title: The natural compound forskolin synergizes with dexamethasone to induce cell death in myeloma cells via BIM.
abstract: We have previously demonstrated that activation of the cyclic adenosine monophosphate (cAMP) pathway kills multiple myeloma (MM) cells both in vitro and in vivo. In the present study we have investigated the potential of enhancing the killing of MM cell lines and primary MM cells by combining the cAMP-elevating compound forskolin with the commonly used MM therapeutic drugs melphalan, cyclophosphamide, doxorubicin, bortezomib and dexamethasone. We observed that forskolin potentiated the killing induced by all the tested agents as compared to treatment with the single agents alone. In particular, forskolin had a synergistic effect on the dexamethasone-responsive cell lines H929 and OM-2. By knocking down the proapoptotic BCL-2 family member BIM, we proved this protein to be involved in the synergistic induction of apoptosis by dexamethasone and forskolin. The ability of forskolin to maintain the killing of MM cells even at lower concentrations of the conventional agents suggests that forskolin may be used to diminish treatment-associated side effects. Our findings support a potential role of forskolin in combination with current conventional agents in the treatment of MM.
authors: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, PO Box 1112-Blindern, N-0317 Oslo, Norway.
authors: Virginie
authors: V
authors: Follin-Arbelet
authors: KG Jebsen Center for Myeloma Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
authors: Kristine
authors: K
authors: Misund
authors: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, PO Box 1112-Blindern, N-0317 Oslo, Norway.
authors: Elin Hallan
authors: EH
authors: Naderi
authors: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, PO Box 1112-Blindern, N-0317 Oslo, Norway.
authors: Hege
authors: H
authors: Ugland
authors: KG Jebsen Center for Myeloma Research and Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway.
authors: Anders
authors: A
authors: Sundan
authors: Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, PO Box 1112-Blindern, N-0317 Oslo, Norway.
authors: Heidi Kiil
authors: HK
authors: Blomhoff
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D005576:Colforsin / Q000008:administration & dosage*; D003907:Dexamethasone / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D005576:Colforsin; D003907:Dexamethasone