Hodgkin disease-derived cell lines expressing ubiquitous mitochondrial creatine kinase show growth inhibition by cyclocreatine treatment independent of apoptosis

Ubiquitous mitochondrial creatine kinase (uMtCK), a key enzyme in energy me tabolism, was identified by differential display PCR to be specifically ove rexpressed in L1236, the first cell line of definite Hodgkin origin. RT-PCR confirmed overexpression of uMtCK in the L1236 cell line and the absence o f cytosolic B-CK, which is co-expressed with MtCK phys logically. Cyclocrea tine (cCr), whose phosphorylated form Is a very poor substrate for CK, inhi bited proliferation of the L1236 cell line nearly entirely. This inhibition by cCr was partially reversed by competition with creatine, which by itsel f had no effect on proliferation of the L1236 cell line. Although these res ults support a role of CK activity in the inhibitory action of cCr, it rema ins open whether the cCr effect is due to its inhibition of CK-linked energ y metabolism or if alternative mechanisms have to be considered. Because th e anti-proliferative effect of cCr was not due to induction of apoptosis, i n contrast to most other anticancer agents, treatment with the creatine ana logue cCr may represent an advantageous therapeutic approach for cells resi stant to programmed cell death. (C) 2001 Wiley-Liss, Inc.