Effect of Metformin and Sitagliptin on Doxorubicin-Induced Cardiotoxicity in Rats: Impact of Oxidative Stress, Inflammation, and Apoptosis

Abstract

Doxorubicin (DOX) is a widely used antineoplastic drug whose efficacy is limited by its cardiotoxicity. The aim of this study was to investigate the possible protective role of the antidiabetic drugs metformin (250 mg/kg dissolved in DW p.o. for seven days) and sitagliptin (10 mg/kg dissolved in DW p.o. for seven days) in a model of DOX-induced (single dose 15 mg/kg i.p. at the fifth day) cardiotoxicity in rats. Results of our study revealed that pretreatment with metformin or sitagliptin produced significant (P < 0.05) cardiac protection manifested by a significant decrease in serum levels of LDH and CK-MB enzymes and cardiac MDA and total nitrites and nitrates levels, a significant increase in cardiac SOD activity, and remarkable improvement in the histopathological features as well as a significant reduction in the immunohistochemical expression of COX-2, iNOS, and caspase-3 enzymes as compared to DOX group. These results may suggest using metformin and/or sitagliptin as preferable drugs for diabetic patients suffering from cancer and receiving DOX in their chemotherapy regimen.

Comparative Study of the Protective Effect of Metformin and Sitagliptin against Doxorubicin-Induced Cardiotoxicity in Rats

“…The findings of the present study are in agreement with Aleisa et al [33] who reported that pre-treatment with metformin could improve doxorubicin-induced increase in MDA in mice and Kelle et al [34] who detected the protective effect of metformin could reduce cardiac MDA and the serum level of CK-MB and LDH in doxorubicin treated rats.…”

Effect of Metformin on Doxorubicin-Induced Memory Dysfunction

“…In addition, a previous study using rats showed DOX impairs memory function in novel place recognition [6], and we also detected a specific impairment in the Y-maze task after DOX treatment in rats. We also hypothesized that MET may have a protective effect on DOX-induced impairments in memory function by blocking the metabolic stress response [28], inhibiting the PI-3-kinase-Akt-mTOR (PI3K/Akt/mTOR) pathway, and/or reducing ROS-mediated stress [29]. However, unlike our previous findings using a rat model of CYP-induced cognitive impairment [15], MET did not ameliorate the DOX-induced memory impairment in this study.…”

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach

“…Glucose metabolism and inflammation may not be the only pathomechanisms affected by metformin/NRF2. In fact, other salutary effects have been described for redox (Kocer et al, 2014;Kelleni et al, 2015) and protein homeostasis (Tsai et al, 2017).…”