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.

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials

“…Recently, the hypothesis of adrenergically mediated cardiotoxicity mediated by DPP-4 inhibition has been proposed [53]. Experimental studies discovered that DDP-4 inhibition potentiates not only GLP-1, but also stromal cell-derived factor 1 (SDF-1), neuropeptide Y, and substance P and so on, bringing out central and peripheral sympathetic overactivity via beta-adrenergic stimulation, thereby effecting changes in cardiac inflammation, fibrosis as well as myocardial apoptosis and loss of viability [54][55][56][57][58][59][60][61][62]. In the SAVOR-TIMI 53 trial, the increase in heart failure hospitalization in patients treated with saxagliptin was significantly attenuated with the concomitant use of beta blockers [63], lending additional proof to the plausibility of such theory.…”

Magnesium isoglycyrrhizinate ameliorates doxorubicin‑induced acute cardiac and hepatic toxicity via anti‑oxidant and anti‑apoptotic mechanisms in mice

“…Elevated ROS may induce apoptotic cell death and damage to tissues and organs (40)(41)(42). NF-κBp65 is predominant in the apoptotic regulation process by regulating the expression of downstream Bcl-2 genes.…”

The Regulation of Pulmonary Vascular Tone by Neuropeptides and the Implications for Pulmonary Hypertension

“…Substance P appears to be a mediator of cardiac toxicity induced by doxorubicin, which is a chemotherapy agent that causes cardiomyocyte death. Inhibition of substance P resulted in lower cardiomyocyte apoptosis after doxorubicin treatment to an isolated cell line ( Robinson et al, 2016 ). Taken together, these findings are clinically exciting, as it suggests that substance P-antagonist based therapies may be able to directly improve right ventricular parameters above simply relieving right ventricular afterload for PAH treatment.…”