Neplanocin A. A cyclopentenyl analog of adenosine with specificity for inhibiting RNA methylation.
The mechanism of action of the adenosine analog, neplanocin A (NPC), was investigated in human colon carcinoma cell line HT-29. Cell viability was reduced to 38 and 17% of control by 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. Cytocidal activity was not affected by inhibition of adenosine deaminase with 2'-deoxycoformycin. Concomitant with decreased cell viability was the reduced incorporation of [14C]dThd and [3H]Leu, and to a lesser extent [3H]Urd, into acid-precipitable material. Labeling of rRNA and tRNA during drug treatment for 24 h with [methyl-3H]Met and [14C]Urd revealed that NPC primarily inhibited RNA methylation, and to a lesser extent, RNA synthesis. RNase T2 digests of total RNA indicated that base and 2'-O-methylation were inhibited to approximately the same degree. Metabolites of NPC were measured by reverse-phase high-performance liquid chromatography and it was found that the major drug metabolite was the drug analog of S-adenosylmethionine with little formation of the respective, S-adenosylhomocysteine metabolite. NPC was utilized to a very small degree for RNA synthesis where only 2 and 30 pmol of NPC/A260 were incorporated into rRNA and tRNA after 24-h exposure to 10(-5) and 10(-4) M NPC, respectively. These results indicate that NPC is metabolized to a metabolite of S-adenosylmethionine which is a poor methyl donor for RNA methyltransferases, and that the accompanying decrease in RNA methylation and protein synthesis appears to be related to its cytocidal activity.
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000473:pathology; D004261:DNA Replication / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008745:Methylation; D015649:Pentostatin; D014176:Protein Biosynthesis / Q000187:drug effects; D012335:RNA, Ribosomal / Q000096:biosynthesis*; D012263:Ribonucleosides / Q000032:analysis; D014158:Transcription, Genetic / Q000187:drug effects
D058892:Adenosine Deaminase Inhibitors; D000903:Antibiotics, Antineoplastic; D012335:RNA, Ribosomal; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin; C031096:neplanocin A; D000241:Adenosine