TY - JOUR
T1 - RNA-directed agent, cordycepin, induces cell death in multiple myeloma cells
AU - Chen, Lisa S.
AU - Stellrecht, Christine M.
AU - Gandhi, Varsha
PY - 2008/3
Y1 - 2008/3
N2 - 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.
AB - 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.
KW - Cordycepin
KW - Met
KW - Multiple myeloma
KW - Polyadenylation
KW - RNA
UR - http://www.scopus.com/inward/record.url?scp=39749115845&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39749115845&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2007.06955.x
DO - 10.1111/j.1365-2141.2007.06955.x
M3 - Article
C2 - 18205859
AN - SCOPUS:39749115845
SN - 0007-1048
VL - 140
SP - 682
EP - 391
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 6
ER -