Synthesis, Characterization, and In Vitro and In Vivo Evaluations of 4-(N)-Docosahexaenoyl 2', 2'-Difluorodeoxycytidine with Potent and Broad-Spectrum Antitumor Activity.

Abstract:

:In this study, a new compound, 4-(N)-docosahexaenoyl 2', 2'-difluorodeoxycytidine (DHA-dFdC), was synthesized and characterized. Its antitumor activity was evaluated in cell culture and in mouse models of pancreatic cancer. DHA-dFdC is a poorly soluble, pale yellow waxy solid, with a molecular mass of 573.3Da and a melting point of about 96°C. The activation energy for the degradation of DHA-dFdC in an aqueous Tween 80-based solution is 12.86kcal/mol, whereas its stability is significantly higher in the presence of vitamin E. NCI-60 DTP Human Tumor Cell Line Screening revealed that DHA-dFdC has potent and broad-spectrum antitumor activity, especially in leukemia, renal, and central nervous system cancer cell lines. In human and murine pancreatic cancer cell lines, the IC50 value of DHA-dFdC was up to 10(5)-fold lower than that of dFdC. The elimination of DHA-dFdC in mouse plasma appeared to follow a biexponential model, with a terminal phase t1/2 of about 58minutes. DHA-dFdC significantly extended the survival of genetically engineered mice that spontaneously develop pancreatic ductal adenocarcinoma. In nude mice with subcutaneously implanted human Panc-1 pancreatic tumors, the antitumor activity of DHA-dFdC was significantly stronger than the molar equivalent of dFdC alone, DHA alone, or the physical mixture of them (1:1, molar ratio). DHA-dFdC also significantly inhibited the growth of Panc-1 tumors orthotopically implanted in the pancreas of nude mice, whereas the molar equivalent dose of dFdC alone did not show any significant activity. DHA-dFdC is a promising compound for the potential treatment of cancers in organs such as the pancreas.

journal_name

Neoplasia

authors

Naguib YW,Lansakara-P D,Lashinger LM,Rodriguez BL,Valdes S,Niu M,Aldayel AM,Peng L,Hursting SD,Cui Z

doi

10.1016/j.neo.2015.11.012

subject

Has Abstract

pub_date

2016-01-01 00:00:00

pages

33-48

issue

1

eissn

1522-8002

issn

1476-5586

pii

S1476-5586(15)00157-8

journal_volume

18

pub_type

杂志文章
  • Noninvasive Bioluminescence Imaging of AKT Kinase Activity in Subcutaneous and Orthotopic NSCLC Xenografts: Correlation of AKT Activity with Tumor Growth Kinetics.

    abstract::Aberrant signaling through the AKT kinase mediates oncogenic phenotypes including cell proliferation, survival, and therapeutic resistance. Here, we utilize a bioluminescence reporter for AKT kinase activity (BAR) to noninvasively assess the therapeutic efficacy of the EGFR inhibitor erlotinib in KRAS-mutated lung can...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2017.02.005

    authors: Suchowski K,Pöschinger T,Rehemtulla A,Stürzl M,Scheuer W

    更新日期:2017-04-01 00:00:00

  • Association of the actin-binding protein transgelin with lymph node metastasis in human colorectal cancer.

    abstract::Metastatic dissemination of primary tumors is responsible for 90% of colorectal cancer (CRC) deaths. The presence of positive lymph nodes, which separates stage I/II from stage III CRC, is a particularly key factor in patient management. Here, we describe results of a quantitative proteomic survey to identify molecula...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.09542

    authors: Lin Y,Buckhaults PJ,Lee JR,Xiong H,Farrell C,Podolsky RH,Schade RR,Dynan WS

    更新日期:2009-09-01 00:00:00

  • Cycling hypoxia induces a specific amplified inflammatory phenotype in endothelial cells and enhances tumor-promoting inflammation in vivo.

    abstract::Abnormal architecture of the tumor blood network, as well as heterogeneous erythrocyte flow, leads to temporal fluctuations in tissue oxygen tension exposing tumor and stromal cells to cycling hypoxia. Inflammation is another feature of tumor microenvironment and is considered as a new enabling characteristic of tumor...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2014.11.003

    authors: Tellier C,Desmet D,Petit L,Finet L,Graux C,Raes M,Feron O,Michiels C

    更新日期:2015-01-01 00:00:00

  • Genes and proteins differentially expressed during in vitro malignant transformation of bovine pancreatic duct cells.

    abstract::Pancreatic carcinoma has an extremely bad prognosis due to lack of early diagnostic markers and lack of effective therapeutic strategies. Recently, we have established an in vitro model recapitulating the first steps in the carcinogenesis of the pancreas. SV40 large T antigen-immortalized bovine pancreatic duct cells ...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.06754

    authors: Jesnowski R,Zubakov D,Faissner R,Ringel J,Hoheisel JD,Lösel R,Schnölzer M,Löhr M

    更新日期:2007-02-01 00:00:00

  • Clinical implications of promoter hypermethylation in RASSF1A and MGMT in retinoblastoma.

    abstract::We investigated the epigenetic silencing and genetic changes of the RAS-associated domain family 1A (RASSF1A) gene and the O6-methylguanine-DNA methyltransferase (MGMT) gene in retinoblastoma. We extracted DNA from microdissected tumor and normal retina tissues of the same patient in 68 retinoblastoma cases. Promoter ...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.04565

    authors: Choy KW,Lee TC,Cheung KF,Fan DS,Lo KW,Beaverson KL,Abramson DH,Lam DS,Yu CB,Pang CP

    更新日期:2005-03-01 00:00:00

  • ZNF198-FGFR1 transforms Ba/F3 cells to growth factor independence and results in high level tyrosine phosphorylation of STATS 1 and 5.

    abstract::The ZNF198- FGFR1 fusion gene arises as a result of the t(8;13)(p11;q12) in the 8p11 myeloproliferative syndrome. To determine the transforming properties of this chimeric protein we transfected ZNF198-FGFR1 into the interleukin (IL)-3 dependent cell line Ba/F3. Growth factor independent subclones were obtained in whi...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1038/sj.neo.7900035

    authors: Smedley D,Demiroglu A,Abdul-Rauf M,Heath C,Cooper C,Shipley J,Cross NC

    更新日期:1999-10-01 00:00:00

  • Defining characteristics of Types I and II apoptotic cells in response to TRAIL.

    abstract::Type I cells have been defined to be independent of mitochondria for the induction of Fas death receptor-mediated apoptosis, whereas Type II cells are mitochondria-dependent. Knock-out studies in mice show that thymocytes are Type I and liver cells are Type II. We have previously shown that primary human hepatocytes a...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1038/sj.neo.7900270

    authors: Ozören N,El-Deiry WS

    更新日期:2002-11-01 00:00:00

  • CF101, an agonist to the A3 adenosine receptor, enhances the chemotherapeutic effect of 5-fluorouracil in a colon carcinoma murine model.

    abstract::NF-kappaB and the upstream kinase PKB/Akt are highly expressed in chemoresistance tumor cells and may hamper the apoptotic pathway. CF101, a specific agonist to the A3 adenosine receptor (A3AR), inhibits the development of colon carcinoma growth in cell cultures and xenograft murine models. Because CF101 has been show...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.04364

    authors: Bar-Yehuda S,Madi L,Silberman D,Gery S,Shkapenuk M,Fishman P

    更新日期:2005-01-01 00:00:00

  • Transgenic expression of Sag/Rbx2 E3 causes early stage tumor promotion, late stage cytogenesis and acinar loss in the Kras-PDAC model.

    abstract::SAG (Sensitive to Apoptosis Gene), also known as RBX2 or ROC2, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our previous studies showed that Sag/Rbx2 co-operated with Kras or Pten loss to promote tumorigenesis in the lung and prostate, respectively, but antagonized Kras to inhibit skin t...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2020.03.002

    authors: Zhang Q,Wei D,Tan M,Li H,Morgan MA,Sun Y

    更新日期:2020-04-24 00:00:00

  • Cellular basis of antiproliferative and antitumor activity of the novel camptothecin derivative, gimatecan, in bladder carcinoma models.

    abstract::To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan ...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.04397

    authors: Ulivi P,Zoli W,Fabbri F,Brigliadori G,Ricotti L,Tesei A,Rosetti M,De Cesare M,Beretta GL,Corna E,Supino R,Zunino F

    更新日期:2005-02-01 00:00:00

  • Ras-mediated suppression of TGFbetaRII expression in intestinal epithelial cells involves Raf-independent signaling.

    abstract::Ras-transformed intestinal epithelial cells are resistant to the growth inhibitory actions of TGFbeta and have a marked decrease in expression of the TGFbeta type II receptor (TGFbetaRII). Rat intestinal epithelial cells (RIE) were stably transfected with activated Ras, Sos and Raf constructs and tested for expression...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1038/sj.neo.7900099

    authors: Bulus NM,Sheng HM,Sizemore N,Oldham SM,Barnett JV,Coffey RJ,Beauchamp DR,Barnard JA

    更新日期:2000-07-01 00:00:00

  • Detection of hypoxia in human brain tumor xenografts using a modified comet assay.

    abstract::We used the standard comet assay successfully to generate in vitro dose-response curves under oxic and hypoxic conditions. We then made mixtures of cells that had been irradiated with 3 and 9 Gy of X-rays to simulate two subpopulations in a tumor, but efforts to accurately detect and quantify the subpopulations using ...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/S1476-5586(03)80022-2

    authors: Wang J,Klem J,Wyrick JB,Ozawa T,Cunningham E,Golinveaux J,Allen MJ,Lamborn KR,Deen DF

    更新日期:2003-07-01 00:00:00

  • Chk1 Inhibitor SCH900776 Effectively Potentiates the Cytotoxic Effects of Platinum-Based Chemotherapeutic Drugs in Human Colon Cancer Cells.

    abstract::Although Chk1 kinase inhibitors are currently under clinical investigation as effective cancer cell sensitizers to the cytotoxic effects of numerous chemotherapeutics, there is still a considerable uncertainty regarding their role in modulation of anticancer potential of platinum-based drugs. Here we newly demonstrate...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2017.08.002

    authors: Herůdková J,Paruch K,Khirsariya P,Souček K,Krkoška M,Vondálová Blanářová O,Sova P,Kozubík A,Hyršlová Vaculová A

    更新日期:2017-10-01 00:00:00

  • Esophageal Adenocarcinoma-Derived Extracellular Vesicle MicroRNAs Induce a Neoplastic Phenotype in Gastric Organoids.

    abstract::There have been no reports describing the effects of cancer cell-derived extracellular vesicles (EVs) on three-dimensional organoids. In this study, we delineated the proneoplastic effects of esophageal adenocarcinoma (EAC)-derived EVs on gastric organoids (gastroids) and elucidated molecular mechanisms underlying the...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2017.06.007

    authors: Ke X,Yan R,Sun Z,Cheng Y,Meltzer A,Lu N,Shu X,Wang Z,Huang B,Liu X,Wang Z,Song JH,Ng CK,Ibrahim S,Abraham JM,Shin EJ,He S,Meltzer SJ

    更新日期:2017-11-01 00:00:00

  • Vascular endothelial-targeted therapy combined with cytotoxic chemotherapy induces inflammatory intratumoral infiltrates and inhibits tumor relapses after surgery.

    abstract::Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovas...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.12208

    authors: Judy BF,Aliperti LA,Predina JD,Levine D,Kapoor V,Thorpe PE,Albelda SM,Singhal S

    更新日期:2012-04-01 00:00:00

  • Tumor necrosis factor receptor signaling modulates carcinogenesis in a mouse model of breast cancer.

    abstract::Pro-inflammatory conditions have long been associated with mammary carcinogenesis and breast cancer progression. The underlying mechanisms are incompletely understood but signaling of pro-inflammatory cytokine TNFα through its receptors TNFR1 and TNFR2 is a major mediator of inflammation in both obesity and in the res...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2020.12.007

    authors: He L,Bhat K,Duhacheck-Muggy S,Ioannidis A,Zhang L,Nguyen NT,Moatamed NA,Pajonk F

    更新日期:2021-02-01 00:00:00

  • Inhibitors of GLUT/SLC2A Enhance the Action of BCNU and Temozolomide against High-Grade Gliomas.

    abstract::Glucose transport across glioblastoma membranes plays a crucial role in maintaining the enhanced glycolysis typical of high-grade gliomas and glioblastoma. We tested the ability of two inhibitors of the glucose transporters GLUT/SLC2A superfamily, indinavir (IDV) and ritonavir (RTV), and of one inhibitor of the Na/glu...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2017.02.009

    authors: Azzalin A,Nato G,Parmigiani E,Garello F,Buffo A,Magrassi L

    更新日期:2017-04-01 00:00:00

  • Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma.

    abstract::Glioblastoma (GBM) represents the most aggressive malignancy of the central nervous system. Increased expression of Angiotensin II Receptor Type 1 (AGTR1) has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplor...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2020.08.002

    authors: Singh A,Srivastava N,Yadav A,Ateeq B

    更新日期:2020-10-01 00:00:00

  • Tumor-initiating and -propagating cells: cells that we would like to identify and control.

    abstract::Identification of the cell types capable of initiating and sustaining growth of the neoplastic clone in vivo is a fundamental problem in cancer research. It is likely that tumor growth can be sustained both by rare cancer stem-like cells and selected aggressive clones and that the nature of the mutations, the cell of ...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章,评审

    doi:10.1593/neo.10290

    authors: Tysnes BB

    更新日期:2010-07-01 00:00:00

  • Fusion of the tumor-suppressor gene CHEK2 and the gene for the regulatory subunit B of protein phosphatase 2 PPP2R2A in childhood teratoma.

    abstract::We characterized the molecular genetic consequences of a balanced chromosome translocation t(8;22)(p21;q12), which occurred as the sole cytogenetic aberration in short-term cultured cells from an intrathoracic mature teratoma in a 15-year-old girl. Fluorescence in situ hybridization and reverse transcription-polymeras...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.06139

    authors: Jin Y,Mertens F,Kullendorff CM,Panagopoulos I

    更新日期:2006-05-01 00:00:00

  • Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells.

    abstract::BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current frontline therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactiva...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2018.02.009

    authors: Mologni L,Costanza M,Sharma GG,Viltadi M,Massimino L,Citterio S,Purgante S,Raman H,Pirola A,Zucchetti M,Piazza R,Gambacorti-Passerini C

    更新日期:2018-05-01 00:00:00

  • Ubiquitin-dependent regulation of TGFbeta signaling in cancer.

    abstract::The transforming growth factorbeta (TGFbeta) superfamily regulates a broad spectrum of biological responses throughout embryonic development and adult life, including cell proliferation and differentiation, epithelial-to-mesenchymal transition, apoptosis, and angiogenesis. TGFbeta members initiate signaling by bringin...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章,评审

    doi:10.1593/neo.06472

    authors: Izzi L,Attisano L

    更新日期:2006-08-01 00:00:00

  • CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling.

    abstract::Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurate...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1016/j.neo.2014.03.001

    authors: Ma MZ,Zhuang C,Yang XM,Zhang ZZ,Ma H,Zhang WM,You H,Qin W,Gu J,Yang S,Cao H,Zhang ZG

    更新日期:2014-03-01 00:00:00

  • B cells are critical to T-cell-mediated antitumor immunity induced by a combined immune-stimulatory/conditionally cytotoxic therapy for glioblastoma.

    abstract::We have demonstrated that modifying the tumor microenvironment through intratumoral administration of adenoviral vectors (Ad) encoding the conditional cytotoxic molecule, i.e., HSV1-TK and the immune-stimulatory cytokine, i.e., fms-like tyrosine kinase 3 ligand (Flt3L) leads to T-cell-dependent tumor regression in rod...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.11024

    authors: Candolfi M,Curtin JF,Yagiz K,Assi H,Wibowo MK,Alzadeh GE,Foulad D,Muhammad AK,Salehi S,Keech N,Puntel M,Liu C,Sanderson NR,Kroeger KM,Dunn R,Martins G,Lowenstein PR,Castro MG

    更新日期:2011-10-01 00:00:00

  • Telomere length on chromosome 17q shortens more than global telomere length in the development of breast cancer.

    abstract::It is known that total telomere length is shorter in invasive breast cancer than in normal breast tissue but the status of individual telomere lengths has not been studied. Part of the difficulty is that usually telomere length in interphase cells is measured on all chromosomes together. In this study we compared norm...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.07106

    authors: Rashid-Kolvear F,Pintilie M,Done SJ

    更新日期:2007-04-01 00:00:00

  • An alternate splicing variant of the human telomerase catalytic subunit inhibits telomerase activity.

    abstract::Telomerase, a cellular reverse transcriptase, adds telomeric repeats to chromosome ends. In normal human somatic cells, telomerase is repressed and telomeres progressively shorten, leading to proliferative senescence. Introduction of the telomerase (hTERT) cDNA is sufficient to produce telomerase activity and immortal...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1038/sj.neo.7900113

    authors: Yi X,White DM,Aisner DL,Baur JA,Wright WE,Shay JW

    更新日期:2000-09-01 00:00:00

  • CREB regulates AChE-R-induced proliferation of human glioblastoma cells.

    abstract::The cyclic adenosine monophosphate (AMP) response element-binding protein, CREB, often modulates stress responses. Here, we report that CREB suppresses the glioblastoma proliferative effect of the stress-induced acetylcholinesterase variant, AChE-R. In human U87MG glioblastoma cells, AChE-R formed a triple complex wit...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.3424

    authors: Perry C,Sklan EH,Soreq H

    更新日期:2004-05-01 00:00:00

  • Paradoxically augmented anti-tumorigenic action of proton pump inhibitor and GastrininAPCMin/+ intestinal polyposis model.

    abstract::Though long-term administration of proton pump inhibitor (PPI) imposed the risk of gastrointestinal track tumorigenesis by accompanied hypergastrinemia, no overt increases of colon cancer risk were witnessed after a long-term cohort study. Our recent investigation revealed that PPI prevented colitis-associated carcino...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.131510

    authors: Han YM,Hahm KB,Park JM,Hong SP,Kim EH

    更新日期:2014-01-01 00:00:00

  • Tel, a frequent target of leukemic translocations, induces cellular aggregation and influences expression of extracellular matrix components.

    abstract::Tel is an Ets transcription factor that is the target of chromosome translocations in lymphoid and myeloid leukemias and in solid tumors. It contains two functional domains, a pointed oligomerization domain and a DNA-binding domain. Retroviral transduction of a wild-type Tel cDNA into a clonal subline of NIH3T3 fibrob...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1038/sj.neo.7900064

    authors: Van Rompaey L,Dou W,Buijs A,Grosveld G

    更新日期:1999-12-01 00:00:00

  • Dynamic contrast-enhanced and diffusion MRI show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF-1alpha using PX-478.

    abstract::PX-478 is a new agent known to inhibit the hypoxia-responsive transcription factor, HIF-1alpha, in experimental tumors. The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint(s) is sensitive to this drug's actions. Dynamic contrast-enhanced (DCE) and diffusi...

    journal_title:Neoplasia (New York, N.Y.)

    pub_type: 杂志文章

    doi:10.1593/neo.04628

    authors: Jordan BF,Runquist M,Raghunand N,Baker A,Williams R,Kirkpatrick L,Powis G,Gillies RJ

    更新日期:2005-05-01 00:00:00