Lapatinib, a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, potentiates the antitumor effects of cisplatin on esophageal carcinoma

Abstract

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) overexpression occurs in over 30% of esophageal carcinomas. Combination therapies of EGFR- and HER2-targeting agents with cytotoxic agents are considered a potential therapeutic strategy for esophageal cancer. The antitumor effects of lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2, cisplatin alone, and the combination of the two drugs on esophageal cancer cells were evaluated. The growth inhibition activity of lapatinib, cisplatin, and lapatinib plus cisplatin was measured by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays, and the combination index values were calculated. Additionally, cell cycle distribution and cell apoptosis treated with lapatinib or cisplatin alone and the combination of the two drugs were detected by flow cytometry analysis. The activation of EGFR and HER2 signaling pathways was monitored by Western blot analysis. These experimental data showed that the combination of lapatinib and cisplatin synergistically inhibited cell proliferation and exhibited an enhanced pro-apoptotic effect on esophageal cancer cells. The underlying mechanisms of potentiated effects of combined treatment were associated with reduced phosphorylation of EGFR and HER2, and the downstream signaling molecules AKT and extracellular regulated protein kinases (ERK). Our findings indicated that the combination of lapatinib and cisplatin is one of the promising treatment strategies for esophageal carcinomas with EGFR and HER2 overexpression.

Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity

“…Because numerous studies have shown increased cisplatin sensitivity after inhibition of EGFR, HER2/neu or VEGFR in different tumor entities, we performed combination assays despite the relative resistance of our investigated cell lines towards AEE788 [74,75]. Even with low sensitivity towards AEE788 in salivary adenoid cystic carcinoma, cisplatin efficacy was enhanced by AEE788 [76].…”

Curcumin Protects Human Keratinocytes against Inorganic Arsenite-Induced Acute Cytotoxicity through an NRF2-Dependent Mechanism

“…The important role of NRF2 in chemoprevention and cellular defense has been clearly demonstrated in NRF2 -null mice which are susceptible to both oxidative and carcinogenic insults [28–31]. Accumulating evidence from both animal models and human epidemiological studies has shown that many naturally occurring phytochemicals, including sulforaphane, epigallocatechin-3-gallate (EGCG), curcumin, and oridonin, possess chemopreventive potential by inducing NRF2-mediated antioxidant/detoxification enzymes [32–34].…”

Prognostic relevance and therapeutic implications of centromere protein F expression in patients with esophageal squamous cell carcinoma

“…The methylthiazolyldiphenyl‐tetrazolium bromide (MTT) assay was done as previously described to assessed the sensitivity of cells to drugs . The IC 50 was calculated from survival curves using the Bliss method .…”

“…The methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay was done as previously described to assessed the sensitivity of cells to drugs. 18 The IC50 was calculated from survival curves using the Bliss method. 19 The results from the assays were analyzed for the combination effect between ZOL and cisplatin according to the Zheng-Jun Jin method.…”