Effect of methimazole treatment on doxorubicin-induced cardiotoxicity in mice

https://doi.org/10.1016/j.fct.2009.06.040Get rights and content

Abstract

The major limiting factor in long-term administration of doxorubicin is the development of cumulative dose-dependent cardiomyopathy and congestive heart failure that limit the use of this drug. The present study was undertaken to find out the chemo protective role of methimazole against doxorubicin-induced cardiotoxicity in experimental animals. In the present study, doxorubicin treatment in a dose of 3 mg/kg, i.p., every other day for six doses showed a significant 2.6-, 3- and 10.5-fold increase in the cardiac enzyme activities CK-MB and LDH and troponin-I, respectively, in the serum of the animals. Histopathological investigation of heart tissues showed swollen muscle fibers with interstitial edema and inflammatory exudate. Pretreatment of the animals with methimazole at a dose level of 40 mg/kg, i.p., 30 min before doxorubicin, returned the cardiac enzyme levels to nearly normal value with partial reversal of the inflammatory lesions and the swollen muscle fibers induced by doxorubicin. Moreover, methimazole pretreatment, decreased the doxorubicin level in the heart tissues with a significant increase in plasma level and non significant effect on doxorubicin level in tumor cells. At the same time, methimazole pretreatment did not significantly interfere with the antitumor activity of doxorubicin.

Introduction

Doxorubicin is the most widely used drug in the treatment of a variety of human neoplasms (Arcamone et al., 1969, Carter, 1975). However, with the increasing the use of doxorubicin, acute as well as chronic cumulative dose-dependent cardiomyopathy have been recognized as the major limiting factor of doxorubicin chemotherapy (Buzadar et al., 1981, Kantrowitz and Bristow, 1984).

Several mechanisms for the doxorubicin-induced cardiotoxicity have been proposed, including membrane lipid peroxidation, free radical formation (Tarasiuk et al., 1989, Yin et al., 1998, Li et al., 2002), mitochondrial damage (Hershko et al., 1993), iron-dependent oxidative damage to macromolecules (Osman et al., 1993) and superoxide accumulation and peroxynitrite formation (Shuai et al., 2007). Oxygen free radicals are apparently involved in all mechanisms proposed. Methimazole is an anti-thyroid drug, containing –SH group. Although it is mainly used in the treatment of hyperthyroidism (Cooper, 1984), it has been found to be effective in reducing the toxicity of several nephrotoxic chemotherapeutic drugs, e.g., cephaloridine (Sausen et al., 1992, Ban et al., 1994), gentamycin (El-Daly, 1997) and cisplatin (Osman et al., 2000). The effect has been attributed to its antioxidant and free radical scavenging capabilities, leading to a reduction of oxidative stress in the kidney without affecting the cytotoxic activity of the drug. Since the renal protective effect of methimazole is largely based on its free radical scavenging capability and its antioxidant effect, and since the cardiotoxic effect of doxorubicin is mainly mediated through free radical generation (Wacker et al., 1956), it was considered of interest to study whether the antioxidant effect of methimazole on the kidney might also be extend to the heart. First, we determined the cardiotoxicity of doxorubicin in presence and absence of methimazole. Secondly, the uptake of doxorubicin in heart and tumor tissue was evaluated in tumor-bearing albino mice. Thirdly, the effect of methimazole treatment on the antitumor activity of doxorubicin was determined to answer the question does the protective effect of methimazole could be at the expense of abolishing the antitumor activity of doxorubicin or not?

Section snippets

Drugs

Doxorubicin was obtained as adriablastina vials from NCI store, Cairo, Egypt (Pharmacia and Upjohn Co.S.P.A., Milan, Italy), Methimazole was purchased from Sigma–Aldrich chemical Co. (St. Louis, MO, USA). All other chemicals included in the current study were from Merck (Darmstadt, Germany).

Animal and tumor

The investigation was performed on albino mice weighing 18–20 g from National Cancer Institute outbreed stock. The animals were housed in a conditioned atmosphere and kept on a standard diet and water ad

Effect of methimazole pretreatment on doxorubicin-induced cardiotoxicity

Table 1 shows the effect of methimazole pretreatment on doxorubicin-induced changes in cardiac enzymes in normal mice. Treatment of mice with six equal doses of doxorubicin (3 mg/kg × 6 every other day) resulted in a significant 2.6-, 3- and 10.5-fold increase in the activities of CK-MB, LDH-Iso and troponin-I, respectively. Pretreatment with methimazole (40 mg/kg, i.p.) 30 min before doxorubicin, resulted in partial reversal of doxorubicin-induced increase in the cardiac enzymes. At the same time

Discussion

Doxorubicin is an excellent antitumor drug for treating several types of solid cancer, leukemia and lymphomas.

However, acute or chronic toxicity is the major limiting complication, whereas, acute cardio toxicity represented mainly by transient symptoms, such as arrhythmias, while chronic toxicity can develop into irreversible cardiomyopathy, which affects approximately 30–40% of the patients who receive 500 mg/mm2 total dose (Lefrak et al., 1973).

In the current study, doxorubicin was injected

Conflict of interest statement

The authors declare that there are no conflicts of interest.

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