The Therapeutic Potential of Aged Garlic Extract in the Protection against Doxorubicin-Induced Cardiotoxicity

Alkreathy, Huda Mohammed (2011) The Therapeutic Potential of Aged Garlic Extract in the Protection against Doxorubicin-Induced Cardiotoxicity. Doctoral thesis (PhD), Manchester Metropolitan University.

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Abstract

Doxorubicin (DOX) is a one of the most potent anticancer drug which is widely used in the treatment of childhood and adult cancer. Cardiac toxicity is a dangerous so far unsolved complication of DOX. Doxorubicin-induced cardiotoxicity is attributed to oxidative stress and p53-dependent apoptosis. The establishment of an effective safe compound would be of great benefit in the management of DOX-induced cardiotoxicity. Aged garlic extract (AGE) is a natural, promising compound to lessen DOX-induced cardiotoxicity due to it antioxidant, antiapoptotic, and multiple health promoting effects. This study investigated the protective effect of AGE against DOX-induced cardiotoxicity in Wistar rats and in rat cardiac myocytes. It also investigated the effect of AGE pretreatment on oxidative stress, p53, active caspase-3 and gene expression in DOX-treated rat cardiac myocytes. The results of this study have revealed that AGE protects against DOX-induced cardiotoxicity in vivo and in vitro. Four groups of rats were assessed for serum cardiac enzymes, plasma and heart malonialdehyde (MDA), serum total antioxidant status (TAS), and light and electron microscopic examination of the heart tissue. Serum cardiac enzymes were found to be elevated in DOX-treated rats. The findings of this study have revealed that there is an oxidative stress in DOX-treated rats, as manifested by increased plasma and heart MDA concentrations and reduced serum TAS. Pre-treatment with AGE reduced MDA concentrations and normalised TAS, which are indicators of oxidative stress in DOX-treated rats and attenuated histopathological alterations in DOX-treated rats. Aged garlic extract pre-treatment did not interfere with the cytotoxic activity of DOX, but it augmented DOX uptake into tumour cells in mice bearing EAC and increased the long term survivors of tumour-bearing mice. Pretreatment of rat cardiac myocytes with AGE lowered DOX-induced elevation of 8- isoprostane, p53 and caspase-3 activity. The results of this study demonstrated that pretreatment with AGE insignificantly reduced increased expression of some antioxidant XIV genes in DOX-treated rat cardiac myocytes. Further studies are needed to identify the detailed molecular mechanisms underlying the protective effects of AGE.