Microtubule stabilization and potentiation of taxol activity by the creatine analog cyclocreatine

Abstract

Creatine kinase (CK), a key enzyme of cellular energetics, has been implicated in tumorigenesis. Cyclocreatine (CCr), which forms a stable phosphagen with a reduced rate of ATP regeneration through CK, inhibits the growth of many solid tumors. We report that CCr induces the formation of unusually stable microtubules that resist depolymerization by nocodazole. By reducing ATP availability, CCr may modulate the activity of kinases that regulate microtubule dynamics. Further, combinations of CCr and taxol resulted in the synergistic killing of breast tumor cells indicating that CCr may be a useful addition to chemotherapy's that include taxanes.