Emerging evidence suggests the insulinlike 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 ␤-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 IntroductionThe insulin-like growth factor-1 receptor (IGF-1R) is strongly suggested to play key roles in malignant transformation and in promoting survival of tumor cells from cancers of, for example, breast, prostate, and colon. 1,2 Also in multiple myeloma (MM) cells the IGF-1R has been shown by us and others to stimulate growth and potently mediate survival. [3][4][5][6][7][8][9][10][11] Some characteristic features of the MM disease include growth of tumor cells almost exclusively restricted to the bone marrow, complex genetic aberrations, the presence at a high frequency of illegitimate translocations of a few identified partner genes (ie, 11q13 [cyclin D1], 6p21 [cyclin D3], 4p16 [FGFR3/MMSET],, and 20q11 [mafB]) to the immunoglobulin heavy chain locus, and the altered expression of c-Myc and Bcl-2 family genes. 12 So far, genetic alterations of the IGF-1R in malignant cells, including MM, have not been reported. 13 However, in the bone marrow environment, the IGF-1R in MM cells may become hyperactive as a result of autocrine and/or paracrine stimulation, making molecules of the IGF-1R signaling pathway equally important targets for intervention as mutated oncogenes. Supporting the notion of the hyperactivated IGF-1R in MM is the recent finding that IGF-1 serum level is a prognostic factor in MM. 14 The fact that IGF-1R signaling seems not to be an absolute requirement for maintenance of normal cell homeostasis 13 would encourage the development of IGF-1R inhibitors for clinical use in MM, as they may not be associated with the severe side effects of conventional cytotoxic drugs.On ligand interaction with the IGF-1R ␣-subunit, tyrosine residues in the intracellular, membrane-bound ␤-subunit become autophosphorylated. 15 This enables docking and phosphorylation of the insulin receptor substrate (IRS) and Shc, thereby activating 2 important pathways mediating proliferation and survival, that is...

IntroductionMultiple myeloma (MM) is an incurable tumor, in which the malignant B cells, although often initially sensitive to treatment, inevitably develop resistance to cytotoxic drugs. Glucocorticoids, such as dexamethasone, are known as highly effective drugs against MM 1 and are mostly used in combination with chemotherapeutic agents. 2 Emerging evidence shows the potency of insulinlike growth factor-I receptor (IGF-IR) in mediating survival of MM cells [3][4][5][6] as well as their resistance to cytotoxic treatment. 7,8 The ligands for the IGF-IR (mainly IGF-I and IGF-II) are, besides being present in plasma, abundant in the bone matrix and also produced by several cell types within the bone marrow, such as osteoblasts. 9 Thus, the selective homing of the MM cells within the bone marrow close to the bone tissue will provide the tumor cells with a milieu enriched with IGFs.The rational of mapping and targeting the IGF-IR signaling pathway for use in improved MM therapy rests on 2 fundamental observations. The first is the modest use of IGF-IR signaling in the proliferation of healthy cells in the adult individual. 10 The second is the previously successful strategy of targeting cellular survival circuits in terms of selective kinase inhibitors such as Although several signaling molecules, such as the mitogenactivated protein kinase (MAPK), are activated downstream of the phosphatidylinositol-3-kinase (PI3-K), the Akt pathway is of particular interest because of its role in inhibiting apoptosis and promoting cell proliferation. 12 One candidate target molecule for antitumor therapy is represented by the phosphoprotein mammalian target of rapamycin, mTOR (also known as FRAP , , or RAPT), in which the PI3-K/Akt pathway has been suggested to affect the mTOR phosphorylation state and catalytic activity. 13 Rapamycin binds to its cellular receptor, the immunophilin FK506 binding protein 12 (FKBP12), to form a complex that interacts with mTOR, thereby blocking its activity. 14 Mitogenactivated signaling through mTOR phosphorylates the serine/ threonine kinase p70S6K and the translational repressor eukaryotic initiation factor (eIF) 4E binding protein (4EBP1) also known as PHAS-I. 15 Activated p70S6K directly phosphorylates the 40S ribosomal protein S6, which correlates with enhanced translation of transcripts with 5Ј-terminal oligo-pyrimidine sequences that encode components of the translational machinery. 16 Multisite phosphorylation of 4EBP1 results in its dissociation from eIF4E, thereby allowing eIF4E to participate in assembly of a translational initiation complex leading to translational up-regulation of proteins required for cell cycle progression from G 1 to S phase. 17 Currently, rapamycin is in clinical use because of its effect on preventing allograft rejection without showing the severe side effects usually associated with traditional immunosuppressive therapy. 18,19 Rapamycin has also shown activity against a variety of 20 In the National Cancer Institute (NCI) cell line screening panel, T-cell leuk...

No abstract

Glioblastoma (GB) is the most common malignant brain tumor in adults. It has limited treatment opportunities and is almost exclusively fatal. Owing to the central role the insulin-like growth factor-1 receptor (IGF-1R) plays in malignant cells, it has been suggested as a target for anticancer therapy including GB. The cyclolignan picropodophyllin (PPP) inhibits IGF-1R without affecting the highly homologous insulin receptor. Here, we show that PPP inhibits growth of human GB cell lines along with reduced phosphorylation of IGF-1R and AKT. In vivo, PPP-treatment causes dramatic tumor regression not only in subcutaneous xenografts but also in intracerebral xenografts, indicating passage of PPP across the blood-brain barrier.