Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity
Aarti Asnani, Baohui Zheng, Yan Liu, You Wang, Howard H. Chen, Anita Vohra, An Chi, Ivan Cornella-Taracido, Huijun Wang, Douglas G. Johns, David E. Sosnovik, Randall T. Peterson
Aarti Asnani, Baohui Zheng, Yan Liu, You Wang, Howard H. Chen, Anita Vohra, An Chi, Ivan Cornella-Taracido, Huijun Wang, Douglas G. Johns, David E. Sosnovik, Randall T. Peterson
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Research Article Cardiology Oncology

Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity

Abstract

Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. However, their use is limited by cardiotoxicity. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnagin-mediated cardioprotection. Structure-activity relationship studies were performed in a zebrafish model of doxorubicin cardiomyopathy. Movement of the 5-carbonyl to the 7 position and addition of short ester side chains led to development of visnagin analogs with 1,000-fold increased potency in zebrafish and 250-fold increased potency in mice. Using proteomics, we discovered that doxorubicin caused robust induction of Cytochrome P450 family 1 (CYP1) that was mitigated by visnagin and its potent analog 23. Treatment with structurally divergent CYP1 inhibitors, as well as knockdown of CYP1A, prevented doxorubicin cardiomyopathy in zebrafish. The identification of potent cardioprotective agents may facilitate the development of new therapeutic strategies for patients receiving cardiotoxic chemotherapy. Moreover, these studies support the idea that CYP1 is an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting.

Authors

Aarti Asnani, Baohui Zheng, Yan Liu, You Wang, Howard H. Chen, Anita Vohra, An Chi, Ivan Cornella-Taracido, Huijun Wang, Douglas G. Johns, David E. Sosnovik, Randall T. Peterson

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Figure 4

C23 attenuates DOX-induced cardiac apoptosis in mice.

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C23 attenuates DOX-induced cardiac apoptosis in mice. DOX uptake in the ...
DOX uptake in the heart was assessed by reflectance fluorescence imaging, and the resultant apoptosis was simultaneously imaged with Anx-750, a near-infrared fluorescent annexin V probe. (A) DOX fluorescence in a phantom calibration study increased linearly with increasing concentration. (B) Representative ex vivo short-axis heart slices of mouse hearts showing differential DOX uptake 24 hours after a 15 mg/kg DOX injection. (C) Representative ex vivo images of Anx-750 accumulation showed marked reduction in Anx fluorescence after cotreatment with C23 at a dose of 2 mg/kg. A significant reduction in apoptosis was seen with all 3 doses of C23 tested. (D) Cardiac annexin uptake increased significantly in the DOX-only group (DOX+carrier) compared with the control mice injected with saline. Annexin uptake was reduced significantly with treatment with C23. C23 administered at doses of 0.1, 1, and 2 mg/kg all conferred a significant cardioprotective effect. Positive DOX uptake in the heart was confirmed by direct imaging. A total of 45 mice were included in the study as follows: 0.9% saline, i.p. injection (n = 7); 15 mg/kg DOX in saline, and carrier only, i.p. (n = 17); 15 mg/kg DOX in saline, and 0.1 mg/kg 23, i.p. (n = 7); 15 mg/kg DOX in saline, and 1 mg/kg 23, i.p. (n = 7); and 15 mg/kg DOX in saline, and 2 mg/kg 23, i.p. (n = 7). Data are represented as mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, 1-way ANOVA followed by the Tukey’s test. Carrier, 10% DMSO + 90% olive oil. (E) DOX retention in the heart was assessed by direct reflectance fluorescence imaging, and quantified as an increase in signal/noise ratio (SNR) compared with the control mice without DOX injection. No significant difference in DOX fluorescence increase was seen between the DOX only and any of the C23-treated mice. P > 0.05, 1-way ANOVA. Veh., 10% DMSO.