RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells.
Multiple myeloma (MM) is an incurable plasma cell malignancy that is slow-growing, and thus traditional DNA-replication directed chemotherapeutics are ineffective. We hypothesized that those agents that target RNA-directed processes would be successful in MM. To test this postulate, cordycepin, a polyadenylation inhibitor was used as a proof-of-principle towards MM cell lines. Cordycepin accumulated in MM.1S cells as its triphosphate metabolite, 3'dATP and subsequently inhibits RNA synthesis and cell growth. Cell death was via apoptosis induction and over 50% of treated cells were annexin-V positive after 48 h. As a consequence of RNA synthesis inhibition, we hypothesized that specific genes with short half-lives may be downregulated, leading to a reduction in protein. Indeed, a reduction in the transcript levels for MET, a survival gene for MM, was detected as early as 4 h and transcripts were reduced to c. 10% of control after 48 h. Interestingly, no significant change in protein levels was observed for Bcl-2, XIAP, Mcl-1 or survivin. Stabilization of p53 was not observed, and caspases-8, -9 and -3 showed activation following cordycepin treatment but were not required for cell death. Our results suggest that RNA-directed agents may be a new group of agents for the treatment of MM.
Chen
Lisa S
LS
Department of Experimental Therapeutics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Stellrecht
Christine M
CM
Gandhi
Varsha
V
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003838:Deoxyadenine Nucleotides / Q000493:pharmacokinetics; D003839:Deoxyadenosines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D017978:Receptors, Growth Factor / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003838:Deoxyadenine Nucleotides; D003839:Deoxyadenosines; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D017978:Receptors, Growth Factor; C011746:3'-deoxyadenosine 5'-triphosphate; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases; C058120:cordycepin