P130A novel angiotensin Type I receptor antagonist, Fimasartan, prevents doxorubicin-induced Cardiotoxicity in rats without altering anticancer effect

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Abstract

Aims: Cardiac toxicity is the most important complications associated with doxorubicin (DOX)-based chemotherapy. Angiotensin receptor blockers (ARB) have been reported to have organ-protective effects in heart failure and may be also effective in DOX-induced cardiomyopathy (DOX-CMP). We performed a preclinical experiment to evaluate the preventive effect of a novel ARB, Fimasartan (Fima), in DOX-CMP.

Methods and Results: All animals underwent baseline echocardiography and were then randomly assigned into three groups: treated daily with vehicle (DOX-only group, n=22), 5 mg/kg of Fima (Low- Fima group, n=22), and 10 mg/kg of Fima (High-Fima group, n=19). DOX was injected intravenously once a week for six weeks. Echocardiography was serially performed after treatment. Survival rate of the High- Fima group at 8th week was greater(100%) than that of the Low-Fima (75%) and DOX-only groups (50%). Echocardiography showed preserved left ventricular (LV) ejection fraction in the High-Fima group, but not in the DOX-only group (P = 0.002). LV dimensions increased progressively in the DOX-only group; however, remodeling was attenuated in the Low- and High-Fima groups. In vivo heart, Fima activated ERK and AKT signal from 1 week through 6 weeks, and also up-regulated transcriptional factor c-Myc and Elk-1at 1 week after DOX+Fima. Fima also activated ERK signal in neonatal rat cardiomyocyte. Moreover, high dose of fima induced cell death; in contrast, it did not altered anticancer effect of DOX in S180 sarcoma cell line.

Conclusion: These results suggest that a novel ARB, Fimasartan, could be used for the prevention of DOX induced cardiac toxicity without altering its anticancer effects.

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