Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Digitoxin decreases cell growth and may work as radiosensitizer in glioblastoma cell lines

ABL Marthinsen PhD 1, T Strickert MSc 1, KM Jensen MSc 1, J Haux MD 1,2

1 Dept Oncology, University Hospital of Trondheim,, 2 Institute of Cancer Research and Molecular Biology, Norwegian University of Science and Technology, Trondheim, Norway

AIM: Digitoxin is lipid soluble and can cross the blood-brain barrier and accumulate in brain tissue. If digitalis drugs have anticancer effects and also possibly work as radiosensitizers, such drugs could be proposed as cancer treatment. It is therefore interesting to study effects of digitoxin on cells from brain tumours. METHODS: Three different glioblastoma cell lines (U-373 MG, U-118 MG and U-87 MG) in exponential growth were exposed to digitoxin (in concentrations up to 100 ng/ml). Growth rates were determined by cell counting at different times after seeding, viability assessed with the MTT assay and proliferation examined by 3H thymidine incorporation. Flowcytometry analyses were used for obtaining DNA histograms. After three days of digitoxin exposure cell lines were irradiated (0 – 8 Gy) and radiosensitivity determined by a clonogenic assay. RESULTS: Digitoxin decreased viability, proliferation and plating efficiency of all three cell lines in a dose dependent manner, the U-373 MG line being most resistant. DNA histogram analysis revealed accumulation of the digitoxintreated cells in the G2M phase as well as increased DNA fragmentation. Morphological changes together with other results suggest cell death through apoptosis. The U-373 MG cell line was more radioresistant and had higher plating efficiency than the other two cell lines. Digitoxin increased the radio sensitivity of the cell lines in a dose dependent response, especially in the most radio resistant line U-373 MG. CONCLUSIONS: Digitoxin introduce growth repression and increase radio sensitivity to different extents in glioblastoma cell lines in vitro. The effects occur at concentrations achieved in brain tissue by therapeutic plasma concentrations of digitoxin. Digitoxin may be of benefit in the treatment of glioblastoma.

KEY WORDS: Digitoxin, glioblastoma, radiosensitizer.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on synergistic therapies.