Cancer stem cells (CSCs) 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.
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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 multi-kinase 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 over-activation 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.
Molecular cancer therapeutics. 2016 Jan 29 [Epub ahead of print]
Gianluca Civenni, Nicole Longoni, Paula Costales, Cecilia Dallavalle, Cristina García Inclán, Domenico Albino, Luz Elena Núñez, Francisco Moris, Giuseppina M Carbone, Carlo V Catapano
Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research. , Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research. , EntreChem, S. L. , Edificio Científico Tecnológico. , Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research. , Deptartment of Otolaryngology, IUOPA, Hospital Universitario Central de Asturias. , Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research. , EntreChem SL, Edificio Científico Tecnológico. , EntreChem SL. , Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research. , 1Tumor Biology and Experimental Therapeutics Program, Institute of Oncology Research