CELL-CYCLE STUDIES OF CYCLOCREATINE, A NEW ANTICANCER AGENT

Cyclocreatine (CCr), a substrate analogue of creatine kinase (CK), exh ibits antitumor activity in vitro and in vivo. To address its mechanis m of action, we have examined its effects on tumor cell proliferation, viability, and cell cycle progression. Complete inhibition of prolife ration of ME-180 cervical carcinoma cells was observed within 8 h of e xposure to CCr and was characterized by an inhibition of progression o ut of all phases of the cell cycle. This initial effect was partially reversible on drug removal. Increased cytotoxicity was observed after several days of drug exposure and was most specific to cells in S. Pre vious studies have shown that CCr supports ATP regeneration through th e CK system less efficiently than the natural substrate creatine and t hat CCr is active against tumor cell lines with elevated levels of CK. We propose here that the general inhibition of cell cycle progression reflects an effect of CCr on tumor cell energy availability through C K; and that impaired energy homeostasis for several days leads to tumo r cell death. Our results point out the unique nature of CCr as an ant icancer agent that inhibits progression out of all phases of the cell cycle.