Furihata 2021 BMC Pharmacol Toxicol

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Furihata T, Maekawa S, Takada S, Kakutani N, Nambu H, Shirakawa R, Yokota T, Kinugawa S (2021) Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice. BMC Pharmacol Toxicol 22:27.

» PMID:33962676 Open Access

Takaaki Furihata, Maekawa Satoshi, Takada Shingo, Kakutani Naoya, Nambu Hideo, Shirakawa Ryosuke, Yokota Takashi, Kinugawa Shintaro (2021) BMC Pharmacol Toxicol

Abstract: Background: Doxorubicin (DOX) is widely used as an effective chemotherapeutic agent for cancers; however, DOX induces cardiac toxicity, called DOX-induced cardiomyopathy. Although DOX-induced cardiomyopathy is known to be associated with a high cumulative dose of DOX, the mechanisms of its long-term effects have not been completely elucidated. Pioglitazone (Pio) is presently contraindicated in patients with symptomatic heart failure owing to the side effects. The concept of drug repositioning led us to hypothesize the potential effects of Pio as a premedication before DOX treatment, and to analyze this hypothesis in mice.

Methods: First, for the hyperacute (day 1) and acute (day 7) DOX-induced dysfunction models, mice were fed a standard diet with or without 0.02% (wt/wt) Pio for 5 days before DOX treatment (15 mg/kg body weight [BW] via intraperitoneal [i.p.] administration). The following 3 treatment groups were analyzed: standard diet + vehicle (Vehicle), standard diet + DOX (DOX), and Pio + DOX. Next, for the chronic model (day 35), the mice were administrated DOX once a week for 5 weeks (5 mg/kg BW/week, i.p.).

Results: In the acute phase after DOX treatment, the percent fractional shortening of the left ventricle (LV) was significantly decreased in DOX mice. This cardiac malfunction was improved in Pio + DOX mice. In the chronic phase, we observed that LV function was preserved in Pio + DOX mice.

Conclusions: Our findings may provide a new pathophysiological explanation by which Pio plays a role in the treatment of DOX-induced cardiomyopathy, but the molecular links between Pio and DOX-induced LV dysfunction remain largely elusive. Keywords: Anticancer agent; Cardiac toxicity; LV dysfunction; Thiazolidinediones.

O2k-Network Lab: JP Sapporo Yokota T


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cardiovascular 

Organism: Mouse  Tissue;cell: Heart  Preparation: Isolated mitochondria 


Coupling state: OXPHOS 

HRR: Oxygraph-2k, O2k-Fluorometer 

2021-05, JP