Abstract

Aim

To explore the radiosensitizing effect of AZD8931, a novel equipotent and reversible inhibitor of signaling by EGFR (HER1), HER2 and HER3 receptors, focusing on cell cycle progression, apoptosis and clonogenic capacity in the human LoVo colorectal cancer (CRC) cell line, also in comparison with the EGFR-blocking monoclonal antibody Cetuximab or the EGFR tyrosine kinase selective small molecular inhibitor Gefitinib.

Materials and methods

Cells were pretreated with EGFR inhibitors for 5 consecutive days and then exposed or not to ionizing radiation (IR) (2 Gy daily for 3 consecutive days). Cell proliferation, cell cycle progression and apoptosis were evaluated by flow cytometry and enzyme-linked immunosorbent assay (ELISA), clonogenic potential and radiosensitivity were studied by colony formation assay.

Results

AZD8931 induced cell cycle arrest and apoptosis more effectively than Gefitinib and Cetuximab and, more importantly, it was significantly more potent than Gefitinib and Cetuximab in radiosensitizing cells. This radiosensitizing action by AZD8931 mainly occurred by markedly reducing cell cycle progression into S phase, the most radioresistant phase of cell cycle, secondly by inducing apoptosis and reducing clonogenic survival.

Conclusions

Our results show that AZD8931 increases IR efficacy in LoVo cells, suggesting that it works as a potent radiosensitizer, even more efficient than Gefitinib and Cetuximab, opening new pathways of investigation for further in vitro and in vivo studies aimed at confirming its potential to improve local radiotherapy in CRC.

中文翻译：

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探索AZD8931的放射增敏潜力：人类LoVo结直肠癌细胞系的初步研究。

摘要

目标

为了探索AZD8931的放射增敏作用，AZD8931是EGFR（HER1），HER2和HER3受体的新型等位且可逆信号转导抑制剂，主要研究人LoVo大肠癌（CRC）细胞系的细胞周期进程，凋亡和克隆形成能力，与EGFR阻断单克隆抗体西妥昔单抗或EGFR酪氨酸激酶选择性小分子抑制剂吉非替尼相比。

材料和方法

将细胞连续用EGFR抑制剂预处理5天，然后暴露于或不暴露于电离辐射（IR）（每天2 Gy，连续3天）。通过流式细胞术和酶联免疫吸附测定（ELISA）评估细胞增殖，细胞周期进程和凋亡，通过菌落形成测定研究克隆形成潜力和放射敏感性。

结果

AZD8931比吉非替尼和西妥昔单抗更有效地诱导细胞周期停滞和凋亡，更重要的是，它在放射增敏细胞中比吉非替尼和西妥昔单抗更有效。AZD8931的这种放射增敏作用主要是通过显着减少细胞周期进入S期（细胞周期最耐放射的阶段）而产生的，其次是通过诱导凋亡和减少克隆形成的存活。

结论

我们的结果表明AZD8931可提高LoVo细胞的IR功效，表明它可作为强效放射增敏剂，甚至比吉非替尼和西妥昔单抗更有效，为进一步的体内外研究开辟了新的研究途径，旨在证实其潜在的改善局部的潜力。 CRC中的放射治疗。