title: Regulation of apoptosis by cyclic nucleotides in human erythroleukemia (HEL) cells and human myelogenous leukemia (K-562) cells.
abstract: The cyclic pyrimidine nucleotides cCMP and cUMP have been recently identified in numerous mammalian cell lines, in primary cells and in intact organs, but very little is still known about their biological function. A recent study of our group revealed that the membrane-permeable cCMP analog cCMP-acetoxymethylester (cCMP-AM) induces apoptosis in mouse lymphoma cells independent of protein kinase A via an intrinsic and mitochondria-dependent pathway. In our present study, we examined the effects of various cNMP-AMs in human tumor cell lines. In HEL cells, a human erythroleukemia cell line, cCMP-AM effectively reduced the number of viable cells, effectively induced apoptosis by altering the mitochondrial membrane potential and thereby caused changes in the cell cycle. cCMP itself was biologically inactive, indicating that membrane penetration is required to trigger intracellular effects. cCMP-AM did not induce apoptosis in K-562 cells, a human chronic myelogenous leukemia cell line, due to rapid export via multidrug resistance-associated proteins. The biological effects of cCMP-AM differed from those of other cNMP-AMs. In conclusion, cCMP effectively induces apoptosis in HEL cells, cCMP export prevents apoptosis of K-562 cells and cNMPs differentially regulate various aspects of apoptosis, cell growth and mitochondrial function. In a broader perspective, our data support the concept of distinct second messenger roles of cAMP, cGMP, cCMP and cUMP.
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: dittmar.fanni@mh-hannover.de.
authors.forename: Fanni
authors.initials: F
authors.lastname: Dittmar
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: wolter.sabine@mh-hannover.de.
authors.forename: Sabine
authors.initials: S
authors.lastname: Wolter
authors.affiliation: Institute of Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: seifert.roland@mh-hannover.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D007951:Leukemia, Myeloid / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D009712:Nucleotides, Cyclic
keywords: Apoptosis; Cyclic CMP; Mitochondrial membrane potential; Z-VAD-FMK (PubChem CID: 5497174); brefeldin A (PubChem CID: 5287620); cAMP (PubChem CID: 6076); cAMP-AM (PubChem CID: 71312192); cCMP (PubChem CID: 19236); cGMP (PubChem CID: 24316); cUMP (PubChem CID: 3081385); probenecid (PubChem CID: 4911)