Substance P Antagonism as a Novel Therapeutic Option to Enhance Efficacy of Cisplatin in Triple Negative Breast Cancer and Protect PC12 Cells against Cisplatin-Induced Oxidative Stress and Apoptosis.

Emma Rodriguez,Sang Kim,Guangsheng Pei,Alexis German,Prema Robinson,Zhongming Zhao

doi:10.3390/cancers13153871

Abstract

Simple SummaryAlthough cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. In the current studies we determined a novel therapeutic option that enhances the efficacy of cisplatin and at the same time protects neuronal cells from cisplatin induced toxicity.Although cisplatin is very effective as a treatment strategy in triple-negative breast cancer (TNBC), it has unwarranted outcomes owing to recurrence, chemoresistance and neurotoxicity. There is critically important to find new, effective and safe therapeutics for TNBC. We determined if SP-receptor antagonism in combination with cisplatin may serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC. We used a neuronal cell line (PC12) and two TNBC cell lines (Sum 185 and Sum 159) for these studies. We determined that the levels of cells expressing the high-affinity SP-receptor (neurokinin 1 receptor (NK1R)), as determined by flow-cytometry was significantly elevated in response to cisplatin in all three cells. We determined that treatment with aprepitant, an SP-receptor antagonist decreased cisplatin-induced, loss of viability (studied by MTT assay), production of reactive oxygen species (by DCFDA assay) and apoptosis (by flow-cytometry) in PC12 cells while it was increased in the two TNBC cells. Furthermore, we demonstrated that important genes associated with metastases, inflammation, chemoresistance and cell cycle progression are attenuated by SP-receptor antagonism in the TNBC cell line, Sum 185. These studies implicate that SP-receptor antagonism in combination with cisplatin may possibly serve as a novel, more efficacious and safer therapeutic option than existing therapies for TNBC.

Highlights

We determined whether cisplatin treatment increased NK1R levels in PC12 cells and in
We demonstrated that (a) aprepitant decreased cisplatin-induced loss of viability, reactive oxygen species (ROS) production and apoptotic cell death in PC12 cells compared with cells treated with cisplatin alone and (b) aprepitant increased cisplatin-induced loss of viability, ROS production and apoptotic cell death in Triple negative breast cancer (TNBC) cells compared with cells treated with cisplatin alone
We demonstrated that Substance P (SP) receptor antagonism enhanced the cisplatin-induced ROS production and apoptosis levels in two TNBC cancer cells

Summary

Introduction

Cisplatin forms the basis of chemotherapy regimens for many malignancies, including TNBC, ovarian and cervical cancers, prostate and testicular cancers, bladder cancer, head and neck cancer, lung cancer and non-Hodgkin’s lymphoma [4,5,6,7]. It mediates its effects by crosslinking with the purine bases on the DNA, leading to interference with DNA repair leading to DNA damage and ensuing apoptosis of tumor cells. Novel therapeutic combinations are needed to increase the efficacy of cisplatin and at the same time ablate or reduce cisplatin-induced toxicity and chemoresistance

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