Inhibition of the self-renewal capacity of blast progenitors from acute myeloblastic leukemia patients by site-selective 8-chloroadenosine 3',5'-cyclic monophosphate.
The physiologic balance between the two regulatory subunit isoforms, RI and RII, of cAMP-dependent protein kinase is disrupted in cancer cells; growth arrest and differentiation of malignant cells can be achieved when the normal ratio of these intracellular signal transducers of cAMP is restored by the use of site-selective cAMP analogs. In this study we evaluated the effects of the site-selective cAMP analog 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP) on clonogenic growth of blast progenitors from 15 patients with acute myeloblastic leukemia and 3 patients affected by advanced myelodysplastic syndrome. Leukemic blast progenitors undergo terminal divisions, giving rise to colonies in methylcellulose. The self-renewal capacity of blast progenitors is conversely reflected in a secondary methylcellulose assay after exponential growth of clonogenic cells in suspension cultures. In all the samples tested, 8-Cl-cAMP, at micromolar concentrations (0.1-50 microM), suppressed in a dose-dependent manner both primary colony formation in methylcellulose and the recovery of clonogenic cells from suspension culture. Strikingly, in the samples from the entire group of patients, 8-Cl-cAMP was more effective in inhibiting the self-renewing clonogenic cells than the terminally dividing blast cells (P = 0.005). In addition, in four out of six cases studied, 8-Cl-cAMP was able to induce a morphologic and/or immunophenotypic maturation of leukemic blasts. An evident reduction of RI levels in fresh leukemic cells after exposure to 8-Cl-cAMP was also detected. Our results showing that 8-Cl-cAMP is a powerful inhibitor of clonogenic growth of leukemic blast progenitors by primarily suppressing their self-renewal capacity indicate that this site-selective cAMP analog represents a promising biological agent for acute myeloblastic leukemia therapy in humans.
Pinto
A
A
Leukemia Unit, Istituti Nazionali di Ricerca e Cura a Carattere Scientifico, Aviano, Italy.
Aldinucci
D
D
Gattei
V
V
Zagonel
V
V
Tortora
G
G
Budillon
A
A
Cho-Chung
Y S
YS
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000345:Affinity Labels / Q000378:metabolism; D000954:Antigens, Surface / Q000032:analysis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001386:Azides / Q000378:metabolism; D001752:Blast Crisis / Q000378:metabolism / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects*; D046508:Culture Techniques / Q000379:methods; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D011953:Receptors, Cyclic AMP / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000345:Affinity Labels; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D001386:Azides; D011953:Receptors, Cyclic AMP; D015124:8-Bromo Cyclic Adenosine Monophosphate; C017042:8-azidoadenosine-3',5'-monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D000242:Cyclic AMP