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 metabolism, was identified by differential display PCR to be specifically overexpressed in L1236, the first cell line of definite Hodgkin origin. RT-PCR confirmed overexpression of uMtCK in the L1236 cell line and the absence of cytosolic B-CK, which is co-expressed with MtCK physiologically. Cyclocreatine (cCr), whose phosphorylated form is a very poor substrate for CK, inhibited proliferation of the L1236 cell line nearly entirely. This inhibition by cCr was partially reversed by competition with creatine, which by itself had no effect on proliferation of the L1236 cell line. Although these results support a role of CK activity in the inhibitory action of cCr, it remains open whether the cCr effect is due to its inhibition of CK-linked energy metabolism or if alternative mechanisms have to be considered. Because the anti-proliferative effect of cCr was not due to induction of apoptosis, in contrast to most other anticancer agents, treatment with the creatine analogue cCr may represent an advantageous therapeutic approach for cells resistant to programmed cell death.
Kornacker
M
M
Department of Medicine V, University of Heidelberg, Heidelberg, Germany. martin_kornacker@med.uni-heidelberg.de
Schlattner
U
U
Wallimann
T
T
Verneris
M R
MR
Negrin
R S
RS
Kornacker
B
B
Staratschek-Jox
A
A
Diehl
V
V
Wolf
J
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D016923:Cell Death; D002455:Cell Division; D003401:Creatine / Q000494:pharmacology; D003402:Creatine Kinase / Q000096:biosynthesis* / Q000378:metabolism; D003404:Creatinine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D008928:Mitochondria / Q000201:enzymology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D012333:RNA, Messenger; C012260:cyclocreatine; D003404:Creatinine; D003402:Creatine Kinase; D003401:Creatine