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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 proliferation.Cells were treated with three different sequences of gefitinib and docetaxel (D→G; G→D; D+G). The drug doses were combined using constant ratios of IC50 values (0.125, 0.25, 0.5, 1, 2 and 4 times of IC50). (A, B) The inhibition rate was determined by MTT assay. *P<0.05, D→G versus G→D; #P<0.05 D→G versus D+G. The D→G sequence produced the most potent inhibitory effect. (C, D) The combination index (CI) was calculated using CompuSyn software. Only the D→G sequence showed synergistic effect. (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. Bars: ± SD, n = 3.
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pone-0114074-g002: Effects of different exposure schedules of gefitinib and docetaxel on cell proliferation.Cells were treated with three different sequences of gefitinib and docetaxel (D→G; G→D; D+G). The drug doses were combined using constant ratios of IC50 values (0.125, 0.25, 0.5, 1, 2 and 4 times of IC50). (A, B) The inhibition rate was determined by MTT assay. *P<0.05, D→G versus G→D; #P<0.05 D→G versus D+G. The D→G sequence produced the most potent inhibitory effect. (C, D) The combination index (CI) was calculated using CompuSyn software. Only the D→G sequence showed synergistic effect. (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. Bars: ± SD, n = 3.

Mentions: We then evaluated the antiproliferative effects of different exposure schedules of gefitinib and docetaxel on both EGFR-TKI-resistant (A549) and EGFR-TKI-sensitive (PC-9) cell lines. As shown in figure 2, only sequential administration of docetaxel followed by gefitinib (D→G) induced a clear synergistic effect (CI<0.9) in both cell lines (inhibitory effects at IC50 were 60.00±4.90% for A549 and 62.15±3.84% for PC-9 cells). On the contrary, the G→D sequence resulted in an antagonistic interaction (CI>1.1) in both cell lines. Concurrent administration of docetaxel and gefitinib (D+G) showed antagonistic and additive (0.9<CI<1.1) effects in A549 cells as the drug concentration increased; whereas in PC-9 cells, D+G showed additive effects in low dose combination and synergistic effects in high dose combination.


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 proliferation.Cells were treated with three different sequences of gefitinib and docetaxel (D→G; G→D; D+G). The drug doses were combined using constant ratios of IC50 values (0.125, 0.25, 0.5, 1, 2 and 4 times of IC50). (A, B) The inhibition rate was determined by MTT assay. *P<0.05, D→G versus G→D; #P<0.05 D→G versus D+G. The D→G sequence produced the most potent inhibitory effect. (C, D) The combination index (CI) was calculated using CompuSyn software. Only the D→G sequence showed synergistic effect. (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. Bars: ± SD, n = 3.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0114074-g002: Effects of different exposure schedules of gefitinib and docetaxel on cell proliferation.Cells were treated with three different sequences of gefitinib and docetaxel (D→G; G→D; D+G). The drug doses were combined using constant ratios of IC50 values (0.125, 0.25, 0.5, 1, 2 and 4 times of IC50). (A, B) The inhibition rate was determined by MTT assay. *P<0.05, D→G versus G→D; #P<0.05 D→G versus D+G. The D→G sequence produced the most potent inhibitory effect. (C, D) The combination index (CI) was calculated using CompuSyn software. Only the D→G sequence showed synergistic effect. (D–G) docetaxel followed by gefitinib; (G–D) gefitinib followed by docetaxel; (D+G) docetaxel and gefitinib administered concurrently. Bars: ± SD, n = 3.
Mentions: We then evaluated the antiproliferative effects of different exposure schedules of gefitinib and docetaxel on both EGFR-TKI-resistant (A549) and EGFR-TKI-sensitive (PC-9) cell lines. As shown in figure 2, only sequential administration of docetaxel followed by gefitinib (D→G) induced a clear synergistic effect (CI<0.9) in both cell lines (inhibitory effects at IC50 were 60.00±4.90% for A549 and 62.15±3.84% for PC-9 cells). On the contrary, the G→D sequence resulted in an antagonistic interaction (CI>1.1) in both cell lines. Concurrent administration of docetaxel and gefitinib (D+G) showed antagonistic and additive (0.9<CI<1.1) effects in A549 cells as the drug concentration increased; whereas in PC-9 cells, D+G showed additive effects in low dose combination and synergistic effects in high dose combination.

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