Doxorubicin-induced cell death in highly invasive human gliomas

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.