Specific targeting of tumor cells by the creatine analog cyclocreatine
Creatine kinase (CK) an enzyme involved in cellular ATP homeostasis has been implicated in tumorigenesis. Cyclocreatine (CCr) a CK substrate analog was shown to be cytotoxic to a broad spectrum of solid tumors. We have measured and compared the CK activity and CCr sensitivity of 49 transformed and non-transformed cell lines. Among tumor cell lines, there was a strong correlation between the two (p = 0.0026, regression analysis); cell lines expressing high levels of CK (> 0.10 Units/mg protein) were generally sensitive to the drug and cell lines with low CK were resistant. Tumor cell lines highest CK and most sensitive to CCr were derived from prostate, small cell lung and neuronal tissue. The hematopoetic tumor lines tested were generally low in CK and all were resistant to CCr. Fourteen non-transformed cell lines were examined and all were resistant to the compound, including six with high levels of CK. Thus, CCr preferentially targeted tumor cells. Further, CCr inhibited tumor cell proliferation more efficiently than macromolecular synthesis indicating that, rather than exerting a general effect on energy metabolism, CCr may act on a specific pathway involved in controlling tumor cell proliferation.
Martin, KJ; Winslow, ER; O'Keefe, M; Khandekar, VS; Hamlin, A; Lillie, JW; Kaddurah-Daouk, R
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