title: In vitro synergistic antitumor efficacy of sequentially combined chemotherapy/icotinib in non‑small cell lung cancer cell lines.
abstract: The concurrent administration of chemotherapy and epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) has previously produced a negative interaction and failed to confer a survival benefit to non‑small cell lung cancer (NSCLC) patients compared with first‑line cytotoxic chemotherapy. The present study aimed to investigate the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib in NSCLC cell lines and clarify the underlying mechanisms. HCC827, H1975, H1299 and A549 human NSCLC cell lines with wild‑type and mutant EGFR genes were used as in vitro models to define the differential effects of various schedules of cisplatin/paclitaxel with icotinib treatments on cell growth, proliferation, cell cycle distribution, apoptosis, and EGFR signaling pathway. Sequence‑dependent antiproliferative effects differed among the four NSCLC cell lines, and were not associated with EGFR mutation, constitutive expression levels of EGFR or downstream signaling molecules. The antiproliferative effect of cisplatin plus paclitaxel followed by icotinib was superior to that of cisplatin or paclitaxel followed by icotinib in the HCC827, H1975, H1299 and A549 cell lines, and induced more cell apoptosis and G0/G1 phase arrest. Cisplatin and paclitaxel significantly increased the expression of EGFR phosphorylation in the HCC827 cell line. However, only paclitaxel increased the expression of EGFR phosphorylation in the H1975 cell line. Cisplatin/paclitaxel followed by icotinib influenced the expression of p‑EGFR and p‑AKT, although the expression of p‑ERK1/2 remained unchanged. The results suggest that the optimal schedule of the combined treatment of cisplatin/paclitaxel and icotinib differed among the NSCLC cell lines. The results also provide molecular evidence to support clinical treatment strategies for NSCLC patients.
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Min-Cong
authors.initials: MC
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Liang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Zhi-Yan
authors.initials: ZY
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Jiang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Jie-Qun
authors.initials: JQ
authors.lastname: Ma
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Li-Li
authors.initials: LL
authors.lastname: Han
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Guo
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Cheng-Cheng
authors.initials: CC
authors.lastname: Yang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Ke-Jun
authors.initials: KJ
authors.lastname: Nan
authors.affiliation: Department of Oncology, The First Affiliated Hospital, College of Medicine of Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D043844:Crown Ethers / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms; D017239:Paclitaxel / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D043844:Crown Ethers; D011799:Quinazolines; C531470:icotinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D017239:Paclitaxel; D002945:Cisplatin