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3',4',5',5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway.

Hou X, Bai X, Gou X, Zeng H, Xia C, Zhuang W, Chen X, Zhao Z, Huang M, Jin J - Mol. Cells (2015)

Bottom Line: In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3',4',5',5,7-Pentamethoxyflavone (PMF), a natural flavonoid extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA.Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA.Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.

ABSTRACT
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important redox-sensitive transcription factor that regulates the expression of several cytoprotective genes. More recently, genetic analyses of human tumors have indicated that Nrf2 may cause resistance to chemotherapy. In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3',4',5',5,7-Pentamethoxyflavone (PMF), a natural flavonoid extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA. Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA. Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.

No MeSH data available.


Related in: MedlinePlus

Nrf2 mediated defense was upregulated in A549/CDDP cells than in A549 cells. (A) The inhibitory effect of cisplatin on the viability of A549 and A549/CDDP cells. Cells were treated with series concentration of CDDP for 48 h and then viabilities were determined by SRB assay. (B–C) The expression of nuclear and total protein of Nrf2 and its target proteins GCLC, HO-1, NQO1 was assessed by western blot in A549 and A549/CDDP cells. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
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f2-molce-38-5-396: Nrf2 mediated defense was upregulated in A549/CDDP cells than in A549 cells. (A) The inhibitory effect of cisplatin on the viability of A549 and A549/CDDP cells. Cells were treated with series concentration of CDDP for 48 h and then viabilities were determined by SRB assay. (B–C) The expression of nuclear and total protein of Nrf2 and its target proteins GCLC, HO-1, NQO1 was assessed by western blot in A549 and A549/CDDP cells. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.

Mentions: To ensure the drug resistance phenotype of A549/CDDP cells, survival rates of cells exposed to CDDP were detected by SRB assay. Figure 2A showed that the IC50 of A549/CDDP cells (1136.3 μM) was significantly higher than that of A549 cells (317.9 μM, P < 0.05), which indicated that A549/CDDP cells were CDDP-resistance.


3',4',5',5,7-pentamethoxyflavone sensitizes Cisplatin-resistant A549 cells to Cisplatin by inhibition of Nrf2 pathway.

Hou X, Bai X, Gou X, Zeng H, Xia C, Zhuang W, Chen X, Zhao Z, Huang M, Jin J - Mol. Cells (2015)

Nrf2 mediated defense was upregulated in A549/CDDP cells than in A549 cells. (A) The inhibitory effect of cisplatin on the viability of A549 and A549/CDDP cells. Cells were treated with series concentration of CDDP for 48 h and then viabilities were determined by SRB assay. (B–C) The expression of nuclear and total protein of Nrf2 and its target proteins GCLC, HO-1, NQO1 was assessed by western blot in A549 and A549/CDDP cells. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4443280&req=5

f2-molce-38-5-396: Nrf2 mediated defense was upregulated in A549/CDDP cells than in A549 cells. (A) The inhibitory effect of cisplatin on the viability of A549 and A549/CDDP cells. Cells were treated with series concentration of CDDP for 48 h and then viabilities were determined by SRB assay. (B–C) The expression of nuclear and total protein of Nrf2 and its target proteins GCLC, HO-1, NQO1 was assessed by western blot in A549 and A549/CDDP cells. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
Mentions: To ensure the drug resistance phenotype of A549/CDDP cells, survival rates of cells exposed to CDDP were detected by SRB assay. Figure 2A showed that the IC50 of A549/CDDP cells (1136.3 μM) was significantly higher than that of A549 cells (317.9 μM, P < 0.05), which indicated that A549/CDDP cells were CDDP-resistance.

Bottom Line: In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3',4',5',5,7-Pentamethoxyflavone (PMF), a natural flavonoid extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA.Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA.Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: School of Pharmaceutical Science, Sun Yat-sen University, Guangzhou 510006, China.

ABSTRACT
Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important redox-sensitive transcription factor that regulates the expression of several cytoprotective genes. More recently, genetic analyses of human tumors have indicated that Nrf2 may cause resistance to chemotherapy. In this study, we found that the expression levels of Nrf2 and its target genes GCLC, HO-1, NQO1 were significantly higher in cisplatin-resistant A549 (A549/CDDP) cells than those in A549 cells, and this resistance was partially reversed by Nrf2 siRNA. 3',4',5',5,7-Pentamethoxyflavone (PMF), a natural flavonoid extracted from Rutaceae plants, sensitized A549/CDDP to CDDP and substantially induced apoptosis compared with that of CDDP alone treated group, and this reversal effect decreased when Nrf2 was downregulated by siRNA. Mechanistically, PMF reduced Nrf2 expression leading to a reduction of Nrf2 downstream genes, and in contrast, this effect was decreased by blocking Nrf2 with siRNA. Taken together, these results demonstrated that PMF could be used as an effective adjuvant sensitizer to increase the efficacy of chemotherapeutic drugs by downregulating Nrf2 signaling pathway.

No MeSH data available.


Related in: MedlinePlus