Topoisomerase poisons differentially activate DNA damage checkpoints through ataxia-telangiectasia mutated-dependent and -independent mechanisms.

Abstract:

:Camptothecin and Adriamycin are clinically important inhibitors for topoisomerase (Topo) I and Topo II, respectively. The ataxia-telangiectasia mutated (ATM) product is essential for ionizing radiation-induced DNA damage responses, but the role of ATM in Topo poisons-induced checkpoints remains unresolved. We found that distinct mechanisms are involved in the activation of different cell cycle checkpoints at different concentrations of Adriamycin and camptothecin. Adriamycin promotes the G(1) checkpoint through activation of the p53-p21(CIP1/WAF1) pathway and decrease of pRb phosphorylation. Phosphorylation of p53(Ser20) after Adriamycin treatment is ATM dependent, but is not required for the full activation of p53. The G(1) checkpoint is dependent on ATM at low doses but not at high doses of Adriamycin. In contrast, the Adriamycin-induced G(2) checkpoint is independent on ATM but sensitive to caffeine. Adriamycin inhibits histone H3(Ser10) phosphorylation through inhibitory phosphorylation of CDC2 at low doses and down-regulation of cyclin B1 at high doses. The camptothecin-induced intra-S checkpoint is partially dependent on ATM, and is associated with inhibitory phosphorylation of cyclin-dependent kinase 2 and reduction of BrdUrd incorporation after mid-S phase. Finally, apoptosis associated with high doses of Adriamycin or camptothecin is not influenced by the absence of ATM. These data indicate that the involvement of ATM following treatment with Topo poisons differs extensively with dosage and for different cell cycle checkpoints.

journal_name

Mol Cancer Ther

authors

Siu WY,Lau A,Arooz T,Chow JP,Ho HT,Poon RY

keywords:

subject

Has Abstract

pub_date

2004-05-01 00:00:00

pages

621-32

issue

5

eissn

1535-7163

issn

1538-8514

journal_volume

3

pub_type

杂志文章
  • Sulindac independently modulates extracellular signal-regulated kinase 1/2 and cyclic GMP-dependent protein kinase signaling pathways.

    abstract::Colorectal cancer is the second leading cause of cancer mortality in the United States. Substantial human and animal data support the ability of nonsteroidal anti-inflammatory drugs to cause regression of existing colon tumors and prevent new tumor formation. The mechanism by which the nonsteroidal anti-inflammatory d...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0210

    authors: Rice PL,Peters SL,Beard KS,Ahnen DJ

    更新日期:2006-03-01 00:00:00

  • EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.

    abstract::Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0137

    authors: Chen KS,Fustino NJ,Shukla AA,Stroup EK,Budhipramono A,Ateek C,Stuart SH,Yamaguchi K,Kapur P,Frazier AL,Lum L,Looijenga LHJ,Laetsch TW,Rakheja D,Amatruda JF

    更新日期:2018-05-01 00:00:00

  • Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells.

    abstract::Chemoresistance is a major reason that patients with osteosarcoma fail to achieve a lasting chemotherapy response, and it contributes to disease relapse, progression, and death. Human glutathione S-transferase P1 (GSTP1), a phase II detoxification enzyme, contributes to chemoresistance in many cancers. However, the ro...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0580

    authors: Huang G,Mills L,Worth LL

    更新日期:2007-05-01 00:00:00

  • Inhibition of STAT3 signaling pathway by nitidine chloride suppressed the angiogenesis and growth of human gastric cancer.

    abstract::STAT3 has been strongly implicated in human malignancies, and constitutive activation of STAT3 serves a crucial role in cell survival, angiogenesis, immune evasion, and inflammation. In this study, we showed that nitidine chloride, a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb) DC, exerts pot...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0648

    authors: Chen J,Wang J,Lin L,He L,Wu Y,Zhang L,Yi Z,Chen Y,Pang X,Liu M

    更新日期:2012-02-01 00:00:00

  • 2-Deoxy-Glucose Downregulates Endothelial AKT and ERK via Interference with N-Linked Glycosylation, Induction of Endoplasmic Reticulum Stress, and GSK3β Activation.

    abstract::Interference with endothelial cell metabolism is a promising, yet unexploited strategy for angiogenesis inhibition. We reported that the glucose analogue 2-deoxy-D-glucose (2-DG) inhibits angiogenesis at significantly lower concentrations than those required for tumor cytotoxicity. Here, we found that hypersensitivity...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0315

    authors: Kovács K,Decatur C,Toro M,Pham DG,Liu H,Jing Y,Murray TG,Lampidis TJ,Merchan JR

    更新日期:2016-02-01 00:00:00

  • Blockade of Rac1 activity induces G1 cell cycle arrest or apoptosis in breast cancer cells through downregulation of cyclin D1, survivin, and X-linked inhibitor of apoptosis protein.

    abstract::Rac1 GTPase regulates a variety of signaling pathways that are implicated in malignant phenotypes. Here, we show that selective inhibition of Rac1 activity by the pharmacologic inhibitor NSC23766 suppressed cell growth in a panel of human breast cancer cell lines, whereas it had little toxicity to normal mammary epith...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0906

    authors: Yoshida T,Zhang Y,Rivera Rosado LA,Chen J,Khan T,Moon SY,Zhang B

    更新日期:2010-06-01 00:00:00

  • The effects of the oral, pan-VEGF-R kinase inhibitor CEP-7055 and chemotherapy in orthotopic models of glioblastoma and colon carcinoma in mice.

    abstract::CEP-7055, a fully synthetic, orally active N,N-dimethylglycine ester of CEP-5214, a C3-(isopropylmethoxy)-fused pyrrolocarbazole with potent pan-vascular endothelial growth factor receptor (VEGFR) kinase inhibitory activity, has recently completed phase I clinical trials in cancer patients. These studies evaluated the...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0327

    authors: Jones-Bolin S,Zhao H,Hunter K,Klein-Szanto A,Ruggeri B

    更新日期:2006-07-01 00:00:00

  • Arsenic Trioxide and Sorafenib Induce Synthetic Lethality of FLT3-ITD Acute Myeloid Leukemia Cells.

    abstract::Acute myeloid leukemia (AML) with Fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutation is notoriously hard to treat. We identified two drugs that together form an effective combination therapy against FLT3-ITD AML. One of the drugs, Sorafenib, an inhibitor of FLT3-ITD and other kinase activity...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0298

    authors: Wang R,Li Y,Gong P,Gabrilove J,Waxman S,Jing Y

    更新日期:2018-09-01 00:00:00

  • BCH-1868 [(-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-yl-methyl) tetrahydrofuran]: a cyclic nucleoside phosphonate with antitumor activity.

    abstract::Nucleoside phosphonates are widely used therapeutic agents with a broad spectrum of antiviral activity. However, only a few of them are reported to have antitumor activity. In this study, we show that a tetrahydrofuran phosphonate analogue of guanosine, (-)-2-R-dihydroxyphosphinoyl-5-(S)-(guanin-9'-ylmethyl) tetrahydr...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Leblond L,Attardo G,Hamelin B,Bouffard DY,Nguyen-Ba N,Gourdeau H

    更新日期:2002-07-01 00:00:00

  • Construction of a novel DNA decoy that inhibits the oncogenic beta-catenin/T-cell factor pathway.

    abstract::The oncogenic beta-catenin/T-cell factor (TCF) signal is a common trigger inducing expressions of various cancer-related genes and is activated in various types of human malignancy. The aim of this study was to create an effective double-stranded DNA decoy that would interfere with endogenous TCF hyperactivity in tumo...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0388

    authors: Seki Y,Yamamoto H,Ngan CY,Yasui M,Tomita N,Kitani K,Takemasa I,Ikeda M,Sekimoto M,Matsuura N,Albanese C,Kaneda Y,Pestell RG,Monden M

    更新日期:2006-04-01 00:00:00

  • Trastuzumab-Resistant HER2+ Breast Cancer Cells Retain Sensitivity to Poly (ADP-Ribose) Polymerase (PARP) Inhibition.

    abstract::HER2-targeted therapies, such as trastuzumab, have increased the survival rates of HER2+ breast cancer patients. However, despite these therapies, many tumors eventually develop resistance to these therapies. Our lab previously reported an unexpected sensitivity of HER2+ breast cancer cells to poly (ADP-ribose) polyme...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0302

    authors: Wielgos ME,Zhang Z,Rajbhandari R,Cooper TS,Zeng L,Forero A,Esteva FJ,Osborne CK,Schiff R,LoBuglio AF,Nozell SE,Yang ES

    更新日期:2018-05-01 00:00:00

  • The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor.

    abstract::Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK i...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0205

    authors: Byth KF,Geh C,Forder CL,Oakes SE,Thomas AP

    更新日期:2006-03-01 00:00:00

  • The Indenoisoquinoline LMP517: A Novel Antitumor Agent Targeting both TOP1 and TOP2.

    abstract::The camptothecin derivatives topoisomerase I (TOP1) inhibitors, irinotecan and topotecan, are FDA approved for the treatment of colorectal, ovarian, lung and breast cancers. Because of the chemical instability of camptothecins, short plasma half-life, drug efflux by the multidrug-resistance ABC transporters, and the s...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-1064

    authors: Marzi L,Sun Y,Huang SN,James A,Difilippantonio S,Pommier Y

    更新日期:2020-08-01 00:00:00

  • Extended treatment with physiologic concentrations of dietary phytochemicals results in altered gene expression, reduced growth, and apoptosis of cancer cells.

    abstract::Dietary phytochemicals exhibit chemopreventive potential in vivo through persistent low-dose exposures, whereas mechanistic in vitro studies with these agents generally use a high-dose single treatment. Because the latter approach is not representative of an in vivo steady state, we investigated antitumor activity of ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0117

    authors: Moiseeva EP,Almeida GM,Jones GD,Manson MM

    更新日期:2007-11-01 00:00:00

  • Improved grading and survival prediction of human astrocytic brain tumors by artificial neural network analysis of gene expression microarray data.

    abstract::Histopathologic grading of astrocytic tumors based on current WHO criteria offers a valuable but simplified representation of oncologic reality and is often insufficient to predict clinical outcome. In this study, we report a new astrocytic tumor microarray gene expression data set (n = 65). We have used a simple arti...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0177

    authors: Petalidis LP,Oulas A,Backlund M,Wayland MT,Liu L,Plant K,Happerfield L,Freeman TC,Poirazi P,Collins VP

    更新日期:2008-05-01 00:00:00

  • The Protein Tyrosine Phosphatase Activity of Eyes Absent Contributes to Tumor Angiogenesis and Tumor Growth.

    abstract::DNA damage repair capacity is required for cells to survive catastrophic DNA damage and proliferate under conditions of intratumoral stress. The ability of the minor histone protein H2AX to serve as a hub for the assembly of a productive DNA damage repair complex is a necessary step in preventing DNA damage-induced ce...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-0057

    authors: Wang Y,Pandey RN,Riffle S,Chintala H,Wikenheiser-Brokamp KA,Hegde RS

    更新日期:2018-08-01 00:00:00

  • Histone Deacetylase Inhibitors Enhance the Therapeutic Potential of Reovirus in Multiple Myeloma.

    abstract::Multiple myeloma remains incurable and the majority of patients die within 5 years of diagnosis. Reolysin, the infusible form of human reovirus (RV), is a novel viral oncolytic therapy associated with antitumor activity likely resulting from direct oncolysis and a virus-mediated antitumor immune response. Results from...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0240-T

    authors: Stiff A,Caserta E,Sborov DW,Nuovo GJ,Mo X,Schlotter SY,Canella A,Smith E,Badway J,Old M,Jaime-Ramirez AC,Yan P,Benson DM,Byrd JC,Baiocchi R,Kaur B,Hofmeister CC,Pichiorri F

    更新日期:2016-05-01 00:00:00

  • Preclinical Development of a WT1 Oral Cancer Vaccine Using a Bacterial Vector to Treat Castration-Resistant Prostate Cancer.

    abstract::Previously, we constructed a recombinant Bifidobacterium longum displaying a partial mouse Wilms' tumor 1 (WT1) protein (B. longum 420) as an oral cancer vaccine using a bacterial vector and demonstrated that oral administration of B. longum 420 significantly inhibited tumor growth compared with the Db126 WT1 peptide ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-1105

    authors: Kitagawa K,Gonoi R,Tatsumi M,Kadowaki M,Katayama T,Hashii Y,Fujisawa M,Shirakawa T

    更新日期:2019-05-01 00:00:00

  • Effects of gefitinib (Iressa) on mammary cancers: preventive studies with varied dosages, combinations with vorozole or targretin, and biomarker changes.

    abstract::The ability of the epidermal growth factor receptor inhibitor gefitinib (Iressa) to prevent/treat methylnitrosourea (MNU)-induced mammary cancers and to modulate biomarkers in female Sprague-Dawley rats was examined. Rats were given a single dose of MNU (75 mg/kg body weight) at 50 days of age. In the prevention studi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-2141

    authors: Lubet RA,Szabo E,Christov K,Bode AM,Ericson ME,Steele VE,Juliana MM,Grubbs CJ

    更新日期:2008-04-01 00:00:00

  • Gamma Secretase Inhibition by BMS-906024 Enhances Efficacy of Paclitaxel in Lung Adenocarcinoma.

    abstract::Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0439

    authors: Morgan KM,Fischer BS,Lee FY,Shah JJ,Bertino JR,Rosenfeld J,Singh A,Khiabanian H,Pine SR

    更新日期:2017-12-01 00:00:00

  • Androgen antagonist activity by the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol in human prostate carcinoma cells.

    abstract::Antioxidants, such as vitamin E, are being investigated for efficacy in prostate cancer prevention. In this study, we show that the antioxidant moiety of vitamin E, 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), has antiandrogen activity in prostate carcinoma cells. In the presence of PMCol, the androgen-stimulated biphas...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Thompson TA,Wilding G

    更新日期:2003-08-01 00:00:00

  • Differing effects of microtubule depolymerizing and stabilizing chemotherapeutic agents on t-SNARE-mediated apical targeting of prostate-specific membrane antigen.

    abstract::Prostate-specific membrane antigen (PSMA) is a protein up-regulated in the vast majority of prostate cancers. Antibodies to PSMA have proved highly specific for prostate cancer cells, and the therapeutic potential of such antibodies is currently being assessed in clinical trials. We have previously shown that PSMA at ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0253

    authors: Christiansen JJ,Weimbs T,Bander N,Rajasekaran AK

    更新日期:2006-10-01 00:00:00

  • Generation of a canine anti-EGFR (ErbB-1) antibody for passive immunotherapy in dog cancer patients.

    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

    authors: Singer J,Fazekas J,Wang W,Weichselbaumer M,Matz M,Mader A,Steinfellner W,Meitz S,Mechtcheriakova D,Sobanov Y,Willmann M,Stockner T,Spillner E,Kunert R,Jensen-Jarolim E

    更新日期:2014-07-01 00:00:00

  • Metabolism and pharmacokinetics of the cyclin-dependent kinase inhibitor R-roscovitine in the mouse.

    abstract::R-roscovitine (seliciclib, CYC202) is a cyclin-dependent kinase inhibitor currently in phase II clinical trials in patients with cancer. Here, we describe its mouse metabolism and pharmacokinetics as well as the identification of the principal metabolites in hepatic microsomes, plasma, and urine. Following microsomal ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Nutley BP,Raynaud FI,Wilson SC,Fischer PM,Hayes A,Goddard PM,McClue SJ,Jarman M,Lane DP,Workman P

    更新日期:2005-01-01 00:00:00

  • Selenium disrupts estrogen receptor (alpha) signaling and potentiates tamoxifen antagonism in endometrial cancer cells and tamoxifen-resistant breast cancer cells.

    abstract::Tamoxifen, a selective estrogen receptor (ER) modulator, is the most widely prescribed hormonal therapy treatment for breast cancer. Despite the benefits of tamoxifen therapy, almost all tamoxifen-responsive breast cancer patients develop resistance to therapy. In addition, tamoxifen displays estrogen-like effects in ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0046

    authors: Shah YM,Al-Dhaheri M,Dong Y,Ip C,Jones FE,Rowan BG

    更新日期:2005-08-01 00:00:00

  • Discovery and development of anticancer aptamers.

    abstract::Aptamers, also termed as decoys or "chemical antibodies," represent an emerging class of therapeutics. They are short DNA or RNA oligonucleotides or peptides that assume a specific and stable three-dimensional shape in vivo, thereby providing specific tight binding to protein targets. In some cases and as opposed to a...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-06-0172

    authors: Ireson CR,Kelland LR

    更新日期:2006-12-01 00:00:00

  • The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitor.

    abstract::The FGF receptors (FGFR) are tyrosine kinases that are constitutively activated in a subset of tumors by genetic alterations such as gene amplifications, point mutations, or chromosomal translocations/rearrangements. Recently, small-molecule inhibitors that can inhibit the FGFR family as well as the VEGF receptor (VEG...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-0248

    authors: Nakanishi Y,Akiyama N,Tsukaguchi T,Fujii T,Sakata K,Sase H,Isobe T,Morikami K,Shindoh H,Mio T,Ebiike H,Taka N,Aoki Y,Ishii N

    更新日期:2014-11-01 00:00:00

  • NF-κB2/p52:c-Myc:hnRNPA1 Pathway Regulates Expression of Androgen Receptor Splice Variants and Enzalutamide Sensitivity in Prostate Cancer.

    abstract::Castration-resistant prostate cancer (CRPC) remains dependent on androgen receptor (AR) signaling. Alternative splicing of the AR to generate constitutively active, ligand-independent variants is one of the principal mechanisms that promote the development of resistance to next-generation antiandrogens such as enzalut...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-14-1057

    authors: Nadiminty N,Tummala R,Liu C,Lou W,Evans CP,Gao AC

    更新日期:2015-08-01 00:00:00

  • Optimizing the development of targeted agents in pancreatic cancer: tumor fine-needle aspiration biopsy as a platform for novel prospective ex vivo drug sensitivity assays.

    abstract::At the present time, the optimal development of molecularly targeted anticancer agents is limited by the lack of clinically applicable tools to predict drug effects. This study aimed to develop methods that might be useful in predicting the efficacy of targeted agents in a novel model system of human pancreatic cancer...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0388

    authors: Rubio-Viqueira B,Mezzadra H,Nielsen ME,Jimeno A,Zhang X,Iacobuzio-Donahue C,Maitra A,Hidalgo M,Altiok S

    更新日期:2007-02-01 00:00:00

  • Targeting the Akt/mammalian target of rapamycin pathway for radiosensitization of breast cancer.

    abstract::The phosphatidylinositol 3-kinase (PI3K)/Akt pathway is known to be activated by radiation. The mammalian target of rapamycin (mTOR) is downstream of Akt, and we investigated the effects of radiation on Akt/mTOR signaling in breast cancer cell models. RAD001 (everolimus), a potent derivative of the mTOR inhibitor rapa...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0400

    authors: Albert JM,Kim KW,Cao C,Lu B

    更新日期:2006-05-01 00:00:00