The HER2 inhibitor lapatinib potentiates doxorubicininduced cardiotoxicity through iNOS signaling
Journal
Theranostics
Journal Volume
8
Journal Issue
12
Pages
3176-3188
Date Issued
2018
Author(s)
Abstract
Rationale: Lapatinib (LAP) is a crucial alternative to trastuzumab upon the onset of drug resistance during treatment of metastatic human epidermal growth factor receptor 2-positive breast cancer. Like trastuzumab, LAP is commonly used alongside anthracyclines as a combination therapy, due to enhanced anti-cancer efficacy. However, this is notably associated with cardiotoxicity so it is imperative to understand the mechanisms driving this cardiotoxicity and develop cardioprotective strategies. To this end, here we utilize human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), which exhibit several characteristics representative of in vivo cardiomyocytes that make them breakthrough models to study drug toxicity. Methods: We investigated LAP- and doxorubicin (DOX)-induced toxicity in hPSC-CMs and evaluated the involvement of inducible nitric oxide (NO) synthase (iNOS). The significance of iNOS-mediated cardiotoxicity was furthermore evaluated in animal studies. Results: LAP synergistically increased DOX toxicity in hPSC-CMs in a dose- and time-dependent manner. At concentrations that were otherwise non-apoptotic when administered separately, LAP significantly potentiated DOX-induced hPSC-CM apoptosis. This was accompanied by increased iNOS expression and pronounced production of NO. iNOS inhibition significantly reduced hPSC-CM sensitivity to LAP and DOX co-treatment (LAP-plus-DOX), leading to reduced apoptosis. Consistent with our observations in vitro, delivery of an iNOS inhibitor in mice treated with LAP-plus-DOX attenuated myocardial apoptosis and systolic dysfunction. Moreover, inhibition of iNOS did not compromise the anti-cancer potency of LAP-plus-DOX in a murine breast cancer xenograft model. Conclusions: Our findings suggest that iNOS inhibition is a promising cardioprotective strategy to accompany HER2-inhibitor/anthracycline combination therapies. Furthermore, these results support the promise of hPSC-CMs as a platform for investigating cardiotoxicity and developing cardioprotectants as a whole. ? Ivyspring International Publisher.
SDGs
Other Subjects
doxorubicin; inducible nitric oxide synthase; lapatinib; antineoplastic agent; doxorubicin; inducible nitric oxide synthase; lapatinib; NOS2 protein, human; Nos2 protein, mouse; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; Article; breast cancer; C57BL 6 mouse; cardiac muscle cell; cardiotoxicity; cohort analysis; concentration response; controlled study; drug potentiation; drug sensitivity; enzyme inhibition; female; heart infarction; heart protection; human; human cell; human epidermal growth factor receptor 2 positive breast cancer; IC50; in vitro study; in vivo study; male; maximum concentration; mouse; nonhuman; pluripotent stem cell; protein expression; signal transduction; SK-BR-3 cell line; systolic dysfunction; tumor xenograft; animal; biological model; cardiac muscle; disease model; drug effect; metabolism; pathology; Animals; Antineoplastic Agents; Cardiotoxicity; Disease Models, Animal; Doxorubicin; Humans; Lapatinib; Mice; Models, Biological; Myocardium; Myocytes, Cardiac; Nitric Oxide Synthase Type II; Signal Transduction
Type
journal article