Erlotinib enhanced chemoradiotherapy sensitivity via inhibiting DNA damage repair in nasopharyngeal carcinoma CNE2 cells

Abstract

Background: Nasopharyngeal carcinoma (NPC), arising from nasopharynx epithelium, is a rare type of malignant carcinoma that has a specific geographical distribution and a high risk of distant metastases. For most of the diagnosed NPC patients, the total survival rate decreased significantly due to the high local recurrence rate and metastasis rate. Concurrent chemoradiotherapy (CCRT), as routine therapy strategy of NPC, usually accompanies with high-dosage cytotoxic agents and serious toxic side reaction. Therefore, there is an urgent need for update the existing therapy strategies. In this study, we sought to investigate the effects of a combined therapy strategy, erlotinib combined with cisplatin and radiotherapy, on biological characteristics of NPC CNE2 cells and the potential reasons.Methods: CNE2 cells in logarithmic phase seeding in 96-well plates received concentration gradients of erlotinib (at 0, 10, 20, 40, 80, 160, 320 mmol/L) or cisplatin (at 0, 0.25, 0.5, 1, 2, 4, 8 mg/L), in order to obtain the optimal working concentration of erlotinib and cisplatin via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Then, cells were divided into control group and four treatment groups (Group I-IV). All treatment groups received irradiation of 4 Gy, moreover, Group II-IV respectively received erlotinib, cisplatin and erlotinib plus cisplatin at optimal working concentration. After 24 and 48 h of irradiation, growth inhibition rate was determined; invasion ability and migration ability was respectively detected by Boyden's chamber assay and cell scratch test; flow cytometry was performed for determining apoptosis rate and cell cycle distribution; the expression levels of epidermal growth factor receptor (EGFR) signal pathway proteins were semi-quantitatively analyzed by Western-blot.Results: Compared with Group I, all the other treatment groups showed better inhibition effect on cell viability, invasion and migration ability and higher apoptosis rate, while Group IV showed the strongest growth inhibition effect and highest apoptosis rate. In addition, EGFR signal pathway proteins of Group IV showed the lowest expression level. Conclusions:In combined therapy with radiotherapy/chemotherapy, erlotinib could enhance radiotherapy/chemotherapy sensitivity, probably because it could suppress DNA damage repair after radiotherapy/chemotherapy, thus weakening radiotherapy/chemotherapy resistance of tumor cells.

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“…The mechanism of Erlotinib is to compete with adenosine triphosphate to bind the intracellular catalytic domain of EGFR and thereby inhibit EGFR phosphorylation [ 107 ]. CNE2 cells treated with Erlotinib or Cisplatin inhibit cell viability and migration ability, increase apoptosis, and enhance tumor sensitivity to radiotherapy/chemotherapy, meaning that Erlotinib and Cisplatin weaken the radiotherapy/chemotherapy resistance of tumor cells [ 105 ].…”

“…The combination of Afatinib and Gemcitabine (GEM) have shown significant anti-tumor efficacy in NPC xenograft models [ 108 , 109 ]. In addition, Erlotinib and Afatinib could enhance the sensitivity of tumors to chemoradiotherapy by inhibiting DNA damage repair [ 105 , 108 ]. However, no clinical trials have shown that TKIs can significantly improve the prognosis of NPC patients [ 107 , 118 ].…”