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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 inhibited Nrf2 signalling pathway. (A) HEK 293T cells were transfected with PGL3-ARE and pRL-TK plasmids., Twenty four hours after the transfection, the cells were treated with PMF (10, 25 and 50 μM) or tBHQ (10 μM) for 24 h. (B–D) A549/CDDP cells were treated with PMF (0–50 μM) for 24 hours. After treatment, nuclear fractions and total proteins were analyzed by western blot assay. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
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f4-molce-38-5-396: PMF inhibited Nrf2 signalling pathway. (A) HEK 293T cells were transfected with PGL3-ARE and pRL-TK plasmids., Twenty four hours after the transfection, the cells were treated with PMF (10, 25 and 50 μM) or tBHQ (10 μM) for 24 h. (B–D) A549/CDDP cells were treated with PMF (0–50 μM) for 24 hours. After treatment, nuclear fractions and total proteins were analyzed by western blot assay. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.

Mentions: To investigate whether the expression of Nrf2 and its target genes was regulated by PMF, A549/CDDP cells were incubated with PMF (10, 25 and 50 μM) for 24 h. Western blot analysis revealed that PMF treatment reduced the protein levels of Nrf2 and its downstream target genes, including HO-1, NQO1 and GCLC in a dose-dependent manner(Figs. 4B–4C).


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 inhibited Nrf2 signalling pathway. (A) HEK 293T cells were transfected with PGL3-ARE and pRL-TK plasmids., Twenty four hours after the transfection, the cells were treated with PMF (10, 25 and 50 μM) or tBHQ (10 μM) for 24 h. (B–D) A549/CDDP cells were treated with PMF (0–50 μM) for 24 hours. After treatment, nuclear fractions and total proteins were analyzed by western blot assay. 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

f4-molce-38-5-396: PMF inhibited Nrf2 signalling pathway. (A) HEK 293T cells were transfected with PGL3-ARE and pRL-TK plasmids., Twenty four hours after the transfection, the cells were treated with PMF (10, 25 and 50 μM) or tBHQ (10 μM) for 24 h. (B–D) A549/CDDP cells were treated with PMF (0–50 μM) for 24 hours. After treatment, nuclear fractions and total proteins were analyzed by western blot assay. Data are presented as means ± SD of three independent experiments and significant differences are indicated as *P < 0.05.
Mentions: To investigate whether the expression of Nrf2 and its target genes was regulated by PMF, A549/CDDP cells were incubated with PMF (10, 25 and 50 μM) for 24 h. Western blot analysis revealed that PMF treatment reduced the protein levels of Nrf2 and its downstream target genes, including HO-1, NQO1 and GCLC in a dose-dependent manner(Figs. 4B–4C).

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