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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

Docetaxel or gefitinib alone inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner.Cells were treated with gradient concentrations (10−4 M∼10−10 M) of gefitinib or docetaxel for 72 h. Cell proliferation was determined by MTT assay. (A) A549 cells; (B) PC-9 cells. *P<0.05 compared with control group. Bars: ± SD, n = 3.
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pone-0114074-g001: Docetaxel or gefitinib alone inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner.Cells were treated with gradient concentrations (10−4 M∼10−10 M) of gefitinib or docetaxel for 72 h. Cell proliferation was determined by MTT assay. (A) A549 cells; (B) PC-9 cells. *P<0.05 compared with control group. Bars: ± SD, n = 3.

Mentions: MTT assay showed that docetaxel (10−4 M∼10−10 M) or gefitinib (10−4 M∼10−8 M for A549 cells; 10−4 M∼10−10 M for PC-9 cells) alone significantly inhibited the proliferation of A549 and PC-9 cells in a dose-dependent manner (P<0.05). The IC50 of docetaxel and gefitinib were 2.05×10−7 mol/L and 1.22×10−5 mol/L respe ctively for A549 cells (Fig. 1A), and were 2.41×10−8 mol/L and 5.65×10−8 mol/L respectively for PC-9 cells (Fig. 1B). In particular, the inhibitory effect of gefitinib on PC-9 cells was almost 103-folds stronger than that on A549 cells (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)

Docetaxel or gefitinib alone inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner.Cells were treated with gradient concentrations (10−4 M∼10−10 M) of gefitinib or docetaxel for 72 h. Cell proliferation was determined by MTT assay. (A) A549 cells; (B) PC-9 cells. *P<0.05 compared with control group. Bars: ± SD, n = 3.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114074-g001: Docetaxel or gefitinib alone inhibited the proliferation of lung adenocarcinoma cells in a dose-dependent manner.Cells were treated with gradient concentrations (10−4 M∼10−10 M) of gefitinib or docetaxel for 72 h. Cell proliferation was determined by MTT assay. (A) A549 cells; (B) PC-9 cells. *P<0.05 compared with control group. Bars: ± SD, n = 3.
Mentions: MTT assay showed that docetaxel (10−4 M∼10−10 M) or gefitinib (10−4 M∼10−8 M for A549 cells; 10−4 M∼10−10 M for PC-9 cells) alone significantly inhibited the proliferation of A549 and PC-9 cells in a dose-dependent manner (P<0.05). The IC50 of docetaxel and gefitinib were 2.05×10−7 mol/L and 1.22×10−5 mol/L respe ctively for A549 cells (Fig. 1A), and were 2.41×10−8 mol/L and 5.65×10−8 mol/L respectively for PC-9 cells (Fig. 1B). In particular, the inhibitory effect of gefitinib on PC-9 cells was almost 103-folds stronger than that on A549 cells (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