title: Doxorubicin-induced cell death in highly invasive human gliomas.
abstract: Glioblastoma is the most invasive form of primary brain tumors, and is often refractory to chemotherapy. Herein, we provide evidence that two highly invasive human glioma cell lines U-87 MG and U-373 MG, entered apoptosis after 48 hours following 24 h growth arrest induced by Doxorubicin (10 micrograms/2 x 10(5) cells/ml). Apoptosis depended solely on the level of intracellular drug accumulation, and it was not related to a functional p53 tumor suppressor factor. The multidrug resistance gene 1 (mdr-1) encoded P-glycoprotein (P-gp) was weakly expressed in these cells upon exposure to Doxorubicin, and exerted no influence on the extent of cellular drug efflux. Drug efflux occurred only in U-373 MG glioma cells subsequent to physical damage of the membrane upon exposure to Doxorubicin. Pretreatment of tumor cells with 10 micrograms/ml Doxorubicin precluded tumor formation on the chorioallantoic membrane (CAM) of embryonated hen eggs. Single-dose application of 0.4 microgram Doxorubicin on CAM/U-87 MG and CAM/U-373 MG tumor transplants inhibited tumor invasion in CAM tissue by 40 to 50%. These data suggest that highly invasive glioblastomas can be driven to apoptosis following growth arrest induced by Doxorubicin, providing that intracellular drug accumulation suffices cytotoxic levels.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
authors.forename: A C
authors.initials: AC
authors.lastname: Stan
authors.forename: S
authors.initials: S
authors.lastname: Casares
authors.forename: D
authors.initials: D
authors.lastname: Radu
authors.forename: G F
authors.initials: GF
authors.lastname: Walter
authors.forename: T D
authors.initials: TD
authors.lastname: Brumeanu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000494:pharmacology*; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D009361:Neoplasm Invasiveness; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin