Doxorubicin-Induced Cardiomyopathy: A Preliminary Study on the Cardioprotective Benefits of 7-Hydroxyflavanone.

The therapeutic properties of flavonoids are reported to offer cardioprotective benefits against doxorubicin (Dox)-induced cardiotoxicity (DIC). In the current study, we aimed to investigate the prophylactic properties of 7-hydroxyflavanone (7H), a flavonoid with antioxidative properties, against DIC. An in vitro model of DIC was established by exposing H9c2 cardiomyoblasts to Dox for 6 days. Similarly, cells were also co-treated with 7H to assess its ability to mitigate DIC. The data obtained indicate that 7H, as a co-treatment, alleviates Dox-induced oxidative stress by enhancing total glutathione content (p ≤ 0.001) and superoxide dismutase activity (p ≤ 0.001) whilst decreasing ROS (p ≤ 0.001), malondialdehyde production (p ≤ 0.001) and the secretion of interleukin-6 (p ≤ 0.001). The data also showed an improvement in mitochondrial function as shown via enhanced bioenergetics, mitochondrial membrane potential, and PGC1-alpha (p ≤ 0.05) and pAMPK (p ≤ 0.001) expression. The cardioprotective potential of 7H was further highlighted by its ability attenuate Dox-induced caspase 3/7 activity (p ≤ 0.001), apoptosis (p ≤ 0.001) and necrosis (p ≤ 0.05). In conclusion, our findings demonstrated the cardioprotective benefits of 7H and thus suggests that it could be a suitable candidate cardioprotective agent against DIC.

Prevention of Anthracycline-Induced Cardiotoxicity: The Good and Bad of Current and Alternative Therapies.

Doxorubicin (Dox)-induced cardiotoxicity (DIC) remains a serious health burden, especially in developing countries. Unfortunately, the high cost of current preventative strategies has marginalized numerous cancer patients because of socio-economic factors. In addition, the efficacy of these strategies, without reducing the chemotherapeutic properties of Dox, is frequently questioned. These limitations have widened the gap and necessity for alternative medicines, like flavonoids, to be investigated. However, new therapeutics may also present their own shortcomings, ruling out the idea of "natural is safe". The U.S. Food and Drug Administration (FDA) has stipulated that the concept of drug-safety be considered in all pre-clinical and clinical studies, to explore the pharmacokinetics and potential interactions of the drugs being investigated. As such our studies on flavonoids, as cardio-protectants against DIC, have been centered around cardiac and cancer models, to ensure that the efficacy of Dox is preserved. Our findings thus far suggest that flavonoids of Galenia africana could be suitable candidates for the prevention of DIC. However, this still requires further investigation, which would focus on drug-interactions as well as in vivo experimental models to determine the extent of cardioprotection.

Molecular insights into the pathophysiology of doxorubicin-induced cardiotoxicity: a graphical representation.

A breakthrough in oncology research was the discovery of doxorubicin (Dox) in the 1960's. Unlike other chemotherapy drugs, Dox was determined to have a greater therapeutic index. Since its discovery, Dox has, in part, contributed to the 5-10-year survival increase in cancer patient outcomes. Unfortunately, despite its efficacy, both in adult and pediatric cancers, the clinical significance of Dox is tainted by its adverse side effects, which usually manifest as cardiotoxicity. The issue stems from Dox's lack of specificity which prevents it from accurately distinguishing between cancer cells and healthy cell lines, like cardiomyocytes. In addition, the high binding affinity of Dox to topoisomerases, which are abundantly found in cancer and cardiac cells in different isoforms, potentiates DNA damage. In both cell lines, Dox induces cytotoxicity by stimulating the production of pro-oxidants whilst inhibiting antioxidant enzymatic activity. Given that the cardiac muscle has an inherently low antioxidant capacity makes it susceptible to oxidative damage thereby, allowing the accumulation of Dox within the myocardium. Subsequently, Dox drives the activation of cell death pathways, such as ferroptosis, necroptosis and apoptosis by triggering numerous cellular responses that have been implicated in diseases. To date, the exact mechanism by which Dox induces the cardiotoxicity remains an aspect of much interest in cardio-oncology research. Hence, the current review summarizes the proposed mechanisms that are associated with the onset and progression of DIC.

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

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.

The differential effects of FTY720 on functional recovery and infarct size following myocardial ischaemia/reperfusion.

AIM: The aim of this study was to evaluate the effects of the sphingosine analogue, FTY720 (Fingolimod), on the outcomes of myocardial ischaemia/reperfusion (I/R) injury. METHODS: Two concentrations of FTY720 (1 or 2.5 µM were administered either prior to (PreFTY), or following (PostFTY) 20 minutes' global (GI) or 35 minutes' regional ischaemia (RI) in the isolated, perfused, working rat heart. Functional recovery during reperfusion was assessed following both models of ischaemia, while infarct size (IFS) was determined following RI. RESULTS: FTY720 at 1 µM exerted no effect on functional recovery, while 2.5 µM significantly impaired aortic output (AO) recovery when administered prior to GI (% recovery: control: 33.88 ± 6.12% vs PreFTY: 0%, n = 6-10; p < 0.001), as well as before and after RI ( % recovery: control: 27.86 ± 13.22% vs PreFTY: 0.62% ; p < 0.05; and PostFTY: 2.08%; p = 0.0585, n = 6). FTY720 at 1 µM administered during reperfusion reduced IFS (% of area at risk (AAR): control: 39.89 ± 3.93% vs PostFTY: 26.56 ± 4.32%, n = 6-8; p < 0.05), while 2.5 µM FTY720 reduced IFS irrespective of the time of administration ( % of AAR: control: 39.89 ± 3.93% vs PreFTY: 29.97 ± 1.03% ; and PostFTY: 30.45 ± 2.16%, n = 6; p < 0.05). CONCLUSION: FTY720 exerted divergent outcomes on function and tissue survival depending on the concentration administered, as well as the timing of administration.

Ischaemic postconditioning: from bench to bedside ...

The increase in the incidence of ischaemic heart disease and acute myocardial infarction (AMI) in both high- and low-income countries necessitates the development of myocardial salvaging/protection interventions, to be applied alongside standard reperfusion therapies. Although the phenomenon of ischaemic preconditioning (IPC) is associated with the desired protective capacity, the necessity of its application before sustained ischaemia limits its clinical potential. The recently described phenomenon of postconditioning (postC), or short cycles of reperfusion/ischaemia applied at the onset of reperfusion, falls within the clinically relevant time period of reperfusion, but can it elicit reliable and potent cardioprotection? The answer to this problem is intimately related to the question whether postC can be translated from a laboratory technique to a clinical therapy. In this brief overview of postconditioning, the experimental set-ups and postC algorithms utilised, and their associated outcomes in all animal models studied (dog, rabbit, mouse, rat and pig) are discussed. The therapeutic potential of postC is also addressed by discussing reported preliminary studies on the efficacy and feasibility of postC (both ischaemic and pharmacological) in humans.

Postconditioning the isolated working rat heart.

PURPOSE: Despite the attention focussed on postconditioning (postC; brief cycles of reperfusion/ischaemia at the onset of reperfusion, conferring cardioprotection against reperfusion injury), an infarct sparing effect for postC in the isolated working heart model has not been reported. The purpose of this study was to develop a cardioprotective postC protocol in this model. METHODS: Hearts from male Wistar rats (210-350 g) were perfused either retrogradely (Langendorff) or in the working mode. For functional studies 30 or 35 min global ischaemia (GI) and 20 or 25 min GI were applied in the Langendorff and working heart models respectively. Infarct size was measured after 35 min regional ischaemia (RI) in both models. In the latter studies hearts were subdivided into low (36.5 degrees C) and high (37 degrees C) temperature groups (during both ischaemia and initial reperfusion). In all groups hearts were either freely reperfused (nonPostC) or postconditioned (postC) by 6x10 s ischaemia/reperfusion cycles. RESULTS: In both perfusion modes postC only elicited an infarct sparing effect after a slight elevation in temperature to 37 degrees C (Langendorff: L-nonPostC=47.99+/-3.31% vs. L-postC=27.81+/-2.49%, p<0.0001; and work=W-nonPostC: 35.81+/-3.67% vs. W-postC=17.74+/-2.72%, p<0.001). However, only in the Langendorff group could postC conserve post-ischaemic function, while no significant recoveries were seen in the working hearts. CONCLUSION: We demonstrated an infarct sparing effect for postC in the working heart model, which unlike the Langendorff model, was not associated with functional preservation. The infarct sparing effect of postC in both models was however extremely sensitive to even slight fluctuations in temperature.