Exploring the radiosensitizing potential of AZD8931: a pilot study on the human LoVo colorectal cancer cell line
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Published on: August 21, 2019
Cinzia Antognelli1, Isabella Palumbo2, Simonetta Piattoni3
1Department of Experimental Medicine, University of Perugia, Perugia, Italy.
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.
Insights
AZD8931 enhances radiotherapy by sensitizing colorectal cancer cells, showing greater efficacy than Gefitinib and Cetuximab. This novel radiosensitizer warrants further investigation for improving cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy Research
Background:
- Epidermal Growth Factor Receptor (EGFR) signaling is crucial in colorectal cancer (CRC) progression.
- Targeting EGFR with inhibitors like Cetuximab and Gefitinib is a standard CRC treatment.
- Novel inhibitors targeting multiple EGFR family members (HER1, HER2, HER3) may offer improved therapeutic strategies.
Purpose of the Study:
- To evaluate the radiosensitizing potential of AZD8931, a pan-EGFR inhibitor.
- To compare AZD8931's efficacy against Cetuximab and Gefitinib in sensitizing LoVo CRC cells to ionizing radiation (IR).
- To investigate AZD8931's effects on cell cycle progression, apoptosis, and clonogenic capacity.
Main Methods:
- LoVo colorectal cancer cells were pretreated with EGFR inhibitors (AZD8931, Cetuximab, Gefitinib) followed by ionizing radiation (IR).
- Cell proliferation, cell cycle distribution, and apoptosis were assessed using flow cytometry and ELISA.
- Clonogenic survival and radiosensitivity were determined via colony formation assays.
Main Results:
- AZD8931 demonstrated superior induction of cell cycle arrest and apoptosis compared to Gefitinib and Cetuximab.
- AZD8931 significantly enhanced radiosensitivity, proving more potent than Gefitinib and Cetuximab.
- The radiosensitizing effect of AZD8931 was attributed to reduced progression into the radioresistant S-phase, increased apoptosis, and decreased clonogenic survival.
Conclusions:
- AZD8931 acts as a potent radiosensitizer, significantly improving IR efficacy in LoVo CRC cells.
- AZD8931 exhibits greater radiosensitizing potential than Gefitinib and Cetuximab.
- These findings suggest AZD8931 as a promising agent for enhancing radiotherapy in CRC, meriting further in vitro and in vivo validation.
