PUBLICATION
Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity
- Authors
- Asnani, A., Zheng, B., Liu, Y., Wang, Y., Chen, H.H., Vohra, A., Chi, A., Cornella-Taracido, I., Wang, H., Johns, D.G., Sosnovik, D.E., Peterson, R.T.
- ID
- ZDB-PUB-180113-2
- Date
- 2018
- Source
- JCI insight 3(1): (Journal)
- Registered Authors
- Peterson, Randall
- Keywords
- Cardiology, Cardiovascular disease, Drug therapy, Oncology, Toxins/drugs/xenobiotics
- MeSH Terms
-
- Animals
- Apoptosis
- Cardiotoxicity/pathology
- Cardiotoxicity/prevention & control*
- Cell Line
- Cytochrome P450 Family 1/antagonists & inhibitors*
- Doxorubicin/antagonists & inhibitors*
- Doxorubicin/toxicity
- Heart/drug effects*
- Khellin/administration & dosage
- Khellin/chemistry
- Khellin/pharmacology*
- Male
- Mice
- Mice, Inbred C57BL
- Models, Animal
- Myocytes, Cardiac/drug effects
- Structure-Activity Relationship
- Xenobiotics
- Zebrafish
- PubMed
- 29321375 Full text @ JCI Insight
Citation
Asnani, A., Zheng, B., Liu, Y., Wang, Y., Chen, H.H., Vohra, A., Chi, A., Cornella-Taracido, I., Wang, H., Johns, D.G., Sosnovik, D.E., Peterson, R.T. (2018) Highly potent visnagin derivatives inhibit Cyp1 and prevent doxorubicin cardiotoxicity. JCI insight. 3(1).
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping