Control of apoptosis in human multiple myeloma by insulin-like growth factor I (IGF-I).
Human multiple myeloma (MM) is characterized by the expansion of neoplastic plasmablasts/plasma cells with complex genetic aberrations and high dependence for survival and growth on cytokines produced in the bone marrow microenvironment. As tools in the study of MM about 80 authentic MM cell lines and a few relevant in vivo mouse models are available. The dependence on insulin-like growth factor receptor (IGF-IR) signaling in the development and maintenance of the malignant phenotype in a variety of cancers is a rationale for attempts to improve tumor treatment by selectively inhibiting the IGF-IR in malignant cells by neutralizing antibodies, dominant negative IGF-IR, and IGF-IR siRNA. Testing the hypothesis that abrogating IGF-IR-mediated signaling of survival should make MM cells more susceptible to apoptosis, our studies have so far provided proof-of-principle by the demonstration that inhibition of a signaling pathway stimulating survival renders cells susceptible to drug-induced apoptosis when the drug (dexamethasone) and inhibitor (rapamycin) converge on the same target, that is p70(S6K). The recent publication of the three-dimensional structure of the IGF-IR kinase domain has facilitated the development of IGF-IR inhibitors of the cyclolignan family, that is picropodophyllin, with capacity to distinguish also in vivo between the IGF-IR and the insulin receptor. Studies in vitro and in vivo with picropodophyllin show promising effects, that is apoptosis induction and growth arrest, and have made it possible to evaluate the biological and therapeutic effects of inhibition of the IGF-IR signaling in MM.
Jernberg-Wiklund
Helena
H
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
Nilsson
Kenneth
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008958:Models, Molecular; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C415032:picropodophyllin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D017526:Receptor, IGF Type 1; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D011034:Podophyllotoxin; D020123:Sirolimus