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Abstract
Doxorubicin is one of the highly effective anti-neoplastic drugs of the anthracyclines family used to treat many pediatric and adult cancers, However the clinical used of doxorubicin is limited due to severe cardiotoxicity side effect. Metformin reducing basal and postprandial glucose levels. The Metformin antihyperglycemic effect seems to reduce cardiovascular death in patients with T2DM, in addition Metformin suggested to have a direct cardioprotective effect which independent on glucose reduction activity. This research aimed to study the protective effect of metformin against doxorubicin cardiotoxicity and fibrosis. Method: Thirty six albino rabbits divided to six groups, six rabbits each. Control group, received 2 ml single dose of saline intraperitoneally. Metformin group, received (300 mg/kg/day, every day for 14 days) oral solution by gavage. Chronic doxorubicin group, received (4mg/kg, twice a week, cumulative dose: 16 mg/ kg) intraperitoneally. Acute doxorubicin group received (16 mg/ kg single dose ) intraperitoneally. Chronic doxorubicin+ metformin group received doxorubicin(4 mg/kg, twice a week intraperitoneally and metformin(300 mg/kg/day, for 14 days, starting three days prior to doxorubicin) orally. Acute doxorubicin+ metformin group received doxorubicin(16 mg/kg single dose) intraperitoneally and metformin (300 mg/kg/day, for 14 days, starting three days prior to doxorubicin) orally. Assessment of serum troponin I, SMAD3 and .RTPCR for TGF-ß1 in addition to trichrome stain.
Result: our result showed that pretreatment with metformin significantly (p<0.05) decreased the level of serum troponin I, SMAD3 and TGFß1 in both MET +acute DOX and MET +chronic DOX group in compare with the acute DOX and chronic DOX group, in addition to significantly decreased collagen fiber production.
Conclusion: this study demonstrated that metformin have a protective effect against doxorubicin cardiotoxicity in both acute and chronic induction, by decreasing serum troponin I, SMAD3 /TGF-ß1 signalling pathway thereby significantly decreasing the collagen fiber production and fibrosis formation.
Keywords: Metformin attenuate; acute doxorubicin; chronic doxorubicin; cardiotoxicity.
Introduction
Anthracyclines including daunorubicin, idarubicin, doxorubicin (DOX), and epirubicin, are regarded as the most effective anticancer drugs against acute myeloblastic and lymphoblastic leukemia. DOX in particular have a highly broad spectrum of action including both solid tumors, such as, sarcomas, breast cancer, and also solid tumors in children (e.g. Wilms tumor) and hematological malignancies, such as, Hodgkin disease, leukemia, and non-Hodgkin lymphomas. . Unfortunately, cardiotoxicity is the most toxic...