IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells.
Emerging evidence suggests the insulin-like growth factor-1 receptor (IGF-1R) to be an important mediator of tumor-cell survival and resistance to cytotoxic therapy in multiple myeloma (MM). Recently, members of the cyclolignan family have been shown to selectively inhibit the receptor tyrosine kinase (RTK) activity of the IGF-1R beta-chain. The effects of the cyclolignan picropodophyllin (PPP) were studied in vitro using a panel of 13 MM cell lines and freshly purified tumor cells from 10 patients with MM. PPP clearly inhibited growth in all MM cell lines and primary MM samples cultured in the presence or absence of bone marrow stromal cells. PPP induced a profound accumulation of cells in the G(2)/M-phase and an increased apoptosis. Importantly, IGF-1, IGF-2, insulin, or IL-6 did not reduce the inhibitory effects of PPP. As demonstrated by in vitro kinase assays, PPP down-regulated the IGF-1 RTK activity without inhibiting the insulin RTK activity. This conferred decreased phosphorylation of Erk1/2 and reduced cyclin dependent kinase (CDK1) activity. In addition, the expression of mcl-1 and survivin was reduced. Taken together, we suggest that interfering with the IGF-1 RTK by using the cyclolignan PPP offers a novel and selective therapeutic strategy for MM.
Strömberg
Thomas
T
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Ekman
Simon
S
Girnita
Leonard
L
Dimberg
Lina Y
LY
Larsson
Olle
O
Axelson
Magnus
M
Lennartsson
Johan
J
Hellman
Ulf
U
Carlson
Kristina
K
Osterborg
Anders
A
Vanderkerken
Karin
K
Nilsson
Kenneth
K
Jernberg-Wiklund
Helena
H
D017209:Apoptosis / Q000187:drug effects*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009101:Multiple Myeloma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077022:Survivin; D014407:Tumor Cells, Cultured
C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D007328:Insulin; D015850:Interleukin-6; D008869:Microtubule-Associated Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D000077022:Survivin; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; D016203:CDC2 Protein Kinase; D019950:Mitogen-Activated Protein Kinase 1; D011034:Podophyllotoxin