We have evaluated the efficacy of the multinuclear
platinum chemotherapeutics
BBR3464,
BBR3571, and
BBR3610 against
glioma cells in culture and animal models and investigated their mechanism of action at the cellular level. In a clonogenic assay,
BBR3610, the most potent compound, had an IC90 dose (achieving 90% colony formation inhibition) that was 250 times lower than that of
cisplatin for both LNZ308 and LN443
glioma cells. In subcutaneous xenografts of U87MG
glioma cells,
BBR3610 approximately doubled the time it took for a
tumor to reach a predetermined size and significantly extended survival when these cells were implanted intracranially. Analysis of apoptosis and cell cycle distribution showed that BBR compounds induced G2/M arrest in the absence of cell death, while
cisplatin predominantly induced apoptosis. Interestingly, the BBR compounds and
cisplatin both induced
extracellular signal-regulated kinase 1/2 phosphorylation, and inhibition of this pathway at the level of
MEK antagonized the induction of G2/M arrest or apoptosis, respectively. Analysis of Chk1 and Chk2 status did not show any differential effects of the drugs, and it is thus unlikely to underlie the difference in response. Similarly, the drugs did not differentially modulate
survivin levels, and knockdown of
survivin did not convert the response to
BBR3610 to apoptosis. Together, these findings support continued development of
BBR3610 for clinical use against
glioma and provide a framework for future investigation of mechanism of action.