Abstract
BackgroundMultiple 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.MethodsAs 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.ResultsIn 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.ConclusionsElevation 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.
Highlights
Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically
The main targets of Cyclic adenosine monophosphate (cAMP) are protein kinase A (PKA) [4], cAMP-gated ion channels [5] and exchange proteins directly activated by cAMP (EPAC) [6]. cAMP affects numerous cellular processes, such as cell differentiation, cell cycle progression and apoptosis, both in a PKA-dependent and PKA-independent manner [7,8,9]
We have explored the role of cAMP in multiple myeloma by primarily using the multiple myeloma cell line MOPC315
Summary
Multiple myeloma is an incurable disease requiring the development of effective therapies which can be used clinically. Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of plasma cells in the bone marrow, osteolytic bone lesions, and immunodeficiency [1]. It accounts for ~10% of hematological malignancies [2] with a median survival of 4 years [3]. Cyclic adenosine monophosphate (cAMP) is an intracellular messenger formed in response to diverse extracellular stimuli including hormones or neurotransmitters. It is generated from ATP by adenylyl cyclases, and is degraded by phosphodiesterases (PDE) into adenosine-5’-monophosphate. There is a growing interest in manipulating the cAMP signaling pathway as a strategy for the treatment of cancer, and in particular a renewed interest for the potential of combining PDE inhibitors and glucocorticoids for treatment of hematological malignancies [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
