Cytotoxic and antimitotic effects of N-containing Monascus metabolites studied using immortalized human kidney epithelial cells.
Recently the first Monascus metabolites with a pyridine ring were detected, the monascopyridines A and B. They are formally dehydrogenated derivatives of the red rice pigments rubropunctamine and monascorubramine. Because of their structural similarity, the toxicological effects of these secondary metabolites were studied using immortalized human kidney epithelial cells. The cytotoxicity was determined with the following different endpoint detection methods: metabolic activity, trypan blue exclusion, and electronic cell counting. The compounds led to EC(50) values between 11 and 31 micromol/L but the pigments caused a stronger reduction of the cell viability. Also, the apoptotic potential was examined by measuring caspase 3 activity and detecting apoptotic bodies, but none of the tested compounds induced apoptosis. All four substances caused a rise of the mitotic index to about 9% (100 micromol/L monascopyridine A and B) and 20% (25 micromol/L rubropunctamine and monascorubramine). The significant decrease of the ratio of cells in the ana- and telophase to cells in the prometa- and metaphase proved a stop of the mitosis at the meta- to anaphase control point. The compounds caused mitotic arrest and the formation of structural damages like c-mitosis through interaction with the mitotic spindle. These effects point to an aneuploidy inducing potential, which is linked to cancer formation.
Knecht
Anja
A
Institut für Lebensmittelchemie, Westfälische Wilhelms-Universität Münster, Germany.
Humpf
Hans-Ulrich
HU
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D002461:Cell Line, Transformed; D002851:Chromatography, High Pressure Liquid; D004847:Epithelial Cells; D005285:Fermentation; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism / Q000633:toxicity; D007668:Kidney; D009682:Magnetic Resonance Spectroscopy; D008938:Mitosis / Q000187:drug effects*; D008940:Mitotic Index; D032741:Monascus / Q000378:metabolism*; D012275:Oryza / Q000382:microbiology; D012844:Sincalide / Q000032:analysis
D007546:Isoquinolines; C477735:monascopyridine A; C477736:monascopyridine B; C510963:rubropunctamine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D012844:Sincalide; D015107:4-Butyrolactone; C510964:monascorubramine