Pamidronate Attenuates Oxidative Stress and Energetic Metabolism Changes but Worsens Functional Outcomes in Acute Doxorubicin-Induced Cardiotoxicity in Rats

Abstract

Background: Cardiotoxicity is the major side effect of doxorubicin. As mechanisms that are involved in cardiotoxicity are ambiguous, new methods for attenuating cardiotoxicity are needed. Recent studies have shown that bisphosphonates can decrease oxidative stress. Therefore, the objective of this study was to evaluate the effect of pamidronate on preventing acute doxorubicin-induced cardiotoxicity. Methods: Sixty-four male Wistar rats were allocated into four groups: the control group (C), the pamidronate group (P), the doxorubicin group (D) and the doxorubicin/pamidronate group (DP). The rats in the P and DP groups received pamidronate injections (3 mg/kg, IP). After 24 hours, the rats in the D and DP groups received doxorubicin injections (20 mg/kg, IP). Forty-eight hours after doxorubicin injection, the rats were killed. Echocardiography, isolated heart study and biochemical analysis were performed. Results: Doxorubicin-induced acute cardiotoxicity showed increased matrix metalloproteinases (MMP)-2 activation, oxidative damage and induced alterations in myocardial energetic metabolism. Pamidronate did not inhibit MMP-2 activation but attenuated oxidative stress and improved myocardial energetic metabolism. Regarding cardiac function, the DP group exhibited a decrease in the left ventricular ejection fraction in the echocardiography and a decrease in +dP/dt in the isolated heart study compared with other groups. The same DP group presented serum hypocalcaemia. Conclusions: Despite its ability to reduce oxidative stress and improve energy metabolism in the heart, pamidronate worsened systolic function in rats treated with doxorubicin, and therefore we cannot recommend its use in conjunction with anthracycline chemotherapy.

Omega-3 fatty acids ameliorate doxorubicin-induced cardiorenal toxicity: In-vivo regulation of oxidative stress, apoptosis and renal Nox4, and in-vitro preservation of the cytotoxic efficacy

“…These results that are concordant with those from other studies [54,55]. Exertion of DOX-induced oxidative stress occurs as a result of DOX reduction by the mitochondrial enzymes following its cellular uptake; a reaction that results in generation of abundant ROS [33,56]. This may explain that DOX-induced toxicity mostly affects cells with a huge number of mitochondria, including cardiac and renal cells [30].…”

Oxymatrine Ameliorates Doxorubicin-Induced Cardiotoxicity in Rats

“…After doxorubicin enters the cardiomyocytes, mitochondrial enzymes reduce it to the semiquinone form. This reaction generates high concentrations of ROS, such as superoxide anion (O 2- ) and hydrogen peroxide (H 2 O 2 )[31, 32]. In addition to producing damaging free radicals, doxorubicin also decreases endogenous antioxidant levels; these effects can lead to cardiomyocyte apoptosis [33].…”

Euterpe oleracea Mart. (Açai) Supplementation Attenuates Acute Doxorubicin-Induced Cardiotoxicity in Rats

“…Approximately 11% of patients can develop acute cardiotoxicity hours or days after treatment [2,3]. Despite these differences in clinical presentation, there is evidence that myocardial damage, including ventricular dysfunction, starts early after doxorubicin administration [4][5][6].…”

“…An oxidative environment is a potent activator of matrix metalloproteinase (MMP) [11]. Indeed, MMP activation is an early event in doxorubicin-induced cardiotoxicity [5,6,12,13]. In addition, doxorubicin could induce changes in myocardial metabolism and mitochondrial dysfunction which is another important source of reactive species [7,14].…”