title: Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway.
abstract: Nuclear factor-E2-related factor 2 (Nrf2) is an important cytoprotective transcription factor which plays a key role in antioxidant and detoxification processes. Recent studies have reported that development of chemoresistance is associated with the constitutive activation of the Nrf2-mediated signaling pathway in many types of cancer cells. Here, we investigated whether Nrf2 was associated with drug resistant in doxorubicin resistant BEL-7402 (BEL-7402/ADM) cells, and if chrysin could reverse drug resistance in BEL-7402/ADM cells. We found that remarkable higher level of Nrf2 and its target proteins in BEL-7402/ADM cells compared to BEL-7402 cells. Similarly, intracellular Nrf2 protein level was significantly decreased and ADM resistance was partially reversed by Nrf2 siRNA in BEL-7402/ADM cells. chrysin is a potent Nrf2 inhibitor which sensitizes BEL-7402/ADM cells to ADM and increases intracellular concentration of ADM. Mechanistically, chrysin significantly reduced Nrf2 expression at both the mRNA and protein levels through down-regulating PI3K-Akt and ERK pathway. Consequently, expression of Nrf2-downstream genes HO-1, AKR1B10, and MRP5 were reduced and the Nrf2-dependent chemoresistance was suppressed. In conclusion, these results clearly indicate that activation of Nrf2 is associated with drug resistance in BEL-7402/ADM cells and chrysin may be an effective adjuvant sensitizer to reduce anticancer drug resistance by down-regulating Nrf2 signaling pathway.
authors.affiliation: Department of Pharmacy, The Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China; Department of Pharmacology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Ai-Mei
authors.initials: AM
authors.lastname: Gao
authors.forename: Zun-Ping
authors.initials: ZP
authors.lastname: Ke
authors.forename: Fang
authors.initials: F
authors.lastname: Shi
authors.forename: Guang-Chun
authors.initials: GC
authors.lastname: Sun
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
mesh_terms: D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D004317:Doxorubicin; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D051267:NF-E2-Related Factor 2; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C495635:NFE2L2 protein, human; C043561:chrysin
keywords: 4′-6′-diamidino-2-phenylindole; ADM; AKR1B10; ATF3; Aldo–keto reductase 1B10; Chemoresistance; Chrysin; DAPI; EGCG; ERα; FCM; HCC; HO-1; Hepatocellular carcinoma; Keap1; MAPKs; MRP5; Nrf2; PI3K; PPAR; RARα; SFERRβ; activating transcription factor 3; doxorubicin; epigallocatechin 3-gallate; estrogenreceptor α; flow cytometry; heme oxygenase-1; hepatocellular carcinoma; kelch-like ECH-associated protein 1; mitogen-activated protein kinases; multidrug resistance-associated protein 5; nuclear factor erythroid 2-related factor 2; peroxisome proliferator-activated receptor; phosphatidylinositol-3 kinase; qRT-PCR; real-time quantitative PCR; retinoic acid receptor α; short-form estrogen-related receptor β