Overexpression of multidrug resistance‐associated protein 1 protects against cardiotoxicity by augmenting the doxorubicin efflux from cardiomyocytes

Doxorubicin is a commonly used anti‐cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induc...

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Bibliographic Details
Published in:The journal of gene medicine 2024-03, Vol.26 (3), p.e3681-n/a
Main Authors: Kok, Cindy Y., Igoor, Sindhu, Rao, Renuka, Tsurusaki, Shinya, Titus, Tracy, MacLean, Lauren M., Kadian, Megha, Skelton, Rhys, Chong, James J. H., Kizana, Eddy
Format: Article
Language:English
Subjects:
Apoptosis
cardiomyocyte
Cardiomyocytes
cardioprotection
Cardiotoxicity
DNA damage
Doxorubicin
Dyes
Fluorescent indicators
Free radicals
gene therapy
lentivirus
Malignancy
MRP1 protein
Multidrug resistance
Proteins
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Summary:Doxorubicin is a commonly used anti‐cancer drug used in treating a variety of malignancies. However, a major adverse effect is cardiotoxicity, which is dose dependent and can be either acute or chronic. Doxorubicin causes injury by DNA damage, the formation of free reactive oxygen radicals and induction of apoptosis. Our aim is to induce expression of the multidrug resistance‐associated protein 1 (MRP1) in cardiomyocytes derived from human iPS cells (hiPSC‐CM), to determine whether this will allow cells to effectively remove doxorubicin and confer cardioprotection. We generated a lentivirus vector encoding MRP1 (LV.MRP1) and validated its function in HEK293T cells and stem cell‐derived cardiomyocytes (hiPSC‐CM) by quantitative PCR and western blot analysis. The activity of the overexpressed MRP1 was also tested, by quantifying the amount of fluorescent dye exported from the cell by the transporter. We demonstrated reduced dye sequestration in cells overexpressing MRP1. Finally, we demonstrated that hiPSC‐CM transduced with LV.MRP1 were protected against doxorubicin injury. In conclusion, we have shown that we can successfully overexpress MRP1 protein in hiPSC‐CM, with functional transporter activity leading to protection against doxorubicin‐induced toxicity. Doxorubicin is a widely used anti‐cancer drug with known cardiotoxic side effects. We aim to protect the heart using gene therapy to augment the ability of cardiomyocytes to efflux doxorubicin. By removing intracellular doxorubicin, cellular damage and subsequent apoptosis downstream would be prevented.
ISSN:1099-498X
1521-2254
DOI:10.1002/jgm.3681