title: Reversal effect of substituted 1,3-dimethyl-1H-quinoxalin-2-ones on multidrug resistance in adriamycin-resistant K562/A02 cells.
abstract: QA1 and QA3 are the derivatives of substituted 1,3-dimethyl-1H-quinoxalin-2-ones that may selectively antagonize P-glycoprotein (P-gp) in multidrug resistance (MDR) cancer cells. Herein, we examined the reversal effect of two compounds on MDR in adriamycin (Adr)-induced resistant K562/A02 cells. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide) assay showed that QA1 and QA3 weakly inhibited the growth of tumor cells. However, the compounds increased Adr-induced cytotoxicity toward K562/A02 cells. The IC(50) values of Adr toward K562/A02 were decreased in the presence of QA1 or QA3. The maximal reversal fold (RF) of QA1 and QA3 was reached 6.9 and 9.0, respectively. The action of QA1 and QA3 was also confirmed by the increase of intracellular Adr accumulation in K562/A02 cells. In mechanism study, the intracellular accumulation and efflux of Rh123 were measured using multilabel counter with excitation/emission wavelengths of 485/535nm. An increase of intracellular Rh123 and the decrease of efflux were observed in K562/A02 cells incubation with QA1 or QA3, indicating that the activity of P-gp was blocked. These results suggested that the derivatives of substituted 1,3-dimethyl-1H-quinoxalin-2-ones might reverse MDR in K562/A02 cells via inhibition activity of P-gp. QA1 and QA3 might be the candidate agents for reversing MDR of cancer.
authors.affiliation: Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, No 44 Wen Hua Xi Road, Jinan, Shandong 250012, China.
authors.forename: Li-rui
authors.initials: LR
authors.lastname: Sun
authors.forename: Xun
authors.initials: X
authors.lastname: Li
authors.forename: Yan-na
authors.initials: YN
authors.lastname: Cheng
authors.forename: Hong-yu
authors.initials: HY
authors.lastname: Yuan
authors.forename: Ming-hui
authors.initials: MH
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Stephen Geoffrey
authors.initials: SG
authors.lastname: Ward
authors.forename: Xian-jun
authors.initials: XJ
authors.lastname: Qu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005456:Fluorescent Dyes / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D011810:Quinoxalines / Q000737:chemistry / Q000494:pharmacology*; D020112:Rhodamine 123 / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D005456:Fluorescent Dyes; D011810:Quinoxalines; D020112:Rhodamine 123; D004317:Doxorubicin