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  1. Article ; Online: Inhibition of FLT3 and PIM Kinases by EC-70124 Exerts Potent Activity in Preclinical Models of Acute Myeloid Leukemia.

    Puente-Moncada, Noelia / Costales, Paula / Antolín, Isaac / Núñez, Luz-Elena / Oro, Patricia / Hermosilla, Maria Ana / Pérez-Escuredo, Jhudit / Ríos-Lombardía, Nicolás / Sanchez-Sanchez, Ana M / Luño, Elisa / Rodríguez, Carmen / Martín, Vanesa / Morís, Francisco

    Molecular cancer therapeutics

    2018  Volume 17, Issue 3, Page(s) 614–624

    Abstract: Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target ... ...

    Abstract Internal tandem duplication (ITD) or tyrosine kinase domain mutations of FLT3 is the most frequent genetic alteration in acute myelogenous leukemia (AML) and are associated with poor disease outcome. Despite considerable efforts to develop single-target FLT3 drugs, so far, the most promising clinical response has been achieved using the multikinase inhibitor midostaurin. Here, we explore the activity of the indolocarbazole EC-70124, from the same chemical space as midostaurin, in preclinical models of AML, focusing on those bearing FLT3-ITD mutations. EC-70124 potently inhibits wild-type and mutant FLT3, and also other important kinases such as PIM kinases. EC-70124 inhibits proliferation of AML cell lines, inducing cell-cycle arrest and apoptosis. EC-70124 is orally bioavailable and displays higher metabolic stability and lower human protein plasma binding compared with midostaurin. Both
    MeSH term(s) Acute Disease ; Animals ; Biological Availability ; Caco-2 Cells ; Carbazoles/pharmacokinetics ; Carbazoles/pharmacology ; Carbazoles/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Cell Survival/genetics ; Female ; Gene Expression Regulation, Leukemic/drug effects ; HL-60 Cells ; Humans ; Indoles/pharmacokinetics ; Indoles/pharmacology ; Indoles/therapeutic use ; Leukemia, Myeloid/drug therapy ; Leukemia, Myeloid/genetics ; Leukemia, Myeloid/metabolism ; Mice, SCID ; Protein Kinase Inhibitors/pharmacokinetics ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors ; Proto-Oncogene Proteins c-pim-1/genetics ; Proto-Oncogene Proteins c-pim-1/metabolism ; THP-1 Cells ; Xenograft Model Antitumor Assays ; fms-Like Tyrosine Kinase 3/antagonists & inhibitors ; fms-Like Tyrosine Kinase 3/metabolism
    Chemical Substances Carbazoles ; EC-7012 ; Indoles ; Protein Kinase Inhibitors ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; Proto-Oncogene Proteins c-pim-1 (EC 2.7.11.1) ; proto-oncogene proteins pim (EC 2.7.11.1)
    Language English
    Publishing date 2018-01-16
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-17-0530
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: The multikinase inhibitor EC-70124 synergistically increased the antitumor activity of doxorubicin in sarcomas.

    Estupiñan, Oscar / Santos, Laura / Rodriguez, Aida / Fernandez-Nevado, Lucia / Costales, Paula / Perez-Escuredo, Jhudit / Hermosilla, Maria Ana / Oro, Patricia / Rey, Veronica / Tornin, Juan / Allonca, Eva / Fernandez-Garcia, Maria Teresa / Alvarez-Fernandez, Carlos / Braña, Alejandro / Astudillo, Aurora / Menendez, Sofia T / Moris, Francisco / Rodriguez, Rene

    International journal of cancer

    2019  Volume 145, Issue 1, Page(s) 254–266

    Abstract: Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an ... ...

    Abstract Cytotoxic drugs like doxorubicin remain as the most utilized agents in sarcoma treatment. However, advanced sarcomas are often resistant, thus stressing the need for new therapies aimed to overcome this resistance. Multikinase inhibitors provide an efficient way to target several pro-tumorigenic pathways using a single agent and may constitute a valuable strategy in the treatment of sarcomas, which frequently show an aberrant activation of pro-tumoral kinases. Therefore, we studied the antitumor activity of EC-70124, an indolocarbazole analog that have demonstrated a robust ability to inhibit a wide range of pro-survival kinases. Evaluation of the phospho-kinase profile in cell-of-origin sarcoma models and/or sarcoma primary cell lines evidenced that PI3K/AKT/mTOR, JAK/STAT or SRC were among the most highly activated pathways. In striking contrast with the structurally related drug midostaurin, EC-70124 efficiently prevented the phosphorylation of these targets and robustly inhibited proliferation through a mechanism associated to the induction of DNA damage, cell cycle arrest and apoptosis. In addition, EC-70124 was able to partially reduce tumor growth in vivo. Importantly, this compound inhibited the expression and activity of ABC efflux pumps involved in drug resistance. In line with this ability, we found that the combined treatment of EC-70124 with doxorubicin resulted in a synergistic cytotoxic effect in vitro and an increased antitumor activity of this cytotoxic drug in vivo. Altogether, these results uncover the capability of the novel multikinase inhibitor EC-70124 to counteract drug resistance in sarcoma and highlight its therapeutic potential when combined with current treatments.
    MeSH term(s) ATP-Binding Cassette Transporters/antagonists & inhibitors ; ATP-Binding Cassette Transporters/metabolism ; Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Carbazoles/pharmacology ; Doxorubicin/administration & dosage ; Doxorubicin/pharmacology ; Drug Synergism ; Female ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Sarcoma/drug therapy ; Sarcoma/enzymology ; Signal Transduction/drug effects ; Staurosporine/analogs & derivatives ; Staurosporine/pharmacology ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/metabolism ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
    Chemical Substances ATP-Binding Cassette Transporters ; Carbazoles ; Protein Kinase Inhibitors ; Doxorubicin (80168379AG) ; MTOR protein, human (EC 2.7.1.1) ; TOR Serine-Threonine Kinases (EC 2.7.1.1) ; Staurosporine (H88EPA0A3N) ; midostaurin (ID912S5VON)
    Language English
    Publishing date 2019-01-14
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 218257-9
    ISSN 1097-0215 ; 0020-7136
    ISSN (online) 1097-0215
    ISSN 0020-7136
    DOI 10.1002/ijc.32081
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 478: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (1.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 576: Show issues

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  3. Article ; Online: Inhibition of SP1 by the mithramycin analog EC-8042 efficiently targets tumor initiating cells in sarcoma.

    Tornin, Juan / Martinez-Cruzado, Lucia / Santos, Laura / Rodriguez, Aida / Núñez, Luz-Elena / Oro, Patricia / Hermosilla, Maria Ana / Allonca, Eva / Fernández-García, Maria Teresa / Astudillo, Aurora / Suarez, Carlos / Morís, Francisco / Rodriguez, Rene

    Oncotarget

    2016  Volume 7, Issue 21, Page(s) 30935–30950

    Abstract: Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and ... ...

    Abstract Tumor initiating cells (TICs), responsible for tumor initiation, and cancer stem cells (CSCs), responsible for tumor expansion and propagation, are often resistant to chemotherapeutic agents. To find therapeutic targets against sarcoma initiating and propagating cells we used models of myxoid liposarcoma (MLS) and undifferentiated pleomorphic sarcoma (UPS) developed from human mesenchymal stromal/stem cells (hMSCs), which constitute the most likely cell-of-origin for sarcoma. We found that SP1-mediated transcription was among the most significantly altered signaling. To inhibit SP1 activity, we used EC-8042, a mithramycin (MTM) analog (mithralog) with enhanced anti-tumor activity and highly improved safety. EC-8042 inhibited the growth of TIC cultures, induced cell cycle arrest and apoptosis and upregulated the adipogenic factor CEBPα. SP1 knockdown was able to mimic the anti-proliferative effects induced by EC-8042. Importantly, EC-8042 was not recognized as a substrate by several ABC efflux pumps involved in drug resistance, and, opposite to the chemotherapeutic drug doxorubicin, repressed the expression of many genes responsible for the TIC/CSC phenotype, including SOX2, C-MYC, NOTCH1 and NFκB1. Accordingly, EC-8042, but not doxorubicin, efficiently reduced the survival of CSC-enriched tumorsphere sarcoma cultures. In vivo, EC-8042 induced a profound inhibition of tumor growth associated to a strong reduction of the mitotic index and the induction of adipogenic differentiation and senescence. Finally, EC-8042 reduced the ability of tumor cells to reinitiate tumor growth. These data suggest that EC-8042 could constitute an effective treatment against both TIC and CSC subpopulations in sarcoma.
    MeSH term(s) ATP-Binding Cassette Transporters/metabolism ; Animals ; Antineoplastic Agents/pharmacokinetics ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Cell Cycle Checkpoints/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/pharmacokinetics ; Drug Resistance, Neoplasm ; Female ; Fluorescent Antibody Technique ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice, Inbred NOD ; Mice, SCID ; NF-kappa B p50 Subunit/metabolism ; Neoplastic Stem Cells/drug effects ; Plicamycin/analogs & derivatives ; Plicamycin/pharmacokinetics ; Plicamycin/therapeutic use ; Proto-Oncogene Proteins c-myc/metabolism ; Receptor, Notch1/metabolism ; SOXB1 Transcription Factors/metabolism ; Sarcoma, Experimental/drug therapy ; Sarcoma, Experimental/genetics ; Sarcoma, Experimental/metabolism ; Signal Transduction/drug effects ; Sp1 Transcription Factor/metabolism ; Xenograft Model Antitumor Assays
    Chemical Substances ATP-Binding Cassette Transporters ; Antineoplastic Agents ; MYC protein, human ; NF-kappa B p50 Subunit ; NFKB1 protein, human ; NOTCH1 protein, human ; Proto-Oncogene Proteins c-myc ; Receptor, Notch1 ; SOX2 protein, human ; SOXB1 Transcription Factors ; Sp1 Transcription Factor ; SP1 protein, human ; demycarosyl-3D-digitoxosylmithramycin SK ; Doxorubicin (80168379AG) ; Plicamycin (NIJ123W41V)
    Language English
    Publishing date 2016-04-19
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2560162-3
    ISSN 1949-2553 ; 1949-2553
    ISSN (online) 1949-2553
    ISSN 1949-2553
    DOI 10.18632/oncotarget.8817
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042.

    Hermida-Prado, Francisco / Villaronga, M Ángeles / Granda-Díaz, Rocío / Del-Río-Ibisate, Nagore / Santos, Laura / Hermosilla, Maria Ana / Oro, Patricia / Allonca, Eva / Agorreta, Jackeline / Garmendia, Irati / Tornín, Juan / Perez-Escuredo, Jhudit / Fuente, Rocío / Montuenga, Luis M / Morís, Francisco / Rodrigo, Juan P / Rodríguez, René / García-Pedrero, Juana M

    Journal of clinical medicine

    2019  Volume 8, Issue 8

    Abstract: The frequent dysregulation of SRC family kinases (SFK) in multiple cancers prompted various inhibitors to be actively tested in preclinical and clinical trials. Disappointingly, dasatinib and saracatinib failed to demonstrate monotherapeutic efficacy in ... ...

    Abstract The frequent dysregulation of SRC family kinases (SFK) in multiple cancers prompted various inhibitors to be actively tested in preclinical and clinical trials. Disappointingly, dasatinib and saracatinib failed to demonstrate monotherapeutic efficacy in patients with head and neck squamous cell carcinomas (HNSCC). Deeper functional and mechanistic knowledge of the actions of these drugs is therefore needed to improve clinical outcome and to develop more efficient combinational strategies. Even though the SFK inhibitors dasatinib and saracatinib robustly blocked cell migration and invasion in HNSCC cell lines, this study unveils undesirable stem cell-promoting functions that could explain the lack of clinical efficacy in HNSCC patients. These deleterious effects were targeted by the mithramycin analog EC-8042 that efficiently eliminated cancer stem cells (CSC)-enriched tumorsphere cultures as well as tumor bulk cells and demonstrated potent antitumor activity in vivo. Furthermore, combination treatment of dasatinib with EC-8042 provided favorable complementary anti-proliferative, anti-invasive, and anti-CSC functions without any noticeable adverse interactions of both agents. These findings strongly support combinational strategies with EC-8042 for clinical testing in HNSCC patients. These data may have implications on ongoing dasatinib-based trials.
    Language English
    Publishing date 2019-08-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662592-1
    ISSN 2077-0383
    ISSN 2077-0383
    DOI 10.3390/jcm8081157
    Database MEDical Literature Analysis and Retrieval System OnLINE

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