Lobaplatin-Induced Apoptosis Requires p53-Mediated p38MAPK Activation Through ROS Generation in Non-Small-Cell Lung Cancer.

Hongming Zhang,Runzhe Chen,Xiaoli Zhu,Haijun Zhang,Xiyong Wang,Jibei Chen

doi:10.3389/fonc.2019.00538

Abstract

Platinum-based chemotherapy is recommended as the first-line treatment regimen for patients with advanced non-small-cell lung cancer (NSCLC). Lobaplatin (LBP), a third-generation platinum anti-neoplastic agent, has shown an improved efficacy. This study is aimed to investigate the mechanisms of LBP-induced apoptosis in the A549 p53 wild-type cell line. The Cell Counting Kit-8 assay (CCK-8), flow cytometry (FCM), Western blot, xenograft tumor models, terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), and RNA interference were used in this study. Our results showed that the proliferation of A549 cells could be inhibited by LBP. At lower concentrations, LBP triggered cell cycle arrest at the G1 phase in A549 cells. LBP could also induce apoptosis of A549 cells. LBP also increased the expression of PARP and Bax and the cleavage of caspase-3, caspase-8, and caspase-9 and reduced Bcl-2 expression. In vivo experiment confirmed that LBP could inhibit tumor growth in the A549 xenograft models and induce apoptosis. Apoptosis of A549 cells was decreased after transfected with p53 shRNA or treated with reactive oxygen species inhibitor NAC and p38MAPK inhibitor SB203580, suggesting that the p53/ROS/p38MAPK pathway appeared to mediate the LBP-induced apoptosis of A549 cells. Our data demonstrate that LBP could be a promising candidate for the treatment of NSCLC with wild-type p53.

Highlights

Lung cancer is the leading cause of cancer-related death worldwide [1], with non-small-cell lung cancer (NSCLC) accounting for 85% of lung cancer cases [2]
The Cell Counting Kit-8 assay (CCK-8) assay was performed to evaluate the effects of LBP on the proliferation of A549, NCI-H1299, and SK-MES-1 cells
The IC50 values for NCI-H1299 cells were 67.26 ± 1.06, 17.98 ± 1.05, and 7.85 ± 1.01 μM for the 24, 48, and 72h treatment times, respectively, while the IC50 values for A549 cells were 11.69 ± 1.05, 5.02 ± 1.11, and 2.43 ± 1.01 μM for the 24, 48, and 72-h treatment times, respectively

Summary

Introduction

Lung cancer is the leading cause of cancer-related death worldwide [1], with non-small-cell lung cancer (NSCLC) accounting for 85% of lung cancer cases [2]. Platinum-based doublet regimens have been used as a standard first-line therapy against NSCLC. There are two kinds of platinumbased agents widely used in NSCLC: cisplatin (DDP) and carboplatin (CBP). Severe toxicity and drug resistance after utilization often occur. Exploration of new effective platinum-based agents with low toxicity for the treatment of NSCLC is urgently required. Lobaplatin (LBP) is a third-generation platinum compound (Figure 1A) and has shown improved stability, a broader spectrum, and higher efficacy compared with DDP and CBP [3]. As a Lobaplatin-Induced Apoptosis by p53/ROS/p38MAPK Pathway result, it has been approved by the China Food and Drug Administration (CFDA) for the treatment of inoperable, metastatic breast cancer, small cell lung cancer (SCLC), and chronic myelocytic leukemia (CML) [4]. Multiple studies have demonstrated its anticancer activity against other types of cancer [5,6,7,8,9,10,11,12,13,14,15]

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