title: Cyclic AMP induces apoptosis in multiple myeloma cells and inhibits tumor development in a mouse myeloma model.
abstract: 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.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. virginie.follin-arbelet@medisin.uio.no
authors.forename: Virginie
authors.initials: V
authors.lastname: Follin-Arbelet
authors.forename: Peter O
authors.initials: PO
authors.lastname: Hofgaard
authors.forename: Harald
authors.initials: H
authors.lastname: Hauglin
authors.forename: Soheil
authors.initials: S
authors.lastname: Naderi
authors.forename: Anders
authors.initials: A
authors.lastname: Sundan
authors.forename: Rune
authors.initials: R
authors.lastname: Blomhoff
authors.forename: Bjarne
authors.initials: B
authors.lastname: Bogen
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Blomhoff
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D013873:Thionucleotides; D005576:Colforsin; C015929:8-((4-chlorophenyl)thio)cyclic-3',5'-AMP; D000242:Cyclic AMP; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D053453:Caspase 9; D015232:Dinoprostone