Insulin-like growth factors and their receptor (IGF-1R) have been implicated in cancer pathophysiology. We demonstrate that IGF-1R is universally expressed in various hematologic (multiple myeloma, lymphoma, leukemia) and solid tumor (breast, prostate, lung, colon, thyroid, renal, adrenal cancer, retinoblastoma, and sarcoma) cells. Specific IGF-1R inhibition with neutralizing antibody, antagonistic peptide, or the selective kinase inhibitor NVP-ADW742 has in vitro activity against diverse tumor cell types (particularly multiple myeloma), even those resistant to conventional therapies, and triggers pleiotropic antiproliferative/proapoptotic molecular sequelae, delineated by global transcriptional and proteomic profiling. NVP-ADW742 monotherapy or its combination with cytotoxic chemotherapy had significant antitumor activity in an orthotopic xenograft MM model, providing in vivo proof of principle for therapeutic use of selective IGF-1R inhibitors in cancer.

Histone deacetylases (HDACs) affect cell growth at the transcriptional level by regulating the acetylation status of nucleosomal histones. HDAC inhibition induces differentiation and͞or apoptosis in transformed cells. We recently showed that HDAC inhibitors, such as suberoylanilide hydroxamic acid (SAHA), potently induce apoptosis of human multiple myeloma (MM) cells. In this study, we focused on MM as a model to study the transcriptional profile of HDAC inhibitor treatment on tumor cells and to address their pathophysiological implications with confirmatory mechanistic and functional assays. We found that MM cells are irreversibly committed to cell death within few hours of incubation with SAHA. The molecular profile of MM cells before their commitment to SAHA-induced cell death is hallmarked by a constellation of antiproliferative and͞or proapoptotic molecular events, including down-regulation of transcripts for members of the insulin-like growth factor (IGF)͞IGF-1 receptor (IGF-1R) and IL-6 receptor (IL-6R) signaling cascades, antiapoptotic molecules (e.g., caspase inhibitors), oncogenic kinases, DNA synthesis͞repair enzymes, and transcription factors (e.g., XBP-1, E2F-1) implicated in MM pathophysiology. Importantly, SAHA treatment suppresses the activity of the proteasome and expression of its subunits, and enhances MM cell sensitivity to proteasome inhibition by bortezomib (PS-341). SAHA also enhances the anti-MM activity of other proapoptotic agents, including dexamethasone, cytotoxic chemotherapy, and thalidomide analogs. These findings highlight the pleiotropic antitumor effects of HDAC inhibition, and provide the framework for future clinical applications of SAHA to improve patient outcome in MM.oligonucleotide microarrays ͉ cell signaling ͉ drug resistance H istone deacetylases (HDACs) and acetyltransferases (HATs) regulate gene expression by removal or addition, respectively, of acetyl groups to -amino groups in lysine residues of core nucleosomal histones. Increased histone acetylation attenuates their electrostatic interaction with the negatively charged DNA backbone, promotes unfolding of the histone-DNA complex, and modulates access of transcription factors to their sites of action and transcription of their target genes (1-6). Normal cell differentiation and function require coordinated gene transcription and appropriate balance of HAT and HDAC activities. Indeed, deletions or inactivating mutations of HATs have been implicated in development of human neoplasms (7-9), whereas inhibition of HDAC activity and increased transcriptionally active chromatin (2-4) promotes differentiation, growth arrest, and͞or apoptosis of tumor cells in vitro (10, 11) and in vivo (2, 11).Suberoylanilide hydroxamic acid (SAHA), the prototype of synthetic hydroxamic acid-based hybrid polar HDAC inhibitors, binds directly to the HDAC catalytic site, inhibits its enzymatic activity (1), and exerts antiproliferative and͞or proapoptotic effects restricted to transformed cells (7). It is orally bioavailable and had objectiv...