Mechanism of the cytotoxicity of asterriquinone, a metabolite of Aspergillus terreus.
Asterriquinone (ARQ) is an antitumor metabolite of Aspergillus terreus IFO 6123. ARQ is a quinone compound and the mechanism of its antitumor action was compared with that of its analog ARQDMe which was dimethylated at the dihydroxy benzoquinone moiety, and adriamycin (ADR). The cytotoxicity of ARQ against P388 cells was less than that of ADR, and ARQDMe showed hardly any cytotoxicity. ARQ and ADR formed DNA-interstrand cross links (ISC) in P388 cells in a concentration while the ISC index by ARQDMe was very low even at 10 microM. P388 cells treated with ARQ and ADR for 18 hours showed, dose-dependently, nucleosomal ladder formation as well as the appearance of degraded DNA. Difference between the action of ARQ and ADR were observed by flow cytometric cell cycle analysis. ARQ caused the cells to accumulate at the G1 phase of the cell cycle, while use of ADR led to arrest in the G2/M phase. ARQDMe never caused apoptotic changes or cell cycle alterations. These results indicate that ARQ intercalates in the genomic DNA, causes G1 arrest, and leads to apoptotic cell death, this suggests that the dihydroxybenzoquinone moiety of the compound is essential to elicit these actions.
Kaji
A
A
Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
Saito
R
R
Nomura
M
M
Miyamoto
K
K
Kiriyama
N
N
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D001230:Aspergillus / Q000737:chemistry; D002453:Cell Cycle / Q000187:drug effects; D003432:Cross-Linking Reagents; D003603:Cytotoxins / Q000633:toxicity*; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000032:analysis; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D003432:Cross-Linking Reagents; D003603:Cytotoxins; D004273:DNA, Neoplasm; D007211:Indoles; C035746:asterriquinone