Dantrolene Attenuates Cardiotoxicity of Doxorubicin Without Reducing its Antitumor Efficacy in a Breast Cancer Model

Figures

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  Figure 1. Effects of chronic DOX, DNT, and DOX + DNT on body weight loss from baseline of surviving rats with implanted breast tumors. Bottoms and tops of boxes respectively show first and third quartiles; horizontal lines dividing boxes show medians, and symbols inside boxes show means. n = 5 Naive controls (both time points), n = 10 Tumor controls (both time points), n = 14 in the DOX group at baseline (n = 11 at sacrifice), n = 14 in the DNT group (both time points), and n = 14 in the DOX + DNT group at baseline (n = 12 at sacrifice).

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  Figure 2. Changes in cardiac output (A) and stroke volume (B) before the treatment (n = 14/group) and after the treatment of the surviving rats with breast tumors (n = 13/DOX group; n = 12/DNT group; n = 12/DOX + DNT group) treated with chronic DOX, DNT and DOX + DNT.

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  Figure 3. Histopathological alterations in the hearts of the surviving rats with breast tumors treated with chronic DOX (n = 9), DNT (n = 14) or DOX + DNT (n = 12) versus no tumor-controls. A. Results from a semiquatitative assessment of histopathological alterations (mean ± SE, n = 9/DOX group; n = 10/DNT group; n = 10/DOX + DNT group; n = 5/control group. *P < 0.05 DOX vs all. B. Composite image of representative histopathologic changes in myocardium of the study groups: B1: normal myocardial histology in naïve controls; B2 cytoplasmic vacuoles (yellow arrows), edema (black arrow) and eosinophilic myocytes with pyknotic nuclei (thick black arrow) in rats treated with DOX; B3: edema (black arrows) in rats treated with DNT + DOX; B4: cytoplasmic vacuoles (yellow arrows) and mild edema (black arrow) in rats treated with DNT. Hematoxylin–eosin stain, magnification 200×.

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  Figure 4. Average plasma cTnI concentration in the surviving rats treated with chronic DOX (n = 8), DNT (n = 12), DOX + DNT (n = 11) and control group (n = 4). Bottoms and tops of boxes, respectively, show first and third quartiles; horizontal lines dividing boxes show medians, and symbols inside boxes show means.

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  Figure 5. Blood GSH levels (A), GSSG (B) and ratio GSH/GSSG (C) in the surviving rats treated with chronic DOX (n = 8), DNT (n = 13), DOX + DNT (n = 11) and control group (n = 3). Bottoms and tops of boxes respectively show first and third quartiles; horizontal lines dividing boxes show medians, and symbols inside boxes show means.

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  Figure 6. Effect of chronic DOX, DNT and DOX + DNT on breast tumor growth in surviving rats. Tumor volumes of rats with treated with chronic DOX (n = 9), DNT (n = 14) and DOX + DNT (n = 12-versus controls with untreated tumor (n = 10) (A). Representative image of tumor necrosis in a rat treated with DOX (B). Arrows show viable tumor nests in a background of prominent tumor necrosis. Hematoxylin and eosin stain, magnification 200×.