Methylated chrysin reduced cell proliferation, but antagonized cytotoxicity of other anticancer drugs in acute lymphoblastic leukemia.
The efficacy of 5,7-dimethoxyflavone (DMF), a methylated analog of chrysin, as a therapeutic agent to treat acute lymphoblastic leukemia (ALL) was investigated. Using a panel of ALL cell lines, the IC50 (half-maximal inhibitory concentration) of DMF varied between 2.8 and 7.0 μg/ml. DMF induced G0/G1 cell cycle arrest, concomitant with a decreased expression of phosphorylated retinoblastoma-associated protein 1. DMF increased the rate of apoptosis, although it was apparent only after a long period of exposure (96 h). The accumulation of oxidative stress was not involved in the growth-inhibitory effects of DMF. As DMF reduced the intracellular levels of glutathione, the combination effects of DMF with other anticancer drugs were evaluated using the improved Isobologram and the combination index method. In the simultaneous drug combination assay, DMF antagonized the cytotoxicity of 4-hydroperoxy-cyclophosphamide, cytarabine, vincristine, and L-asparaginase in all tested ALL cells. This study demonstrated that DMF, a methylated flavone, was an effective chemotherapy agent that could inhibit cell cycle arrest and induce apoptosis in ALL cell lines. However, combination therapy with DMF and other anticancer drugs is not recommended.
Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Japan. hgoto39@med.yokohama-cu.ac.jp
Hiroaki
H
Goto
Masakatsu
M
Yanagimachi
Shoko
S
Goto
Masanobu
M
Takeuchi
Hiromi
H
Kato
Tomoko
T
Yokosuka
Ryosuke
R
Kajiwara
Shumpei
S
Yokota
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001215:Asparaginase / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D003561:Cytarabine / Q000494:pharmacology; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D050687:E2F1 Transcription Factor / Q000187:drug effects*; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D014750:Vincristine / Q000494:pharmacology
D000970:Antineoplastic Agents; D050687:E2F1 Transcription Factor; D005419:Flavonoids; D003561:Cytarabine; C060298:5,7-dimethoxyflavone; D014750:Vincristine; D003520:Cyclophosphamide; D001215:Asparaginase; C011272:perfosfamide