title: EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB.
abstract: Cancer stem cells (CSC) contribute to disease progression and treatment failure in prostate cancer because of their intrinsic resistance to current therapies. The transcription factors NF-κB and STAT3 are frequently activated in advanced prostate cancer and sustain expansion of prostate CSCs. EC-70124 is a novel chimeric indolocarbazole compound generated by metabolic engineering of the biosynthetic pathways of glycosylated indolocarbazoles, such as staurosporine and rebeccamycin. In vitro kinome analyses revealed that EC-70124 acted as a multikinase inhibitor with potent activity against IKKβ and JAK2. In this study, we show that EC-70124 blocked concomitantly NF-κB and STAT3 in prostate cancer cells and particularly prostate CSCs, which exhibited overactivation of these transcription factors. Phosphorylation of IkB and STAT3 (Tyr705), the immediate targets of IKKβ and JAK2, respectively, was rapidly inhibited in vitro by EC-70124 at concentrations that were well below plasma levels in mice. Furthermore, the drug blocked activation of NF-κB and STAT3 reporters and suppressed transcription of their target genes. Treatment with EC-70124 impaired proliferation and colony formation in vitro and delayed development of prostate tumor xenografts. Notably, EC-70124 had profound effects on the prostate CSC subpopulation both in vitro and in vivo Thus, EC-70124 is a potent inhibitor of the NF-κB and STAT3 signaling pathways and blocked tumor growth and maintenance of prostate CSCs. EC-70124 may provide the basis for developing new therapeutic strategies that combine agents directed to the CSC component and the bulk tumor cell population for treatment of advanced prostate cancer. Mol Cancer Ther; 15(5); 806-18. ©2016 AACR.
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Civenni
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Longoni
authors.affiliation: Campus El Cristo, EntreChem, S.L., Edificio Científico Tecnológico, Oviedo, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Costales
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Dallavalle
authors.affiliation: Department of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: García Inclán
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland.
authors.forename: Domenico
authors.initials: D
authors.lastname: Albino
authors.affiliation: Campus El Cristo, EntreChem, S.L., Edificio Científico Tecnológico, Oviedo, Spain.
authors.forename: Luz Elena
authors.initials: LE
authors.lastname: Nuñez
authors.affiliation: Campus El Cristo, EntreChem, S.L., Edificio Científico Tecnológico, Oviedo, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Morís
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland. Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland.
authors.forename: Giuseppina M
authors.initials: GM
authors.lastname: Carbone
authors.affiliation: Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research (IOR), Bellinzona, Switzerland. Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland. Department of Oncology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland. carlo.catapano@ior.iosi.ch.
authors.forename: Carlo V
authors.initials: CV
authors.lastname: Catapano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism*; D004195:Disease Models, Animal; D006031:Glycosylation; D006801:Humans; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor