Abstract:
:Overexpression of Notch receptors and ligands has been associated with various cancers and developmental disorders, making Notch a potential therapeutic target. Here, we report characterization of Notch1 monoclonal antibodies (mAb) with therapeutic potential. The mAbs generated against epidermal growth factor (EGF) repeats 11 to 15 inhibited binding of Jagged1 and Delta-like4 and consequently, signaling in a dose-dependent manner, the antibodies against EGF repeats 11 to 12 being more effective than those against repeats 13 to 15. These data emphasize the role of EGF repeats 11 to 12 in ligand binding. One of the mAbs, 602.101, which specifically recognizes Notch1, inhibited ligand-dependent expression of downstream target genes of Notch such as HES-1, HES-5, and HEY-L in the breast cancer cell line MDA-MB-231. The mAb also decreased cell proliferation and induced apoptotic cell death. Furthermore, exposure to this antibody reduced CD44(Hi)/CD24(Low) subpopulation in MDA-MB-231 cells, suggesting a decrease in the cancer stem-like cell subpopulation. This was confirmed by showing that exposure to the antibody decreased the primary, secondary, and tertiary mammosphere formation efficiency of the cells. Interestingly, effect of the antibody on the putative stem-like cells appeared to be irreversible, because the mammosphere-forming efficiency could not be salvaged even after antibody removal during the secondary sphere formation. The antibody also modulated expression of genes associated with stemness and epithelial-mesenchymal transition. Thus, targeting individual Notch receptors by specific mAbs is a potential therapeutic strategy to reduce the potential breast cancer stem-like cell subpopulation.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Sharma A,Paranjape AN,Rangarajan A,Dighe RRdoi
10.1158/1535-7163.MCT-11-0508subject
Has Abstractpub_date
2012-01-01 00:00:00pages
77-86issue
1eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-11-0508journal_volume
11pub_type
杂志文章abstract::Passive immunotherapy with monoclonal antibodies represents a cornerstone of human anticancer therapies, but has not been established in veterinary medicine yet. As the tumor-associated antigen EGFR (ErbB-1) is highly conserved between humans and dogs, and considering the effectiveness of the anti-EGFR antibody cetuxi...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0288
更新日期:2014-07-01 00:00:00
abstract::We reported previously a significant increase in survival of nude rats harboring orthotopic A549 human non-small cell lung cancer tumors after treatment with a combination of exisulind (Sulindac Sulfone) and docetaxel (D. C. Chan, Clin. Cancer Res., 8: 904-912, 2002). The purpose of the current study was to determine ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:
更新日期:2003-05-01 00:00:00
abstract::In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical librar...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0397
更新日期:2006-04-01 00:00:00
abstract::In patients with advanced bladder cancer, glucocorticoids are frequently given to reduce acute toxicity, particularly hyperemesis, during chemotherapy, as well as to improve cachectic conditions. However, it remains unclear whether glucocorticoids directly affect the development and progression of bladder cancer throu...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-12-0621
更新日期:2012-12-01 00:00:00
abstract::Tumor recurrence after curative resection remains a major problem in patients with locally advanced colorectal cancer treated with adjuvant chemotherapy. Genetic single-nucleotide polymorphisms (SNP) may serve as useful molecular markers to predict clinical outcomes in these patients and identify targets for future dr...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0646
更新日期:2014-02-01 00:00:00
abstract::Viral-based chimeric antigen receptor-engineered T (CAR T)-cell manufacturing has potential safety risks and relatively high costs. The nonviral minicircle DNA (mcDNA) is safer for patients, cheaper to produce, and may be a more suitable technique to generate CAR T cells. In this study, we produced mcDNA-based CAR T c...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0204
更新日期:2020-01-01 00:00:00
abstract::Ewing's sarcoma is a pediatric cancer of the bone that is characterized by the expression of the chimeric transcription factor EWS-FLI1 that confers a highly malignant phenotype and results from the chromosomal translocation t(11;22)(q24;q12). Poor overall survival and pronounced long-term side effects associated with...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0100
更新日期:2011-10-01 00:00:00
abstract::This work is based on previous evidence showing that chemotactic sequence of the urokinase receptor (uPAR(88-92)) drives angiogenesis in vitro and in vivo in a protease-independent manner, and that the peptide Ac-Arg-Glu-Arg-Phe-NH(2) (RERF) prevents both uPAR(88-92)- and VEGF-induced angiogenesis. New N-acetylated an...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-0949
更新日期:2014-05-01 00:00:00
abstract::Betulinic acid (BA), a pentacyclic triterpene isolated from birch bark and other plants, selectively inhibits the growth of human cancer cell lines. However, the poor potency of BA hinders its clinical development, despite a lack of toxicity in animal studies even at high concentrations. Here, we describe six BA deriv...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0180
更新日期:2007-07-01 00:00:00
abstract::TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T7...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-0645
更新日期:2019-05-01 00:00:00
abstract::Increasing literature suggests that cell adhesion molecule alpha4beta1 integrin plays a pivotal role in autoimmune diseases and cancer development. Noninvasive visualization of alpha4beta1 integrin in vivo will facilitate the understanding of its involvement in disease progression and development of targeted therapies...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-07-0575
更新日期:2008-02-01 00:00:00
abstract::p53 is a critical tumor suppressor and is the most frequently inactivated gene in human cancer. Inhibition of the interaction of p53 with its negative regulator MDM2 represents a promising clinical strategy to treat p53 wild-type tumors. AMG 232 is a potential best-in-class inhibitor of the MDM2-p53 interaction and is...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-14-0710
更新日期:2015-03-01 00:00:00
abstract::Despite significant advances in combinations of radiotherapy and chemotherapy, altered fractionation schedules and image-guided radiotherapy, many cancer patients fail to benefit from radiation. A prevailing hypothesis is that targeting repair of DNA double strand breaks (DSB) can enhance radiation effects in the tumo...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-0288
更新日期:2018-02-01 00:00:00
abstract::Glycosylation is a complex multienzyme-related process that is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface-specific glycotopes that can be targeted by antibodies. Murine DS6 mAb (muDS6) was generated from serous ovary adenocarcinoma immunization. It recogn...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-0826
更新日期:2020-08-01 00:00:00
abstract::Inactivation of NF2/Merlin causes the autosomal-dominant cancer predisposition syndrome familial neurofibromatosis type 2 (NF2) and contributes to the development of malignant pleural mesothelioma (MPM). To develop a targeted therapy for NF2-mutant tumors, we have exploited the recent realization that Merlin loss driv...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0821
更新日期:2017-08-01 00:00:00
abstract::Small cell lung cancer (SCLC) easily acquires multidrug resistance after successful initial therapy. Overexpression of ATP-binding cassette (ABC) transporters is important for the multidrug resistance. Among them, ABCB1 and ABCG2 are known to be upregulated in chemoresistant SCLC cells. We found that human epidermal g...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0884
更新日期:2012-04-01 00:00:00
abstract::Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-17-1076
更新日期:2018-08-01 00:00:00
abstract::With current techniques, it remains a challenge to assess coregulator binding of nuclear receptors, for example, the estrogen receptor alpha (ERα). ERα is critical in many breast tumors and is inhibited by antiestrogens such as tamoxifen in cancer therapy. ERα is also modified by acetylation and phosphorylation that a...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-11-0855
更新日期:2012-04-01 00:00:00
abstract::Metastasis is the primary determinant of death in patients with diverse solid tumors and MDA-9/Syntenin (SDCBP), a pro-metastatic and pro-angiogenic gene, contributes to this process. Recently, we documented that by physically interacting with IGF-1R, MDA-9/Syntenin activates STAT3 and regulates prostate cancer pathog...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-18-1019
更新日期:2019-11-01 00:00:00
abstract::Aminoflavone (AF), a clinically investigational novel anticancer agent, requires sequential metabolic activation by CYP1A1 and SULT1A1 to exert its antitumor activities. The purpose of this study was to determine the functional significance of common polymorphisms of human CYP1A1 and SULT1A1 on the metabolism and cyto...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-10-0597
更新日期:2010-10-01 00:00:00
abstract::The traditional maximum dose density chemotherapy renders the tumor patients not only the tumor remission but the chemotherapy resistance and more adverse side effects. According to the widely positive expression of Toll-like receptor (TLR)-3 in oral squamous cell carcinoma (OSCC) patients (n = 166), we here provided ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-16-0454
更新日期:2017-06-01 00:00:00
abstract::There is a growing recognition that current preclinical models do not reflect the tumor microenvironment in cellular, biological, and biophysical content and this may have a profound effect on drug efficacy testing, especially in the era of molecular-targeted agents. Here, we describe a method to directly embed low-pa...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0598
更新日期:2016-04-01 00:00:00
abstract::Nasopharyngeal carcinoma (NPC) is a common cancer in Southern China and EBV is the most important pathogenesis. In this study, we explore the potential that a recombinant adeno-associated virus (rAAV) carrying a fusing gene containing heat shock protein as an adjuvant, EBV latent membrane proteins (LMP1 and LMP2) CTL ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-08-1176
更新日期:2009-09-01 00:00:00
abstract::The PI3K/AKT/mTOR pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), but pathway inhibition has variable efficacy. Identification of predictive biomarkers and mechanisms of resistance would allow selection of patients most likely to respond and novel therapeutic combinations. The purpose...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-13-1090
更新日期:2014-11-01 00:00:00
abstract::Many genes, with products involved in the protection of cells against carcinogens, oxidants, and other toxic chemicals, are under the transcriptional control of a simple DNA regulatory element [i.e., the antioxidant response element (ARE)]. One or more functional AREs have been confirmed or are believed to exist in th...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:
更新日期:2004-07-01 00:00:00
abstract::Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in ...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章,评审
doi:10.1158/1535-7163.MCT-05-0375
更新日期:2006-05-01 00:00:00
abstract::Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug ta...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-19-1013
更新日期:2020-10-01 00:00:00
abstract::Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-resistant 2008/C13*5...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-05-0102
更新日期:2005-10-01 00:00:00
abstract::There is considerable interest in the clinical development of inhibitors of mTOR complexes mTORC1 and 2. Because mTORC1 and its downstream mRNA translation effectors may protect against genotoxic DNA damage, we investigated the inhibition of mTORC1 and mTORC1/2 in the ability to reverse platinum resistance in tissue c...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-15-0926
更新日期:2016-07-01 00:00:00
abstract::Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-...
journal_title:Molecular cancer therapeutics
pub_type: 杂志文章
doi:10.1158/1535-7163.MCT-06-0678
更新日期:2007-04-01 00:00:00