Potentiation of bleomycin in Jurkat cells by fungal pycnidione.
Most cancer cells have mutations in genes at the G1 checkpoint and repair DNA only in the G2 phase; therefore, the G2 checkpoint is a potential target to develop novel therapy. In the course of screening, a known compound, pycnidione, was isolated from the fungal culture broth of Gloeotinia sp. FKI-3416. Pycnidione irreversibly abrogated bleomycin-induced G2 arrest in Jurkat cells and synergically potentiated the cytotoxicity of bleomycin. To elucidate the mechanism of action, the effect of pycnidione on the signal transduction of the G2 checkpoint was analyzed, showing that the increased phospho-cyclin dependent kinase-1 (CDK1) level caused by bleomycin was abrogated in the presence of pycnidione, indicating that cells did not arrest at the G2 phase. Moreover, under these conditions, Chk1 and Chk2 levels were markedly down-regulated. Thus, we concluded that pycnidione abrogated bleomycin-induced G2 arrest by decreasing Chk1 and Chk2.
Graduate School of Pharmaceutical Sciences, Kitasato University, 5–9–1 Shirokane, Minato-ku, Tokyo 108–8641, Japan.
Mayumi
M
Kaneko
Daisuke
D
Matsuda
Masaki
M
Ohtawa
Takashi
T
Fukuda
Tohru
T
Nagamitsu
Takao
T
Yamori
Hiroshi
H
Tomoda
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001203:Ascomycota / Q000737:chemistry*; D001688:Biological Products / Q000494:pharmacology* / Q000627:therapeutic use; D001761:Bleomycin / Q000494:pharmacology* / Q000627:therapeutic use; D016203:CDC2 Protein Kinase / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2; D015536:Down-Regulation; D004357:Drug Synergism; D016195:G2 Phase / Q000187:drug effects*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014334:Tropolone / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001688:Biological Products; D006576:Heterocyclic Compounds, 4 or More Rings; C572726:pycnidione; D001761:Bleomycin; D014334:Tropolone; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase