Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.