Abstract 185: Role of Substance P in Pathogenesis of Chemotherapy Associated Cardiotoxicity.

Abstract

Doxorubicin (DOX), is broadly considered the most active single agent available for many cancers. Doxorubicin has been known to induce, cardiotoxicity and life-threatening heart failure or acute coronary syndromes in some patients. There is an urgent need to develop new non-cardiotoxic therapies in cancer. Substance P (SP) is a neuropeptide involved in pain transmission. We had previously determined that aprepitant, an antagonist of SP receptor (neurokinin1 receptor (NK-1R)), that is routinely used to treat chemotherapy associated nausea, prevents DOX induced cardiomyocyte death in vitro. In the current studies, we determined if SP receptor antagonism could prevent chemotherapy induced cardiotoxicity in vivo. Six week old, male C57BL/6 mice were administered DOX (5 mg/kg of body weight, intraperitoneally (IP) once a week for 5 wks. In the aprepitant treated group, five days before the first injection of DOX, aprepitant (0.5 mg/kg) was administered in the drinking water, and then consequently every day until the end of the experiment. The control groups were treated with vehicle alone (1X PBS) instead of DOX without or with aprepitant pretreatment. Mice were euthanized 6 weeks after the first dose of DOX. We determined heart functions by echocardiogram in all mice. The mean ejection fraction (EF) and fractional shortening (FS), percentage, following treatment with DOX respectively decreased significantly by 25.85% and 30.73% compared to that in the control vehicle group (EF: 40.428 ± 6.68 (DOX; n = 4) vs 54.526 ± 11.15% (Control Vehicle group; n = 4) (FS: 19.51 ± 3.66% (DOX; n = 4) vs. 28.16 ± 7.38% (Control Vehicle group; n = 4) (both, P < 0.05, ANOVA). Importantly, treatment with aprepitant in DOX treated mice normalized the EF and FS values to that present in the control vehicle group (EF; 56.80 ± 6.81 (DOX+aprepitant; n = 4) vs 54.526 ± 11.15% (Control Vehicle group; n = 4) (FS; 29.64 ± 4.46% (DOX+aprepitant; n = 4) v 28.16 ± 7.38% (Control Vehicle group; n = 4) (both, P < 0.05, ANOVA). These findings indicate that SP contributes to chemotherapy associated cardiac-dysfunction via interaction with its high affinity receptor, NK1R. These studies suggest that SP-receptor antagonism may be a novel option to prevent chemotherapy associated cardiotoxicity in cancer.