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8-Cl-Adenosine Inhibits Proliferation and Causes Apoptosis in B-Lymphocytes via Protein Kinase A-Dependent and Independent Effects: Implications for Treatment of Carney Complex-Associated Tumors

Section on Endocrinology and Genetics (A.J.R.-W., H.-P.H., M.N., C.A.S.), Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, and Dermatology Branch (W.W.L.), National Cancer Institute, Bethesda, Maryland 20892; Department of Veterinary Medicine (I.B.), University of Maryland, College Park, Maryland 20742; and Department of Pediatrics (H.-P.H.), Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Address all correspondence and requests for reprints to: Audrey Robinson-White, Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 1-3330, 10 Center Drive, Bethesda, Maryland 20892. E-mail: robinsoa{at}mail.nih.gov.

Context: Carney complex, a multiple neoplasia syndrome, characterized primarily by spotty skin pigmentation and a variety of endocrine and other tumors, is caused by mutations in PRKAR1A, the gene that codes for the RI subunit of protein kinase A (PKA). PKA controls cell proliferation in many cell types. The cAMP analogue 8-Cl-adenosine (8-Cl-ADO) is thought to inhibit cancer cell proliferation.

Objective: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B-lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors.

Design: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and ³H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes.

Results: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and ³H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors.

Conclusions: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors.