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Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.

Serizawa M, Murakami H, Watanabe M, Takahashi T, Yamamoto N, Koh Y - Cancer Sci. (2014)

Bottom Line: Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation.Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays.Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

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Efatutazone attenuates enhanced cell motility and migration. (a) Cells were seeded and grown to 100% confluence, and then a wound was created by scraping the cells with a 200-μL pipette tip. The wounded cells were then incubated for 16 h in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. (b) Cells were seeded into transwell chambers and incubated in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The number of cells that migrated through the filter and attached to the bottom of the lower chamber was counted 48 h after seeding. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
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fig01: Efatutazone attenuates enhanced cell motility and migration. (a) Cells were seeded and grown to 100% confluence, and then a wound was created by scraping the cells with a 200-μL pipette tip. The wounded cells were then incubated for 16 h in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. (b) Cells were seeded into transwell chambers and incubated in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The number of cells that migrated through the filter and attached to the bottom of the lower chamber was counted 48 h after seeding. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.

Mentions: The EGFR-TKI-resistant cell lines, PC-9ER and PC-9ZD, were approximately 100-fold more resistant to erlotinib than PC-9 cells (Fig. S1). PC-9ER and PC-9ZD cells migrated faster to close a wound than the parental PC-9 cells (Fig. 1a), and this enhanced cell migration was also confirmed by a transwell assay (Fig. 1b). Erlotinib not only effectively abolished the motility of PC-9 cells but also attenuated the enhanced cell motility of PC-9ER cells (Fig. 1a,b). However, erlotinib could not suppress the enhanced cell motility of PC-9ZD cells harboring the T790M resistance mutation (Fig. 1a,b). These results suggest that continuous treatment with erlotinib may have a therapeutic effect by preventing metastasis even after EGFR-TKI failure, except in cases of resistance due to the T790M mutation. In contrast, efatutazone attenuated the motility of not only PC-9 and PC-9ER cells but also PC-9ZD cells in a dose-dependent manner (Fig. 1a and Fig. S2); this was also confirmed by the transwell assay (Fig. 1b). These results imply that efatutazone would be beneficial in preventing metastasis even after EGFR-TKI treatment failure, regardless of the resistance mechanism. Moreover, combined treatment with efatutazone and erlotinib showed a more potent inhibitory effect on the migration of PC-9ER cells than either treatment alone (Fig. 1b), indicating that this combination treatment may be effective for preventing metastasis in patients with EGFR-TKI-resistant NSCLC who do not harbor the EGFR T790M resistance mutation. Efatutazone had no significant antiproliferative effect on any of the tested cell lines (Fig. S1), indicating that cell motility and cell growth are driven by different mechanisms.


Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.

Serizawa M, Murakami H, Watanabe M, Takahashi T, Yamamoto N, Koh Y - Cancer Sci. (2014)

Efatutazone attenuates enhanced cell motility and migration. (a) Cells were seeded and grown to 100% confluence, and then a wound was created by scraping the cells with a 200-μL pipette tip. The wounded cells were then incubated for 16 h in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. (b) Cells were seeded into transwell chambers and incubated in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The number of cells that migrated through the filter and attached to the bottom of the lower chamber was counted 48 h after seeding. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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fig01: Efatutazone attenuates enhanced cell motility and migration. (a) Cells were seeded and grown to 100% confluence, and then a wound was created by scraping the cells with a 200-μL pipette tip. The wounded cells were then incubated for 16 h in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. (b) Cells were seeded into transwell chambers and incubated in 1% FBS medium with DMSO (0.1%; control), erlotinib (1 μmol/L), efatutazone (10 μmol/L), or a combination of erlotinib and efatutazone. The number of cells that migrated through the filter and attached to the bottom of the lower chamber was counted 48 h after seeding. *P < 0.05; **P < 0.01; ***P < 0.001 (Student's t-test). The error bars indicate the standard deviations of the mean.
Mentions: The EGFR-TKI-resistant cell lines, PC-9ER and PC-9ZD, were approximately 100-fold more resistant to erlotinib than PC-9 cells (Fig. S1). PC-9ER and PC-9ZD cells migrated faster to close a wound than the parental PC-9 cells (Fig. 1a), and this enhanced cell migration was also confirmed by a transwell assay (Fig. 1b). Erlotinib not only effectively abolished the motility of PC-9 cells but also attenuated the enhanced cell motility of PC-9ER cells (Fig. 1a,b). However, erlotinib could not suppress the enhanced cell motility of PC-9ZD cells harboring the T790M resistance mutation (Fig. 1a,b). These results suggest that continuous treatment with erlotinib may have a therapeutic effect by preventing metastasis even after EGFR-TKI failure, except in cases of resistance due to the T790M mutation. In contrast, efatutazone attenuated the motility of not only PC-9 and PC-9ER cells but also PC-9ZD cells in a dose-dependent manner (Fig. 1a and Fig. S2); this was also confirmed by the transwell assay (Fig. 1b). These results imply that efatutazone would be beneficial in preventing metastasis even after EGFR-TKI treatment failure, regardless of the resistance mechanism. Moreover, combined treatment with efatutazone and erlotinib showed a more potent inhibitory effect on the migration of PC-9ER cells than either treatment alone (Fig. 1b), indicating that this combination treatment may be effective for preventing metastasis in patients with EGFR-TKI-resistant NSCLC who do not harbor the EGFR T790M resistance mutation. Efatutazone had no significant antiproliferative effect on any of the tested cell lines (Fig. S1), indicating that cell motility and cell growth are driven by different mechanisms.

Bottom Line: Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation.Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays.Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone.

View Article: PubMed Central - PubMed

Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.

Show MeSH
Related in: MedlinePlus