Apatinib inhibits the growth of small cell lung cancer via a mechanism mediated by VEGF, PI3K/Akt and Ki-67/CD31.

Ning Zhong,Qiang Wang,Qian Huang,Wei Zhuang,Wenjian Jin

doi:10.1111/jcmm.16926

Abstract

This study aimed to investigate the anti‐tumour effect of apatinib on extensive‐stage small cell lung cancer (SCLC) and elucidate the associated mechanisms. NCI‐H345 cells were selected as model cells because of high expression of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2) and phosphorylated‐VEGFR2 (pVEGFR2). Cells were exposed to recombinant human VEGF (rhVEGF) and apatinib. Cells were then divided into eight groups, namely, control, rhVEGF, apatinib, rhVEGF+apatinib, serum‐free medium (SM), SM+rhVEGF, SM+apatinib and SM+rhVEGF+apatinib. In comparison with the control group, cell proliferation in vitro in apatinib, SM, SM+apatinib and SM+rhVEGF+apatinib groups was inhibited, particularly in SM+apatinib group. The effect of apatinib on tumour growth in vivo was investigated using a mouse xenograft tumour model. In comparison with the control group, tumour sizes were reduced in apatinib‐treated group on days 34 and 37. Immunohistochemical and immunofluorescence staining revealed that VEGF, pVEGFR2, PI3K, AKT, p‐ERK1/2, Ki‐67 and CD31 in the tumour cells of apatinib‐treated group were downregulated compared with control group. Haematoxylin and eosin staining revealed that apatinib promoted the necrosis of SCLC cells in vivo. In conclusion, apatinib inhibited the growth of SCLC cells by downregulating the expression of VEGF, pVEGFR2, p‐PI3K, p‐AKT, p‐ERK1/2, Ki‐67 and CD31.

Highlights

Small cell lung cancer (SCLC) is a type of poorly differentiated neuroendocrine tumour characterized by rapid growth, early metastasis, and sensitivity to radiotherapy and chemotherapy.[1]
Apatinib mesylate is a small molecule VEGF receptor 2 (VEGFR2) tyrosine kinase inhibitor developed in China that can be administered orally
Apatinib competitively binds to the adenosine triphosphate binding site in VEGFR2, blocking the downstream signalling pathways and inhibiting tumour angiogenesis.18–21 vascular endothelial growth factor (VEGF) has an angiogenesis- promoting effect.[22]

Summary

| INTRODUCTION

Small cell lung cancer (SCLC) is a type of poorly differentiated neuroendocrine tumour characterized by rapid growth, early metastasis, and sensitivity to radiotherapy and chemotherapy.[1] SCLC accounts for 14% of lung cancer cases and is closely associated with smoking. Apatinib is a highly selective VEGFR2 inhibitor, which inhibits the angiogenesis of nasopharyngeal carcinoma, non-Hodgkin lymphoma and small-c ell carcinoma of oesophagus.13–16 The clinical efficacy of apatinib in advanced tumours, including relapsed or refractory non- Hodgkin lymphoma, metastatic gastric cancer, colorectal cancer, non-SCLC (NSCLC), neuroendocrine tumours and mesothelioma, has been demonstrated in several clinical trials.[14,15] apatinib may be a suitable therapeutic agent for the maintenance treatment of patients with extensive-stage (ES)-SCLC. The present study aimed to investigate the anti-tumour effect of apatinib in ES-SCLC by using in vivo and in vitro models

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION