Abstract:
:Multiple myeloma cells secrete more disulfide bond-rich proteins than any other mammalian cell. Thus, inhibition of protein disulfide isomerases (PDI) required for protein folding in the endoplasmic reticulum (ER) should increase ER stress beyond repair in this incurable cancer. Here, we report the mechanistically unbiased discovery of a novel PDI-inhibiting compound with antimyeloma activity. We screened a 30,355 small-molecule library using a multilayered multiple myeloma cell-based cytotoxicity assay that modeled disease niche, normal liver, kidney, and bone marrow. CCF642, a bone marrow-sparing compound, exhibited a submicromolar IC50 in 10 of 10 multiple myeloma cell lines. An active biotinylated analog of CCF642 defined binding to the PDI isoenzymes A1, A3, and A4 in MM cells. In vitro, CCF642 inhibited PDI reductase activity about 100-fold more potently than the structurally distinct established inhibitors PACMA 31 and LOC14. Computational modeling suggested a novel covalent binding mode in active-site CGHCK motifs. Remarkably, without any further chemistry optimization, CCF642 displayed potent efficacy in an aggressive syngeneic mouse model of multiple myeloma and prolonged the lifespan of C57BL/KaLwRij mice engrafted with 5TGM1-luc myeloma, an effect comparable to the first-line multiple myeloma therapeutic bortezomib. Consistent with PDI inhibition, CCF642 caused acute ER stress in multiple myeloma cells accompanied by apoptosis-inducing calcium release. Overall, our results provide an illustration of the utility of simple in vivo simulations as part of a drug discovery effort, along with a sound preclinical rationale to develop a new small-molecule therapeutic to treat multiple myeloma. Cancer Res; 76(11); 3340-50. ©2016 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Vatolin S,Phillips JG,Jha BK,Govindgari S,Hu J,Grabowski D,Parker Y,Lindner DJ,Zhong F,Distelhorst CW,Smith MR,Cotta C,Xu Y,Chilakala S,Kuang RR,Tall S,Reu FJdoi
10.1158/0008-5472.CAN-15-3099subject
Has Abstractpub_date
2016-06-01 00:00:00pages
3340-50issue
11eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-15-3099journal_volume
76pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract::We used comparative genomic hybridization to study malignant fibrous histiocytomas (MFHs) from 19 patients to detect changes in the copy number of DNA sequences, along entire chromosomes. Together with losses and gains in various chromosomal regions, distinct high-level amplifications were found at six loci (4q12-21, ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1999-02-01 00:00:00
abstract::It has been shown in previous studies that a variety of estrogen receptor (ER) beta mRNA transcripts are expressed in human breast cancer cell lines and tumors. To complement the RNA expression studies, we have developed ER-beta-specific antibodies to characterize ER-beta protein expression in breast cancer cell lines...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1999-11-01 00:00:00
abstract::Isozymes of carbamyl phosphate synthetase (CPS), CPS I, a mitochondrial enzyme found exclusively in liver and involved in urea synthesis, and of CPS II, a soluble cytoplasmic enzyme widely distributed in animal tissues, were assayed in rat liver and in a series of rat liver neoplasms ranging widely in growth rate and ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1975-01-01 00:00:00
abstract::2'-Deoxycoformycin (2'-dCF), a tight-binding inhibitor of adenosine deaminase, was administered to 26 pediatric patients with acute lymphoblastic leukemia in a Phase I study. Doses ranged from 0.25 to 1.0 mg/kg given i.v. for 3 consecutive days. Common toxicity included nausea, vomiting, diarrhea, hepatocellular enzym...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1981-09-01 00:00:00
abstract::This set of experiments is the second of a series designed to explore alterations in cell dynamics and growth control of new populations of hepatocytes that appear to play a role in the carcinogenic process induced in the liver by chemical carcinogens. This is part of an ongoing study of the biochemical and molecular ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1986-05-01 00:00:00
abstract::A synergistic interaction of Bcl-2 and c-Myc plays a role in lymphomagenesis in mice and in some patients as well. Progression of follicular lymphoma to a more aggressive lymphoma is seen in the majority of patients, and approximately 10% of the transformed lymphomas have a translocation of c-myc in addition to the tr...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2001-07-01 00:00:00
abstract::The human MAGE-3 gene encodes a melanoma antigenic epitope recognized by specific cytotoxic T lymphocytes, but its gene product has not been identified thus far. We produced a recombinant MAGE-3 gene product by expression cloning of the entire reading frame in the context of a fusion protein characterized by a 10-hist...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1995-06-01 00:00:00
abstract::A crucial ingredient of any hyperthermia procedure is the accurate measurement of achieved temperature. In this paper, we present some accuracy and resolution suggestions and address the problem of temperature measurements when electromagnetic energy is used as the mode of heating. In such cases, conventional metallic...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1979-06-01 00:00:00
abstract::The sonic hedgehog (SHH) receptor Patched 1 (Ptch1) is critical for embryonic development, and its loss is linked to tumorigenesis. Germ line inactivation of one copy of Ptch1 predisposes to basal cell carcinoma and medulloblastoma in mouse and man. In many cases, medulloblastoma arising from perturbations of Ptch1 fu...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-06-0505
更新日期:2006-07-15 00:00:00
abstract::Mouse teratocarcinoma cells from embryoid bodies were cultured in vitro to permit their differentiation into a number of cell types. Two enzyme activities, creatine phosphokinase (CPK) and the protease plasminogen activator, were studied to follow the developmental sequence of events in these embryoid body-derived cel...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1976-11-01 00:00:00
abstract::A previous study demonstrated inhibition of growth of primary rat mammary carcinomas after infusion of tumor-bearer plasma absorbed against Sepharose derivatives. In this report we have quantitated changes in individual complement components that occur during absorption of rat plasma with Sepharose derivatives and def...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1985-09-01 00:00:00
abstract::Monoclonal antibodies (MABs) reactive with human renal cell carcinoma (RCC) were generated following immunization of mice with either RCC homogenates, RCC cell lines, or fetal kidney homogenates. The characteristics of four highly reactive immunoglobulin G1 MABs, designated UMVA-RCC-A6H, UMVA-RCC-A36, UMVA-RCC-C5H and...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1985-12-01 00:00:00
abstract::Batracylin (8-aminoisoindolo [1,2-b]quinazolin-10(12H)-one; NSC320846) is an investigational clinical anticancer agent. Previous animal studies showed activity against solid tumors and Adriamycin-resistant leukemia. We initially sought to test the proposed Top2-mediated DNA cleavage activity of batracylin and identify...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-0804
更新日期:2007-10-15 00:00:00
abstract::Stathmin is a p53-regulated protein known to influence microtubule dynamics. Because several chemotherapeutic agents used to treat breast cancer alter the dynamic equilibrium of tubulin polymerization, stathmin may play an important role in determining the sensitivity to these drugs. Therefore, we evaluated the effect...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-12-01 00:00:00
abstract::Expression of non-self antigens by tumors can induce activation of T cells in vivo, although this activation can lead to either immunity or tolerance. CD8+ T-cell activation can be direct (if the tumor expresses MHC class I molecules) or indirect (after the capture and cross-presentation of tumor antigens by dendritic...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-07-3163
更新日期:2008-02-15 00:00:00
abstract::The MRP (multidrug resistance protein) gene, a member of the ubiquitous superfamily of ATP-binding cassette transporters, is associated with the multidrug resistance of mammalian cells to natural product anticancer agents. We have previously shown that abrogation of MRP expression by gene targeting leads to hypersensi...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-12-01 00:00:00
abstract::A new tumor model is described that is suitable for the evaluation of antibody-directed drug-delivery protocols and a modification in the procedure for covalently coupling antibody to the surface of drug-containing liposomes is presented. These immunospecific liposomes containing cytosine arabinonucleoside (Ara-C) hav...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-01-15 00:00:00
abstract::Oncogene activation and loss of tumor suppressor function changes the metabolic activity of cancer cells to drive unrestricted proliferation. Moreover, cancer cells adapt their metabolism to sustain growth and survival when access to oxygen and nutrients is restricted, such as in poorly vascularized tumor areas. We sh...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-19-0650
更新日期:2020-01-15 00:00:00
abstract::Significant efforts are being devoted toward the development of effective therapeutic vaccines against cancer. Specifically, well-characterized subunit vaccines, which are designed to generate antitumor cytotoxic CD8 T-cell responses. Because CD4 T cells participate at various stages of CD8 T-cell responses, it is imp...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-08-3134
更新日期:2008-12-01 00:00:00
abstract::The mammary carcinoma cell line MFM-223 is characterized by high androgen and low estrogen and progesterone receptor levels. With the dextran charcoal method, androgen binding was determined at 160 fmol/mg protein corresponding to approximately 100,000 binding sites per cell in whole cell binding assays. The estrogen ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1991-10-15 00:00:00
abstract::We have applied Raman spectroscopy to analyze the chemical composition of microcalcifications occurring in benign and malignant lesions in the human breast. Microcalcifications were initially separated into two categories based on their Raman spectrum: type I, calcium oxalate dihydrate, and type II, calcium hydroxyapa...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:2002-09-15 00:00:00
abstract::Tumor cell-derived selectin ligands mediate contact to the endothelium, platelets, and leukocytes through binding to selectins that facilitates metastasis. Here, we describe the mechanism of how endogenous (non-tumor derived) selectin ligands contribute to metastasis using α(1,3)fucosyltransferase 7 (Fuc-TVII(-/-))-de...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-13-0946
更新日期:2014-02-01 00:00:00
abstract::Aberrant FLT3 expression and/or mutation plays a significant role in leukemogenesis. This has prompted the development of selective small molecule tyrosine kinase inhibitors against FLT3. However, like most tyrosine kinase inhibitors, those against FLT3 are not completely specific and at the doses required to complete...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-3081
更新日期:2005-02-15 00:00:00
abstract::Resistance to antineoplastic drugs is a major problem in the clinical management of cancer. Previous studies have demonstrated that the cytotoxicity of certain anticancer drugs is increased by lowering the glutathione (GSH) levels with buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthe...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1989-02-01 00:00:00
abstract::N4G3, a cell line that overexpresses translation initiation factor eIF4G, one of the components of eIF4F, was made by stable transfection of the human eIF4G cDNA into NIH3T3 cells. The cells expressed 80-100 times greater levels of eIF4G mRNA than did NIH3T3 cells. N4G3 cells formed transformed foci on a monolayer of ...
journal_title:Cancer research
pub_type: 杂志文章
doi:
更新日期:1997-11-15 00:00:00
abstract::Species evolve by mutations and epigenetic changes acting on individuals in a population; tumors evolve by similar mechanisms at a cellular level in a tissue. This article reviews growing evidence about tumor dormancy and suggests that (i) cellular malignancy is a natural byproduct of evolutionary mechanisms, such as ...
journal_title:Cancer research
pub_type: 杂志文章,评审
doi:10.1158/0008-5472.CAN-17-0068
更新日期:2017-05-15 00:00:00
abstract::Continuous cell lines are widely used, but can result in invalid, irreproducible research data. Cell line misidentification is a common problem that can be detected by authentication testing; however, misidentified cell lines continue to be used in publications. Here we explore the impact of one misidentified cell lin...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-16-2258
更新日期:2017-06-01 00:00:00
abstract::Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic a...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-09-1682
更新日期:2009-09-01 00:00:00
abstract::In this study, we identified 53 aberrantly hypermethylated DNA sequences in adult T-cell leukemia (ATL) cells using methylated CpG island amplification/representational difference analysis method. We also observed a proportionate increase in the methylation density of these regions with disease progression. Seven gene...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-04-1422
更新日期:2004-09-01 00:00:00
abstract::Tumor hypoxia is associated clinically with therapeutic resistance and poor patient outcomes. One feature of tumor hypoxia is activated expression of carbonic anhydrase IX (CA9), a regulator of pH and tumor growth. In this study, we investigated the hypothesis that impeding the reuptake of bicarbonate produced extrace...
journal_title:Cancer research
pub_type: 杂志文章
doi:10.1158/0008-5472.CAN-15-1862
更新日期:2016-07-01 00:00:00