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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

PMF increased the sensitivity of A549/CDDP cells to CDDP by inhibition of Nrf2. (A–B) Effect of Nrf2 knockdown on the sensitivity to CDDP. Cells were treated with CDDP (10 – 400 μM) alone or combination with 50 μM PMF for 48 h. Cell viability was determined by SRB assay. (C–D) Effect of Nrf2 knockdown on the expression of Nrf2-mediated antioxidant genes. *P < 0.05, versus resistance. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
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f6-molce-38-5-396: PMF increased the sensitivity of A549/CDDP cells to CDDP by inhibition of Nrf2. (A–B) Effect of Nrf2 knockdown on the sensitivity to CDDP. Cells were treated with CDDP (10 – 400 μM) alone or combination with 50 μM PMF for 48 h. Cell viability was determined by SRB assay. (C–D) Effect of Nrf2 knockdown on the expression of Nrf2-mediated antioxidant genes. *P < 0.05, versus resistance. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.

Mentions: To confirm whether Nrf2 was involved in the chemoresistance of A549/CDDP cells, Nrf2 siRNA was transfected to knock down Nrf2 expression in A549/CDDP cells. The sensitivity of cells to CDDP was detected by SRB assay. Figure 6A showed that Nrf2 siRNA-transfected A549/CDDP cells were much more sensitive to CDDP than A549/CDDP cells.


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)

PMF increased the sensitivity of A549/CDDP cells to CDDP by inhibition of Nrf2. (A–B) Effect of Nrf2 knockdown on the sensitivity to CDDP. Cells were treated with CDDP (10 – 400 μM) alone or combination with 50 μM PMF for 48 h. Cell viability was determined by SRB assay. (C–D) Effect of Nrf2 knockdown on the expression of Nrf2-mediated antioxidant genes. *P < 0.05, versus resistance. 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

f6-molce-38-5-396: PMF increased the sensitivity of A549/CDDP cells to CDDP by inhibition of Nrf2. (A–B) Effect of Nrf2 knockdown on the sensitivity to CDDP. Cells were treated with CDDP (10 – 400 μM) alone or combination with 50 μM PMF for 48 h. Cell viability was determined by SRB assay. (C–D) Effect of Nrf2 knockdown on the expression of Nrf2-mediated antioxidant genes. *P < 0.05, versus resistance. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
Mentions: To confirm whether Nrf2 was involved in the chemoresistance of A549/CDDP cells, Nrf2 siRNA was transfected to knock down Nrf2 expression in A549/CDDP cells. The sensitivity of cells to CDDP was detected by SRB assay. Figure 6A showed that Nrf2 siRNA-transfected A549/CDDP cells were much more sensitive to CDDP than A549/CDDP cells.

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