Lupeol and Its Ester Exhibit Protective Role Against Cyclophosphamide-Induced Cardiac Mitochondrial Toxicity

Abstract

Cyclophosphamide (CP), an anti-cancer and immunosuppressant drug, causes fatal cardiotoxicity during high dose chemotherapy. Lupeol, a pentacyclic triterpene, isolated from Crataeva nurvala stem bark and its ester, lupeol linoleate, possess wide range of medicinal properties. The objective of this study was to establish the pharmacological efficacy of lupeol and its ester against CP-induced mitochondrial-cardiomyopathy. Male albino rats of Wistar strain were injected with a single dose of CP (200 mg/kg body weight, i.p.). A decrease in the activities of TCA cycle enzymes such as succinate dehydrogenase, malate dehydrogenase, and isocitrate dehydrogenase were noted in CP-treated rats. Simultaneously there was a decrease in the activities of mitochondrial complexes of electron transport chain. Electron microscopical observations were also in agreement with the above changes. Mitochondria were swollen with numerous electron dense granules and showed damaged cristae, revealing the cytotoxic effect of CP. Lupeol (50 mg/kg body weight for 10 days orally) and its ester, lupeol linoleate (50 mg/kg body weight for 10 days orally) showed reversal of the above alterations induced by CP. These data suggest that the protective effects of lupeol and its ester against CP-induced cardiac damage were achieved by restoration of mitochondrial structure and function.

Thymoquinone supplementation attenuates cyclophosphamide‐induced cardiotoxicity in rats

“…Data presented here demonstrated that CP increased serum cardiotoxicity enzymatic indices, LDH, and CK-MB. These results are consistent with the data presented by several authors [12,16,[40][41][42], who demonstrated a marked elevation of CK-MB, LDH, ALT, and AST, 10 days after administration of a single dose of CP (200 mg/kg). This increase in cardiotoxicity enzymatic indices could be explained on the basis of CPinduced lipid peroxidation of cardiac membranes with the consequent leakage of cardiac enzymes from damaged cardiac myocytes to the serum.…”

Aegle marmelos (L.) Correa (Bael) and Its Phytochemicals in the Treatment and Prevention of Cancer

“…48 Electron microscopic studies showed that the degree of damage to the myofibres, characterized by the swollen and loss of myofilaments, mitochondrial swelling, and damaged cristae were also decreased. 46,47 Together, all these observations indicate that the hydroalcoholic extract of Bael leaf and its phytochemicals lupeol and cardenolide possess cardioprotective effects…”

“…44,45 Lupeol alleviated the cyclophosphamideinduced increase in the activities of lysosomal hydrolases in serum and heart, and concomitantly increased the levels of cellular thiols. 46 Lupeol increased the activities of TCA cycle enzymes and mitochondrial complexes of electron transport chain in the cardiac tissue 47 and normalized the activities of ATPases, urea, uric acid, and creatinine. 48 Electron microscopic studies showed that the degree of damage to the myofibres, characterized by the swollen and loss of myofilaments, mitochondrial swelling, and damaged cristae were also decreased.…”

Cyclophosphamide induces premature senescence in normal human fibroblasts by activating MAP kinases

“…Several authors have shown that CP induces damage to mitochondrial membranes, proteins, nucleic acids, and lysosomal membrane (Selvakumar et al 2005;Mythili et al 2007). In addition, CP is known to be involved in the opening of inner mitochondrial membrane pores in cardiac cells and has been implicated as a primary cause for CP-induced cardiac toxicity (Sudharsan et al 2006).…”