8Cl-cAMP cytotoxicity in both steroid sensitive and insensitive multiple myeloma cell lines is mediated by 8Cl-adenosine.
We have examined the cytotoxic effects of cyclic adenosine-3', 5'-monophosphate (cAMP) derivatives on multiple myeloma cells lines and determined that the 8-Chloro substituted derivative (8Cl-cAMP) is one of the most potent. We report here that 8Cl-cAMP is cytotoxic to both steroid sensitive and insensitive myeloma cells with a half maximal concentration of approximately 3 micromol/L. 8Cl-cAMP toxicity in myeloma cells is dependent on phosphodiesterase activity in the serum of cell culture medium. A metabolite of 8Cl-cAMP, 8-Chloro-adenosine (8Cl-AD), kills myeloma cells as effectively as 8Cl-cAMP. Adenosine deaminase (ADA) converts 8Cl-AD into 8Cl-inosine and abrogates the cytotoxic effects of 8Cl-cAMP, 8Cl-AMP, and 8Cl-AD, as does 5-(p-Nitrobenzyl)-6-Thio-Inosine (NBTI), an inhibitor of nucleoside uptake. These data suggest that 8Cl-cAMP must be converted to 8Cl-AD and that 8Cl-AD is the compound that enters the cell. Contrary to glucocorticoid-mediated cell death in myeloma cells, the pathway of 8Cl-AD-mediated cell death appears to be independent of interleukin-6 (IL-6) actions. Although the exact mode of action for this agent is currently unknown, its ability to kill steroid sensitive and insensitive multiple myeloma cells in an IL-6 independent fashion may offer exciting new therapeutic options.
Lurie Comprehensive Cancer Center and Department of Medicine, Northwestern University, Chicago, IL, USA. r-halgren@nwu.edu
R G
RG
Halgren
A E
AE
Traynor
S
S
Pillay
J L
JL
Zell
K F
KF
Heller
N L
NL
Krett
S T
ST
Rosen
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000633:toxicity; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000378:metabolism; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport; D001711:Biotransformation; D002417:Cattle; D003470:Culture Media; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009101:Multiple Myeloma / Q000473:pathology*; D010727:Phosphoric Diester Hydrolases / Q000097:blood; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D003470:Culture Media; D015850:Interleukin-6; D011355:Prodrugs; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D013868:Thioinosine; C044258:8-chloro-cyclic adenosine monophosphate; D010727:Phosphoric Diester Hydrolases; D000243:Adenosine Deaminase; C001789:4-nitrobenzylthioinosine; C075440:8-chloroadenosine; D015056:1-Methyl-3-isobutylxanthine