrane potential (ΔΨm) dissipation, loss of mitochondria, and cell death. The results described above led to the conclusion that TG might protect the H9c2 cells from cisplatin-induced apoptosis by AMPK phosphorylation, which was consistent with the protective effect of TG administration myocardial necrosis in a mouse model of cisplatin-induced cardiotoxicity. Taken together, these results provided mechanistic evidence to support the view that TG-mediated protection against cisplatin-induced injury occurs through AMPK activation and prevention of mitochondrial dysfunction.
Cisplatin has been clinically used as a chemotherapeutic drug for more than 30 years. The cytotoxic-based platinum compound, cisplatin, and platinum-based chemotherapy is still the first-line treatment of many solid tumors at present, especially cisplatin-based combination chemotherapy [4, 35]. The current study demonstrated the beneficial cumulative effect of other treatments combined with cisplatin chemotherapy was more effective and produces fewer toxic effects. Cardiotoxicity is one of the main side effects of cisplatin, which limits its clinical application [7]. To investigate the cytotoxic effect of TG on cisplatin-induced cardiotoxicity we treated the H9c2 cells with various concentrations of cisplatin in the presence or absence of TG. We have demonstrated that the effect of TG diminished the toxicity of cisplatin both in vitro and in vivo, in part explained by the increased expression of p-AMPK levels and decreased mitochondrial membrane permeability. Some recent studies show that TG has great potential for development as a new drug for the treatment of cancer [46, 47], however, further studies are needed with the optimal dose and time of TG in combination with cisplatin to observe potential synergy between the two drugs.
In conclusion, in this report we have demonstrated that TG treatment contributed to protecting cells against cisplatin-induced apoptosis by AMPK phosphorylation and controlling mitochondria stability both in structure and function (Fig. 7). Combination of TG with cisplatin may reduce cardiovascular morbidity and mortality in cancer patients and survivors. The findings highly suggested a translational potential of TG as a natural drug for treating cisplatin-induced cardiotoxicity in the clinic.