title: Pankiller effect of prolonged exposure to menadione on glioma cells: potentiation by vitamin C.
abstract: Menadione (Vitamin K3) has anti-tumoral effects against a wide range of cancer cells. Its potential toxicity to normal cells and narrow therapeutic range limit its use as single agent but in combination with radiation or other anti-neoplastic agents can be of therapeutic use. In this paper, we first evaluated the early (within 3 h) effect of menadione on ongoing DNA replication. In normal rat cerebral cortex mini-units menadione showed an age dependent anti-proliferative effect. In tissue mini-units prepared from newborn rats, menadione inhibited ongoing DNA replication with an IC (50) of approximately 10 μM but 50 μM had no effect on mini-units from prepared adult rat tissue. The effect of short (72 h) and prolonged exposure (1-2 weeks) to menadione alone in the DBTRG.05MG human glioma cells line and in combination with vitamin C was studied. After short period of exposure data show that menadione alone or in combination with vitamin C provided similar concentration-response curves (and IC(50) values). Prolonged exposure to these drugs was evaluated by their ability to kill 100% of glioma cells and prevent regrowth when cells are re-incubated in drug-free media. In this long-term assay, menadione:vitamin C at a ratio 1:100 showed higher anti-proliferative activity when compared to each drug alone and allowed to reduce each drug concentration between 2.5 to 5-fold. Similar anti-proliferative effect was demonstrated in 8 patient derived glioblastoma cell cultures. Our data should be able to encourage further advanced studies on animal models to evaluate the potential use of this combination therapy for glioma treatment.
authors.affiliation: Department of Clinical Neuroscience R54, Karolinska Institute, Karolinska University Hospital, Sweden Hospital, 141 86, Huddinge, Stockholm, Sweden.
authors.forename: Marina F
authors.initials: MF
authors.lastname: Vita
authors.forename: Nivedita
authors.initials: N
authors.lastname: Nagachar
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramidis
authors.forename: Zahid M
authors.initials: ZM
authors.lastname: Delwar
authors.forename: Mabel H
authors.initials: MH
authors.lastname: Cruz
authors.forename: Åke
authors.initials: Å
authors.lastname: Siden
authors.forename: Kajsa M
authors.initials: KM
authors.lastname: Paulsson
authors.forename: Juan Sebastian
authors.initials: JS
authors.lastname: Yakisich
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D020128:Inhibitory Concentration 50; D051381:Rats; D013997:Time Factors; D024483:Vitamin K 3 / Q000008:administration & dosage / Q000494:pharmacology*; D014815:Vitamins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014815:Vitamins; D024483:Vitamin K 3; D001205:Ascorbic Acid