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Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody.

Zhuang HQ, Zhuang H, Bo Q, Guo Y, Wang J, Zhao LJ, Yuan ZY, Wang P - Cancer Cell Int. (2014)

Bottom Line: The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib.The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China ; Tianjin Lung Cancer Center, Tianjin, China.

ABSTRACT

Purpose: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization.

Methods: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis.

Results: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.

Conclusions: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

No MeSH data available.


Related in: MedlinePlus

Apoptosis and colony formation under the combined treatment of erlotinib(20 nM) and 6 Gy radiation. (A) Control group: the apoptotic rate was 2.43 ± 1.03%; the colony formation rate was 71.45 ± 4.64%. (B) Erlotinib group: the apoptotic rate was 11.26 ± 2.14%; the colony formation rate was 43.56 ± 3.38%. (C) Radiation group: the apoptotic rate was 23.45 ± 4.35%; the colony formation rate was 15.6 ± 2.26%. (D) combined treatment with erlotinib and radiation group: the apoptotic rate was 47.68 ± 6.73%; the colony formation rate was 2.04 ± 1.02%.
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Fig1: Apoptosis and colony formation under the combined treatment of erlotinib(20 nM) and 6 Gy radiation. (A) Control group: the apoptotic rate was 2.43 ± 1.03%; the colony formation rate was 71.45 ± 4.64%. (B) Erlotinib group: the apoptotic rate was 11.26 ± 2.14%; the colony formation rate was 43.56 ± 3.38%. (C) Radiation group: the apoptotic rate was 23.45 ± 4.35%; the colony formation rate was 15.6 ± 2.26%. (D) combined treatment with erlotinib and radiation group: the apoptotic rate was 47.68 ± 6.73%; the colony formation rate was 2.04 ± 1.02%.

Mentions: Our results showed that the apoptotic rates of cells in the blank control group, erlotinib alone group, radiation alone group, and combined erlotinib and radiation group after 24 hours of treatment were 2.43 ± 1.03%, 11.26 ± 2.14%, 23.45 ± 4.35%, and 47.68 ± 6.73%, respectively. The apoptotic rate in the combined treatment group was significantly higher than those in the other groups (ANOVA analysis, P < 0.05). The number of colonies was counted after 14 days of treatment, and the colony-forming rates of cells in the blank control group, erlotinib alone group, radiation alone group, and combined erlotinib and radiation group were 71.45 ± 4.64%, 43.56 ± 3.38%, 15.6 ± 2.26%, and 2.04 ± 1.02%, respectively. Although the colony-forming rate in the combined treatment group was the lowest (Figure 1, ANOVA analysis, P < 0.05). These results showed that erlotinib exhibited a clear radiosensitizing effect. However, a portion of the tumor cells survived the combined treatment with erlotinib and radiation and eventually formed colonies.Figure 1


Experimental study on the regulation of erlotinib-induced radiosensitization with an anti-c-MET monoclonal antibody.

Zhuang HQ, Zhuang H, Bo Q, Guo Y, Wang J, Zhao LJ, Yuan ZY, Wang P - Cancer Cell Int. (2014)

Apoptosis and colony formation under the combined treatment of erlotinib(20 nM) and 6 Gy radiation. (A) Control group: the apoptotic rate was 2.43 ± 1.03%; the colony formation rate was 71.45 ± 4.64%. (B) Erlotinib group: the apoptotic rate was 11.26 ± 2.14%; the colony formation rate was 43.56 ± 3.38%. (C) Radiation group: the apoptotic rate was 23.45 ± 4.35%; the colony formation rate was 15.6 ± 2.26%. (D) combined treatment with erlotinib and radiation group: the apoptotic rate was 47.68 ± 6.73%; the colony formation rate was 2.04 ± 1.02%.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4263203&req=5

Fig1: Apoptosis and colony formation under the combined treatment of erlotinib(20 nM) and 6 Gy radiation. (A) Control group: the apoptotic rate was 2.43 ± 1.03%; the colony formation rate was 71.45 ± 4.64%. (B) Erlotinib group: the apoptotic rate was 11.26 ± 2.14%; the colony formation rate was 43.56 ± 3.38%. (C) Radiation group: the apoptotic rate was 23.45 ± 4.35%; the colony formation rate was 15.6 ± 2.26%. (D) combined treatment with erlotinib and radiation group: the apoptotic rate was 47.68 ± 6.73%; the colony formation rate was 2.04 ± 1.02%.
Mentions: Our results showed that the apoptotic rates of cells in the blank control group, erlotinib alone group, radiation alone group, and combined erlotinib and radiation group after 24 hours of treatment were 2.43 ± 1.03%, 11.26 ± 2.14%, 23.45 ± 4.35%, and 47.68 ± 6.73%, respectively. The apoptotic rate in the combined treatment group was significantly higher than those in the other groups (ANOVA analysis, P < 0.05). The number of colonies was counted after 14 days of treatment, and the colony-forming rates of cells in the blank control group, erlotinib alone group, radiation alone group, and combined erlotinib and radiation group were 71.45 ± 4.64%, 43.56 ± 3.38%, 15.6 ± 2.26%, and 2.04 ± 1.02%, respectively. Although the colony-forming rate in the combined treatment group was the lowest (Figure 1, ANOVA analysis, P < 0.05). These results showed that erlotinib exhibited a clear radiosensitizing effect. However, a portion of the tumor cells survived the combined treatment with erlotinib and radiation and eventually formed colonies.Figure 1

Bottom Line: The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib.The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiotherapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China ; Tianjin Lung Cancer Center, Tianjin, China.

ABSTRACT

Purpose: Erlotinib is a novel therapeutic agent for cancer treatment. This study was performed to investigate the role of c-MET-PI3K-AKT pathway in the regulation of erlotinib-induced radiosensitization.

Methods: A973 lung adenocarcinoma cells treated with 6 Gy of radiation were incubated in the presence of erlotinib. The apoptotic rate after 24 hours, the colony-formating rate after 14 days, and changes in the c-MET expression levels after 14 days of irradiation were examined. Surviving fractions in different treatment groups (blank control, radiation alone, erlotinib alone, anti-c-MET monoclonal antibody alone, combined erlotinib and radiation, and combined erlotinib and radiation with anti-c-MET monoclonal antibody groups) were determined, the survival curves were plotted, and the sensitizer enhancement ratio was calculated using colony formation assays. Expressions of c-MET, p-c-MET, PI3K, AKT, and p-AKT in cells in different treatment groups were examined by Western blot analysis.

Results: The apoptotic rate in the combined erlotinib and radiation group was higher than those in single treatment groups; however, the colony-forming rate remained approximately 2.04 ± 1.02%. The expression of c-MET in colony-forming cells in the combined group significantly increased, and the blockade of c-MET activity significantly enhanced the radiosensitizing effect of erlotinib. The expression of c-Met, p-c-MET, PI3K, AKT, and p-AKT among colony-forming cells significantly decreased upon the inhibition of c-MET.

Conclusions: Upregulated activity of the c-MET-PI3K-AKT pathway was found to be important for cell survival under combined the treatment with erlotinib and radiation. The blockade of the c-MET-PI3K-AKT signaling pathway enhanced the radiosensitizing effect of erlotinib.

No MeSH data available.


Related in: MedlinePlus