title: Substance P Receptor Signaling Mediates Doxorubicin-Induced Cardiomyocyte Apoptosis and Triple-Negative Breast Cancer Chemoresistance.
abstract: Doxorubicin (DOX), an anthracycline, is broadly considered the most active single agent available for treating breast cancer but has been known to induce cardiotoxicity. Although DOX is highly effective in treating triple-negative breast cancer (TNBC), DOX can have poor outcomes owing to induction of chemoresistance. There is an urgent need to develop new therapies for TNBC aimed at improving DOX outcome and DOX-induced cardiotoxicity. Substance P (SP), a neuropeptide involved in pain transmission is known to stimulate production of reactive oxygen species (ROS). Elevated cardiac ROS is linked with heart injury and failure. We investigated the role of SP in chemotherapy-associated death of cardiomyocytes and chemoresistance. We showed that pretreating a cardiomyocyte cell line (H9C2) and a TNBC cell line (MDA-MB 231) with aprepitant, a SP receptor antagonist that is routinely used to treat chemotherapy-associated associated nausea, decreased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in cardiomyocytes and increased DOX-induced reduction of cell viability, apoptotic cell death, and ROS production in TNBC cells compared with cells treated with DOX alone. Our findings demonstrate the ability of aprepitant to decrease DOX-induced killing of cardiomyocytes and to increase cancer cell sensitivity to DOX, which has tremendous clinical significance.
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Prema
authors.initials: P
authors.lastname: Robinson
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Moses
authors.initials: M
authors.lastname: Kasembeli
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Uddalak
authors.initials: U
authors.lastname: Bharadwaj
authors.affiliation: Department of Natural Science and Mathematics, Lee University, Cleveland, TN 37311, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Engineer
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kris T
authors.initials: KT
authors.lastname: Eckols
authors.affiliation: Department of Infectious Diseases, Infection Control, and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077608:Aprepitant; D066126:Cardiotoxicity / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology
chemical_list: D009025:Morpholines; D018040:Receptors, Neurokinin-1; D000077608:Aprepitant; D004317:Doxorubicin