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.

Keyword

Apoptosis/*drug effects

CDC2 Protein Kinase/metabolism

Cell Division/*drug effects

Cell Proliferation/drug effects

Enzyme Activation

G2 Phase/*drug effects

Humans

Insulin/pharmacology

Insulin-Like Growth Factor I/pharmacology

Interleukin-6/pharmacology

Microtubule-Associated Proteins/metabolism

Mitogen-Activated Protein Kinase 1/antagonists & inhibitors/metabolism

Multiple Myeloma/blood supply/*drug therapy/metabolism

Neoplasm Proteins/metabolism

Phosphorylation

Podophyllotoxin/*analogs & derivatives/pharmacology

Proto-Oncogene Proteins c-bcl-2/metabolism

Receptor; IGF Type 1/*antagonists & inhibitors/metabolism

Receptor; Insulin/antagonists & inhibitors/metabolism

Research Support; Non-U.S. Gov't

Tumor Cells; Cultured

Publication and Content Type

ref (subject category)

art (subject category)