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Sequence-dependent antiproliferative effects of gefitinib and docetaxel on non-small cell lung cancer (NSCLC) cells and the possible mechanism.

Chen B, Zheng J, Zeng Y, Li B, Xie B, Zheng J, Zhou J, Zhang W - PLoS ONE (2014)

Bottom Line: Only sequential administration of docetaxel followed by gefitinib (D → G) induced significant synergistic effect in both cell lines (Combination Index<0.9).The reverse sequence (G → D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9<CI<1.1)-synergistic effect in PC-9 cells and antagonistic-additive effect in A549 cells.The gefitinib-repressed phosphorylation of EGFR and ERK was reversed neither by concurrent nor by subsequent administration of docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.

ABSTRACT

Purpose: Recent clinical trials showed that the sequential combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy could prolong the PFS and/or OS of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation. The aim of present study was to assess the optimal combination sequence and to explore its possible mechanism.

Methods: PC-9 cells and A549 cells, the lung adenocarcinoma cells with mutant and wide-type EGFR respectively, were treated with docetaxel/gefitinib alone or in different combination schedules. The EGFR and K-ras gene status was determined by qPCR-HRM technique. Cell proliferation was detected by MTT assay. The expression and phosphorylation of EGFR, ERK, Akt and IGF-1R were detected by western blot. Cell cycle distribution was observed by flow cytometry.

Results: Only sequential administration of docetaxel followed by gefitinib (D → G) induced significant synergistic effect in both cell lines (Combination Index<0.9). The reverse sequence (G → D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9

Conclusions: The cytotoxic drugs followed by EGFR-TKIs may be the optimal combination for antiproliferative effects in EGFR-mutant NSCLC cells, and the phosphorylation of EGFR and ERK might contribute to this effect.

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Related in: MedlinePlus

Effects of different exposure schedules of gefitinib and docetaxel on cell cycle distribution.The effects of different administration schedules of gefitinib and docetaxel on cell cycle distribution were detected by flow cytometry. (C) control group; (D) docetaxel alone; (G) gefitinib alone; (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. *P<0.05 compared with control group. n = 3.
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pone-0114074-g004: Effects of different exposure schedules of gefitinib and docetaxel on cell cycle distribution.The effects of different administration schedules of gefitinib and docetaxel on cell cycle distribution were detected by flow cytometry. (C) control group; (D) docetaxel alone; (G) gefitinib alone; (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. *P<0.05 compared with control group. n = 3.

Mentions: Figure 4 showed that for PC-9 cells, gefitinib alone induced significant G0/G1 phase arrest comparing to control group (86.94±2.33% vs. 57.32±3.79%, P<0.05); while docetaxel alone induced significant G2/M phase arrest (45.67±3.90% vs. 15.54±2.57%, P<0.05). D→G also significantly arrested the cell cycle in G2/M phase (56.31±1.86% vs. 15.54±2.57%, P<0.05). However, G→D showed merely a trend of increased G0/G1 phase (74.39±2.78% vs. 57.32±3.79%, P>0.05).


Sequence-dependent antiproliferative effects of gefitinib and docetaxel on non-small cell lung cancer (NSCLC) cells and the possible mechanism.

Chen B, Zheng J, Zeng Y, Li B, Xie B, Zheng J, Zhou J, Zhang W - PLoS ONE (2014)

Effects of different exposure schedules of gefitinib and docetaxel on cell cycle distribution.The effects of different administration schedules of gefitinib and docetaxel on cell cycle distribution were detected by flow cytometry. (C) control group; (D) docetaxel alone; (G) gefitinib alone; (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. *P<0.05 compared with control group. n = 3.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256223&req=5

pone-0114074-g004: Effects of different exposure schedules of gefitinib and docetaxel on cell cycle distribution.The effects of different administration schedules of gefitinib and docetaxel on cell cycle distribution were detected by flow cytometry. (C) control group; (D) docetaxel alone; (G) gefitinib alone; (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. *P<0.05 compared with control group. n = 3.
Mentions: Figure 4 showed that for PC-9 cells, gefitinib alone induced significant G0/G1 phase arrest comparing to control group (86.94±2.33% vs. 57.32±3.79%, P<0.05); while docetaxel alone induced significant G2/M phase arrest (45.67±3.90% vs. 15.54±2.57%, P<0.05). D→G also significantly arrested the cell cycle in G2/M phase (56.31±1.86% vs. 15.54±2.57%, P<0.05). However, G→D showed merely a trend of increased G0/G1 phase (74.39±2.78% vs. 57.32±3.79%, P>0.05).

Bottom Line: Only sequential administration of docetaxel followed by gefitinib (D → G) induced significant synergistic effect in both cell lines (Combination Index<0.9).The reverse sequence (G → D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9<CI<1.1)-synergistic effect in PC-9 cells and antagonistic-additive effect in A549 cells.The gefitinib-repressed phosphorylation of EGFR and ERK was reversed neither by concurrent nor by subsequent administration of docetaxel.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong, China.

ABSTRACT

Purpose: Recent clinical trials showed that the sequential combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and chemotherapy could prolong the PFS and/or OS of advanced non-small cell lung cancer (NSCLC) patients with EGFR mutation. The aim of present study was to assess the optimal combination sequence and to explore its possible mechanism.

Methods: PC-9 cells and A549 cells, the lung adenocarcinoma cells with mutant and wide-type EGFR respectively, were treated with docetaxel/gefitinib alone or in different combination schedules. The EGFR and K-ras gene status was determined by qPCR-HRM technique. Cell proliferation was detected by MTT assay. The expression and phosphorylation of EGFR, ERK, Akt and IGF-1R were detected by western blot. Cell cycle distribution was observed by flow cytometry.

Results: Only sequential administration of docetaxel followed by gefitinib (D → G) induced significant synergistic effect in both cell lines (Combination Index<0.9). The reverse sequence (G → D) resulted in an antagonistic interaction in both cell lines (CI>1.1), whereas the concurrent administration (D+G) showed additive (0.9

Conclusions: The cytotoxic drugs followed by EGFR-TKIs may be the optimal combination for antiproliferative effects in EGFR-mutant NSCLC cells, and the phosphorylation of EGFR and ERK might contribute to this effect.

Show MeSH
Related in: MedlinePlus