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Background  Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. We have elucidated the potential for manipulating the cAMP signaling pathway as a target for inhibiting the growth of multiple myeloma cells.    Methods  As a model system, we primarily used the murine multiple myeloma cell line MOPC315 which can be grown both  in vivo  and  in vitro . Human multiple myeloma cell lines U266, INA-6 and the B-cell precursor acute lymphoblastic leukemia cell line Reh were used only for  in vitro  studies. Cell death was assessed by flow cytometry and western blot analysis after treatment with cAMP elevating agents (forskolin, prostaglandin E2 and rolipram) and cAMP analogs. We followed tumor growth  in vivo  after forskolin treatment by imaging DsRed-labelled MOPC315 cells transplanted subcutaneously in BALB/c nude mice.    Results  In contrast to the effect on Reh cells, 50 μM forskolin more than tripled the death of MOPC315 cells after 24 h  in vitro . Forskolin induced cell death to a similar extent in the human myeloma cell lines U266 and INA-6. cAMP-mediated cell death had all the typical hallmarks of apoptosis, including changes in the mitochondrial membrane potential and cleavage of caspase 3, caspase 9 and PARP. Forskolin also inhibited the growth of multiple myeloma cells in a mouse model  in vivo .    Conclusions  Elevation of intracellular levels of cAMP kills multiple myeloma cells  in vitro  and inhibits development of multiple myeloma  in vivo . This strongly suggests that compounds activating the cAMP signaling pathway may be useful in the field of multiple myeloma.

Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model