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  • br A Khanjari I K Karabagias M G Kontominas

    2020-08-12


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    Contents lists available at ScienceDirect
    Pathology - Research and Practice
    journal homepage: www.elsevier.com/locate/prp
    Apatinib enhanced anti-tumor activity of cisplatin on triple-negative breast T cancer through inhibition of VEGFR-2
    Zhenyuan Gao, Mohan Shi, Yaping Wang, Juan Chen, Yimei Ou
    Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233004, PR China
    Keywords:
    Triple-Negative breast cancer
    Apatinib
    Cisplatin
    VEGFR2 
    Background: Triple-negative breast cancer (TNBC) was known as a fast-growing and an aggressive tumor. Cisplatin is the effective cytotoxic drug used for the treatment of TNBC. In addition, apatinib, a VEGFR2 in-hibitor, exhibits antitumor activity in patients with TNBC. However, the effects of combination of apatinib with cisplatin on TNBC remain unclear. Thus, this study aimed to investigate the effects of apatinib in combination with cisplatin on MDA-MB-231 cells.
    Methods: Immunohistochemistry was used to detect the expression of VEGFR2. In addition, CCK-8, flow cyto-metric, transwell assays were used to measure the cell proliferation, apoptosis, migration and invasion, re-spectively. Moreover, western blotting was used to detect the expressions of Bax, active caspase 3, p-VEGFR2, p-Akt and p-mTOR.
    Results: VEGFR2 was significantly upreguated in patients with TNBC. In addition, the inhibitory effects of cis-platin on the proliferation, migration and invasion of MDA-MB-231 191471-52-0 were enhanced by apatinib. Moreover, apatinib increased cisplatin-induced apoptosis on MDA-MB-231 cells via increasing the level of Bax and active caspase 3 and decreasing the expression of Bcl-2. Importantly, apatinib enhanced anti-tumor effect of cisplatin on MDA-MB-231 cells via inhibiting the levels of p-VEGFR2, p-Akt and p-mTOR.
    Conclusion: Our findings indicated that apatinib enhanced the anti-tumor effects of cisplatin on MDA-MB-231 cells via inhibition of VEGFR2. Thus, the combination of apatinib with cisplatin may serve as a potential ap-proach in the treatment of patients with TNBC.
    1. Introduction
    Breast cancer is the most leading malignant tumor in women all over the world [1]. According to the estimation, there are 252,710 new cases and 40,610 deaths cases in America [1]. Triple-negative breast cancer (TNBC) accounts for approximately 15% of all breast cancers, which is a fast-growing and an aggressive tumor [2]. Molecular pro-filing has identified TNBC as a disease which contains several intrinsic subtypes, such as “basal-like” and Her2-enriched [3]. Triple-negative basal-like (TNBL) are characterized by lacking estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth receptor 2 (Her2) proteins expression [4]. The “basal-like” subtype is more com-monly negative for all 3 markers (ER, PR and HER2), which belong to the “triple-negative” phenotypic classification [4]. Previous study has suggested that TNBC has a relatively high rate of recurrence and distant metastasis, with poor overall survival (OS) [5]. The common
    therapeutic option is chemotherapy for the treatment of TNBC [6]. However, TNBC develops resistance to chemotherapy treatment widely [7]. Therefore, investigations of novel effective therapies for TNBC are urgently needed.
    Cisplatin (cis-diamminedichloroplatinum II), a most common che-motherapeutic drug, which kills cancer cells by damaging their DNA [8]. Ciaplatin is widely used to combat multiple cancers, including breast, ovary, testes and bladder cancer [8]. Some studies have showed that cisplatin is an important cytotoxic drug for treatment of TNBC [9,10]. However, its clinical usefulness is limited by renal, neurological, and gastrointestinal toxicity [11]. Thus, the development of novel tar-geted therapies for this aggressive type of breast cancer is of paramount importance.
    Apatinib, a novel vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor, has potential antiangiogenic and antineoplastic activities [3,12]. Previous study indicated that VEGF and VEGFRs play
    Corresponding author: Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical College, No. 287 Changhuai Road, Longzihu District, Bengbu, Anhui, 233004, PR China.
    an important role in angiogenesis of breast and other cancers [13]. Apatinib could inhibit VEGF-induced endothelial cell proliferation and migration [14]. Recently, apatinib exerts satisfying efficacy on various types of cancers such as lung cancer, nasopharyngeal carcinoma and hepatocellular carcinoma [15–17]. Previous study also indicated that apatinib exhibited substantial antitumor activity in patients with TNBC [3]. Therefore, this study aimed to investigate the anti-tumor effects of apatinib in combination with cisplatin on TNBC, in order to provide new ideas and methods for the treatment of TNBC.