Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance.

Abstract:

:Imatinib mesylate is a potent, molecularly targeted therapy against the oncogenic tyrosine kinase BCR-ABL. Although imatinib mesylate has considerable efficacy against chronic myeloid leukemia (CML), advanced-stage CML patients frequently become refractory to this agent. The bone marrow is the predominant microenvironment of CML and is a rich source of both soluble factors and extracellular matrices, which may influence drug response. To address the influence of the bone marrow microenvironment on imatinib mesylate sensitivity, we used an in vitro bone marrow stroma model. Our data show culturing K562 cells, in bone marrow stroma-derived conditioned medium (CM), is sufficient to cause resistance to BCR-ABL inhibitors. Drug resistance correlated with increased pTyrStat3, whereas no increases in pTyrStat5 was noted. Moreover, resistance was associated with increased levels of the Stat3 target genes Bcl-xl, Mcl-1, and survivin. Finally, reducing Stat3 levels with small interfering RNA sensitized K562 cells cultured in CM to imatinib mesylate-induced cell death. Importantly, Stat3 dependency was specific for cells grown in CM, as reducing Stat3 levels in regular growth conditions had no effect on imatinib mesylate sensitivity. Together, these data support a novel mechanism of BCR-ABL-independent imatinib mesylate resistance and provides preclinical rationale for using Stat3-inhibitors to increase the efficacy of imatinib mesylate within the context of the bone marrow microenvironment.

journal_name

Mol Cancer Ther

authors

Bewry NN,Nair RR,Emmons MF,Boulware D,Pinilla-Ibarz J,Hazlehurst LA

doi

10.1158/1535-7163.MCT-08-0314

subject

Has Abstract

pub_date

2008-10-01 00:00:00

pages

3169-75

issue

10

eissn

1535-7163

issn

1538-8514

pii

7/10/3169

journal_volume

7

pub_type

杂志文章
  • Preclinical evaluation of 213Bi-labeled plasminogen activator inhibitor type 2 in an orthotopic murine xenogenic model of human breast carcinoma.

    abstract::Tumor-associated urokinase plasminogen activator (uPA) is a critical marker of invasion and metastasis, has strong prognostic relevance, and is thus a potential therapeutic target. Experimental data published to date has established the proof-of-principle of uPA targeting by (213)Bi-labeled plasminogen activator inhib...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0264

    authors: Stutchbury TK,Al-Ejeh F,Stillfried GE,Croucher DR,Andrews J,Irving D,Links M,Ranson M

    更新日期:2007-01-01 00:00:00

  • Nitric oxide initiates progression of human melanoma via a feedback loop mediated by apurinic/apyrimidinic endonuclease-1/redox factor-1, which is inhibited by resveratrol.

    abstract::It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Measurement of proliferative and metastatic capacity by MTS and Matrigel invasion assays, respectively, was done and showed that NO-treated melanoma cells exhibited a higher capacity compared with control, especially met...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-08-0562

    authors: Yang Z,Yang S,Misner BJ,Chiu R,Liu F,Meyskens FL Jr

    更新日期:2008-12-01 00:00:00

  • Extrinsic pathway- and cathepsin-dependent induction of mitochondrial dysfunction are essential for synergistic flavopiridol and vorinostat lethality in breast cancer cells.

    abstract::The present studies have determined whether interactions between the cyclin-dependent kinase inhibitor flavopiridol and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA; vorinostat; Zolinza) occur in breast cancer cells. MDA-MB-231 and MCF7 cells were treated with flavopiridol (25-100 nmol/L) an...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0561

    authors: Mitchell C,Park MA,Zhang G,Yacoub A,Curiel DT,Fisher PB,Roberts JD,Grant S,Dent P

    更新日期:2007-12-01 00:00:00

  • Combination drug scheduling defines a "window of opportunity" for chemopotentiation of gemcitabine by an orally bioavailable, selective ChK1 inhibitor, GNE-900.

    abstract::Checkpoint kinase 1 (ChK1) is a serine/threonine kinase that functions as a central mediator of the intra-S and G2-M cell-cycle checkpoints. Following DNA damage or replication stress, ChK1-mediated phosphorylation of downstream effectors delays cell-cycle progression so that the damaged genome can be repaired. As a t...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-12-1218

    authors: Blackwood E,Epler J,Yen I,Flagella M,O'Brien T,Evangelista M,Schmidt S,Xiao Y,Choi J,Kowanetz K,Ramiscal J,Wong K,Jakubiak D,Yee S,Cain G,Gazzard L,Williams K,Halladay J,Jackson PK,Malek S

    更新日期:2013-10-01 00:00:00

  • A urokinase-activated recombinant anthrax toxin is selectively cytotoxic to many human tumor cell types.

    abstract::Urokinase plasminogen activator (uPA) is a tumor-specific protease highly expressed in several types of solid tumors and rarely present on normal cells under physiologic conditions. Due to its high expression on metastatic tumors, several different strategies have been used to target the urokinase system. These have m...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0315

    authors: Abi-Habib RJ,Singh R,Liu S,Bugge TH,Leppla SH,Frankel AE

    更新日期:2006-10-01 00:00:00

  • SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility.

    abstract::Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-beta(2) ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effect...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Hjelmeland MD,Hjelmeland AB,Sathornsumetee S,Reese ED,Herbstreith MH,Laping NJ,Friedman HS,Bigner DD,Wang XF,Rich JN

    更新日期:2004-06-01 00:00:00

  • 1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes inhibit colon cancer cell and tumor growth through PPARgamma-dependent and PPARgamma-independent pathways.

    abstract::1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing p-trifluoromethyl, t-butyl, and phenyl [1,1-bis(3'-indolyl)-1-(p-phenyl)methane (DIM-C-pPhC(6)H(5))] substituents induce peroxisome proliferator-activated receptor gamma (PPARgamma)-mediated transactivation in SW480 colon cancer cells. These PPARgamma-act...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0002

    authors: Chintharlapalli S,Papineni S,Safe S

    更新日期:2006-05-01 00:00:00

  • A Spatio-Temporal Model of Macrophage-Mediated Drug Resistance in Glioma Immunotherapy.

    abstract::The emergence of drug resistance is often an inevitable obstacle that limits the long-term effectiveness of clinical cancer chemotherapeutics. Although various forms of cancer cell-intrinsic mechanisms of drug resistance have been experimentally revealed, the role and the underlying mechanism of tumor microenvironment...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0634

    authors: Zheng Y,Bao J,Zhao Q,Zhou T,Sun X

    更新日期:2018-04-01 00:00:00

  • Cell-penetrating TAT-FOXO3 fusion proteins induce apoptotic cell death in leukemic cells.

    abstract::FOXO proteins are Akt-regulated transcription factors involved in the control of cell cycle, DNA repair, stress defense, apoptosis, and tumor suppression. We reported that plasmid-based overexpression of constitutively active FOXO3 in cells from chronic lymphocytic leukemia (CLL) reduced their survival, suggesting tha...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0482

    authors: Essafi M,Baudot AD,Mouska X,Cassuto JP,Ticchioni M,Deckert M

    更新日期:2011-01-01 00:00:00

  • Cyclophosphamide-Mediated Tumor Priming for Enhanced Delivery and Antitumor Activity of HER2-Targeted Liposomal Doxorubicin (MM-302).

    abstract::Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody-liposomal drug conjugate designed to deliver doxoru...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-15-0314

    authors: Geretti E,Leonard SC,Dumont N,Lee H,Zheng J,De Souza R,Gaddy DF,Espelin CW,Jaffray DA,Moyo V,Nielsen UB,Wickham TJ,Hendriks BS

    更新日期:2015-09-01 00:00:00

  • Interstitial gene delivery in human xenograft prostate tumors using titanium metal seeds.

    abstract::Gene therapy is a promising approach for the treatment of cancers. Strategies for gene vector delivery include systemic and local-regional approaches. Intratumoral delivery of vectors has generally employed direct injections into single or multiple locations throughout the tumor volume. However, this approach leads to...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Jung M,Zhang Y,Dimtchev A,Subramanian MR,Suthanthiran K,Dritschilo A

    更新日期:2004-06-01 00:00:00

  • From NPC therapeutic target identification to potential treatment strategy.

    abstract::Nasopharyngeal carcinoma (NPC) is relatively rare in Western countries but is a common cancer in southern Asia. Many differentially expressed genes have been linked to NPC; however, how to prioritize therapeutic targets and potential drugs from unsorted gene lists remains largely unknown. We first collected 558 upregu...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-09-0966

    authors: Lan MY,Chen CL,Lin KT,Lee SA,Yang WL,Hsu CN,Wu JC,Ho CY,Lin JC,Huang CY

    更新日期:2010-09-01 00:00:00

  • Cell Death Induced by Cationic Amphiphilic Drugs Depends on Lysosomal Ca2+ Release and Cyclic AMP.

    abstract::Repurposing cationic amphiphilic drugs (CAD) for cancer treatment is emerging as an attractive means to enhance the efficacy of chemotherapy. Many commonly used CADs, including several cation amphiphilic antihistamines and antidepressants, induce cancer-specific, lysosome-dependent cell death and sensitize cancer cell...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-18-1406

    authors: Anand A,Liu B,Dicroce Giacobini J,Maeda K,Rohde M,Jäättelä M

    更新日期:2019-09-01 00:00:00

  • GPR54 is a target for suppression of metastasis in endometrial cancer.

    abstract::Invasion into deep myometrium and/or lymphovascular space is a well-known risk factor for endometrial cancer metastasis, resulting in poor prognosis. It is therefore clinically important to identify novel molecules that suppress tumor invasion. Reduced expression of the metastasis suppressor, kisspeptin (KISS1), and i...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-10-0763

    authors: Kang HS,Baba T,Mandai M,Matsumura N,Hamanishi J,Kharma B,Kondoh E,Yoshioka Y,Oishi S,Fujii N,Murphy SK,Konishi I

    更新日期:2011-04-01 00:00:00

  • UPARANT: a urokinase receptor-derived peptide inhibitor of VEGF-driven angiogenesis with enhanced stability and in vitro and in vivo potency.

    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

    authors: Carriero MV,Bifulco K,Minopoli M,Lista L,Maglio O,Mele L,Di Carluccio G,De Rosa M,Pavone V

    更新日期:2014-05-01 00:00:00

  • Characterization of the cellular and antitumor effects of MPI-0479605, a small-molecule inhibitor of the mitotic kinase Mps1.

    abstract::Mps1 is a dual specificity protein kinase that is essential for the bipolar attachment of chromosomes to the mitotic spindle and for maintaining the spindle assembly checkpoint until all chromosomes are properly attached. Mps1 is expressed at high levels during mitosis and is abundantly expressed in cancer cells. Disr...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-11-0453

    authors: Tardif KD,Rogers A,Cassiano J,Roth BL,Cimbora DM,McKinnon R,Peterson A,Douce TB,Robinson R,Dorweiler I,Davis T,Hess MA,Ostanin K,Papac DI,Baichwal V,McAlexander I,Willardsen JA,Saunders M,Christophe H,Kumar DV,Wet

    更新日期:2011-12-01 00:00:00

  • Superior antitumor activity of a novel bispecific antibody cotargeting human epidermal growth factor receptor 2 and type I insulin-like growth factor receptor.

    abstract::The humanized anti-HER2 monoclonal antibody (mAb) trastuzumab (Herceptin; Genentech) effectively inhibits human epidermal growth factor receptor 2 (HER2)-positive breast tumors. However, many patients responding to treatment often develop resistance. Cross-talk between type I insulin-like growth factor receptor (IGF-I...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0558

    authors: Chen C,Zhang Y,Zhang Y,Li J,Tsao SW,Zhang MY

    更新日期:2014-01-01 00:00:00

  • Radiosensitization In Vivo by Histone Deacetylase Inhibition with No Increase in Early Normal Tissue Radiation Toxicity.

    abstract::As the population ages, more elderly patients require radiotherapy-based treatment for their pelvic malignancies, including muscle-invasive bladder cancer, as they are unfit for major surgery. Therefore, there is an urgent need to find radiosensitizing agents minimally toxic to normal tissues, including bowel and blad...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-17-0011

    authors: Groselj B,Ruan JL,Scott H,Gorrill J,Nicholson J,Kelly J,Anbalagan S,Thompson J,Stratford MRL,Jevons SJ,Hammond EM,Scudamore CL,Kerr M,Kiltie AE

    更新日期:2018-02-01 00:00:00

  • Fasudil inhibits vascular endothelial growth factor-induced angiogenesis in vitro and in vivo.

    abstract::Vascular endothelial growth factor (VEGF)-induced endothelial cell migration is an important component of tumor angiogenesis. Rho and Rho-associated kinase (ROCK) are key regulators of focal adhesion, stress fiber formation, and thus cell motility. Inhibitors of this pathway have been shown to inhibit endothelial cell...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-06-0689

    authors: Yin L,Morishige K,Takahashi T,Hashimoto K,Ogata S,Tsutsumi S,Takata K,Ohta T,Kawagoe J,Takahashi K,Kurachi H

    更新日期:2007-05-01 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

  • Zoledronic acid inhibits osteosarcoma growth in an orthotopic model.

    abstract::Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There ...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-07-0546

    authors: Dass CR,Choong PF

    更新日期:2007-12-01 00:00:00

  • Butyric acid prodrugs are histone deacetylase inhibitors that show antineoplastic activity and radiosensitizing capacity in the treatment of malignant gliomas.

    abstract::Histone modification has emerged as a promising approach to cancer therapy. We explored the efficacy of a novel class of histone deacetylase inhibitors in the treatment of malignant gliomas. Treatment of glioma cell lines with two butyric acid derivatives, pivaloylomethyl butyrate (AN-9) and butyroyloxymethyl butyrate...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0087

    authors: Entin-Meer M,Rephaeli A,Yang X,Nudelman A,VandenBerg SR,Haas-Kogan DA

    更新日期:2005-12-01 00:00:00

  • Z-FA-fmk inhibits effector caspases but not initiator caspases 8 and 10, and demonstrates that novel anticancer retinoid-related molecules induce apoptosis via the intrinsic pathway.

    abstract::Synthetic retinoid-related molecules (RRMs) have been described that show strong antiproliferative activity and induce apoptosis in cancer cells. These RRMs induce caspase activity independently of the retinoid receptors in Jurkat T cells. We observed that the inhibitor of cathepsins B and L Z-FA-fmk blocks the induct...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:

    authors: Lopez-Hernandez FJ,Ortiz MA,Bayon Y,Piedrafita FJ

    更新日期:2003-03-01 00:00:00

  • Preclinical Characterization of Linrodostat Mesylate, a Novel, Potent, and Selective Oral Indoleamine 2,3-Dioxygenase 1 Inhibitor.

    abstract::Tumors can exploit the indoleamine 2,3-dioxygenase 1 (IDO1) pathway to create an immunosuppressive microenvironment. Activated IDO1 metabolizes tryptophan into immunosuppressive kynurenine, leading to suppressed effector T-cell (Teff) proliferation, allowing for tumor escape from host immune surveillance. IDO1 inhibit...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-20-0251

    authors: Balog A,Lin TA,Maley D,Gullo-Brown J,Kandoussi EH,Zeng J,Hunt JT

    更新日期:2020-12-09 00:00:00

  • A novel antisense oligonucleotide inhibiting several antiapoptotic Bcl-2 family members induces apoptosis and enhances chemosensitivity in androgen-independent human prostate cancer PC3 cells.

    abstract::Bcl-2 and Bcl-xL are associated with treatment resistance and progression in many cancers, including prostate cancer. The objective of this study was to determine whether a novel bispecific antisense oligonucleotide targeting both Bcl-2 and Bcl-xL induces apoptosis and enhances chemosensitivity in androgen-independent...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-05-0064

    authors: Yamanaka K,Rocchi P,Miyake H,Fazli L,Vessella B,Zangemeister-Wittke U,Gleave ME

    更新日期:2005-11-01 00:00:00

  • HGF as a circulating biomarker of onartuzumab treatment in patients with advanced solid tumors.

    abstract::The objective of this study was to evaluate circulating hepatocyte growth factor (cHGF) as a pharmacodynamic biomarker of Met inhibition for onartuzumab (MetMAb, OA5D5v2) in a phase I trial in patients with advanced cancers and a phase II trial in non-small cell lung cancer (NSCLC). The phase I study was a dose escala...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,随机对照试验

    doi:10.1158/1535-7163.MCT-13-0015

    authors: Penuel E,Li C,Parab V,Burton L,Cowan KJ,Merchant M,Yauch RL,Patel P,Peterson A,Hampton GM,Lackner MR,Hegde PS

    更新日期:2013-06-01 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

  • Targeting multiple key signaling pathways in melanoma using leelamine.

    abstract::Melanoma is a highly drug-resistant cancer with resistance developing to agents targeting single proteins. To circumvent this problem, a new class of agent inhibiting multiple key pathways important in this disease is being developed to reduce the likelihood of developing resistant disease. The phosphoinositide 3-kina...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-13-0867

    authors: Gowda R,Madhunapantula SV,Kuzu OF,Sharma A,Robertson GP

    更新日期:2014-07-01 00:00:00

  • Monoclonal Antibody Targeting Sialyl-di-Lewisa-Containing Internalizing and Noninternalizing Glycoproteins with Cancer Immunotherapy Development Potential.

    abstract::Tumor glycans constitute attractive targets for therapeutic antibodies. The sialylated glycocalyx plays a prominent role in cancer progression and immune evasion. Here, we describe the characterization of the mAb, FG129, which targets tumor-associated sialylated glycan, and demonstrate its potential for multimodal can...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章

    doi:10.1158/1535-7163.MCT-19-0221

    authors: Tivadar ST,McIntosh RS,Chua JX,Moss R,Parsons T,Zaitoun AM,Madhusudan S,Durrant LG,Vankemmelbeke M

    更新日期:2020-03-01 00:00:00

  • Targeting STAT3 with Proteolysis Targeting Chimeras and Next-Generation Antisense Oligonucleotides.

    abstract::STAT3 has been recognized for its key role in the progression of cancer, where it is frequently upregulated or constitutively hyperactivated, contributing to tumor cell proliferation, survival, and migration, as well as angiogenesis and suppression of antitumor immunity. Given the ubiquity of dysregulated STAT3 activi...

    journal_title:Molecular cancer therapeutics

    pub_type: 杂志文章,评审

    doi:10.1158/1535-7163.MCT-20-0599

    authors: Shiah JV,Grandis JR,Johnson DE

    更新日期:2020-11-17 00:00:00