Cyclic adenosine-3',5'-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma

Multiple myeloma is a neoplastic proliferation of plasma cells. Glucocorticoids are among the most effective agents against multiple myeloma, acting through the glucocorticoid receptor to induce programmed cell death. However, some patients do not respond to glucocorticoids, and those that do respond eventually develop resistance to this therapy. Alternative strategies using drugs that mediate cytotoxicity through complementary pathways have theoretical appeal. Cyclic adenosine-3',5'-monophosphate (cAMP) derivatives are cytotoxic to a number of cell lines of lymphocytic origin. cAMP analogues activate protein kinase A, affecting cell growth and differentiation. The cascade of events initiated by cAMP derivatives and glucocorticoid, although distinct, may share some distal molecular targets. We have found that pharmacological concentrations of 8-chloro-cAMP, dibutyryl-cAMP, and 8-bromo-cAMP are cytotoxic to multiple myeloma cells, enhance glucocorticoid effects, and can kill glucocorticoid-resistant clones. cAMP analogues induce apoptosis as demonstrated by the fragmentation of myeloma DNA chromatin in a distinctive ladder pattern. In contrast to glucocorticoids, cAMP growth inhibition cannot be reversed by exogenous interleukin 6. cAMP derivatives have activity against multiple myeloma and are appropriate candidates for clinical trials.