Abstract
Cardiotoxicity as an off-target effect of doxorubicin therapy is a major limiting factor for its clinical use as a choice cytotoxic agent. Seeds of Irvingia gabonensis have been reported to possess both nutritional and medicinal values which include antidiabetic, weight losing, antihyperlipidemic, and antioxidative effects. Protective effects of Irvingia gabonensis ethanol seed extract (IGESE) was investigated in doxorubicin (DOX)-mediated cardiotoxicity induced with single intraperitoneal injection of 15 mg/kg of DOX following the oral pretreatments of Wistar rats with 100-400 mg/kg/day of IGESE for 10 days, using serum cardiac enzyme markers (cardiac troponin I (cTI) and lactate dehydrogenase (LDH)), cardiac tissue oxidative stress markers (catalase (CAT), malonyldialdehyde (MDA), superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GSH-Px), and reduced glutathione (GSH)), and cardiac histopathology endpoints. In addition, both qualitative and quantitative analyses to determine IGESE's secondary metabolites profile and its in vitro antioxidant activities were also conducted. Results revealed that serum cTnI and LDH were significantly elevated by the DOX treatment. Similarly, activities of tissue SOD, CAT, GST, and GSH levels were profoundly reduced, while GPx activity and MDA levels were profoundly increased by DOX treatment. These biochemical changes were associated with microthrombi formation in the DOX-treated cardiac tissues on histological examination. However, oral pretreatments with 100-400 mg/kg/day of IGESE dissolved in 5% DMSO in distilled water significantly attenuated increases in the serum cTnI and LDH, prevented significant alterations in the serum lipid profile and the tissue activities and levels of oxidative stress markers while improving cardiovascular disease risk indices and DOX-induced histopathological lesions. The in vitro antioxidant studies showed IGESE to have good antioxidant profile and contained 56 major secondary metabolites prominent among which are γ-sitosterol, Phytol, neophytadiene, stigmasterol, vitamin E, hexadecanoic acid and its ethyl ester, Phytyl palmitate, campesterol, lupeol, and squalene. Overall, both the in vitro and in vivo findings indicate that IGESE may be a promising prophylactic cardioprotective agent against DOX-induced cardiotoxicity, at least in part mediated via IGESE's antioxidant and free radical scavenging and antithrombotic mechanisms.
Highlights
Doxorubicin is one of the antibiotic cytotoxic agent belonging to the anthracycline class of anticancer agents [1]
For breast cancer management, doxorubicin is typically combined and given with cyclophosphamide; for lymphomas and leukemias, it is combined with other cytotoxic agents to make regimens like CHOP, R-CHOP, and ABVD [9,10,11,12]
In view of the above, the current study was designed at evaluating the possible protective effect of the crude nondefatted ethanol seed extract of Irvingia gabonensis against doxorubicin-mediated cardiotoxicity in rats using cardiac injury markers, oxidative stress markers, and histopathology results as endpoint outcomes
Summary
Doxorubicin (otherwise known as Adriamycin) is one of the antibiotic cytotoxic agent belonging to the anthracycline class of anticancer agents [1]. The effectiveness of dexrazoxane (an iron chelating agent) [5, 23], dextromethionine [24, 25], and angiotensinconverting enzyme inhibitors—zofenopril and lisinopril [26, 27]—in ameliorating doxorubicin-related cardiotoxicity have been reported These agents, especially dexrazoxane, are known to mitigate oxidative stress by chelating iron and catalytically inhibiting topoisomerase II, preventing doxorubicin-induced double strand DNA breaks [28, 29]. These chemopreventive agents are expensive and not readily accessible to patients, necessitating the need for the discovery and development of more effective but cheaper and more readily accessible alternatives especially ones of medicinal plant origin. In view of the above, the current study was designed at evaluating the possible protective effect of the crude nondefatted ethanol seed extract of Irvingia gabonensis against doxorubicin-mediated cardiotoxicity in rats using cardiac injury markers, oxidative stress markers, and histopathology results as endpoint outcomes
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