Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment.

Autor: Koschorke A; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Faraci S; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Giani D; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Chiodoni C; Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Iorio E; Core Facilities, NMR and MRI Unit, Istituto Superiore di Sanità, Rome, Italy., Canese R; Core Facilities, NMR and MRI Unit, Istituto Superiore di Sanità, Rome, Italy., Colombo MP; Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Lamolinara A; Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), G. D'Annunzio University, Chieti-Pescara, Italy., Iezzi M; Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), G. D'Annunzio University, Chieti-Pescara, Italy., Ladomery M; Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Frenchay, Bristol, BS16 1QY, UK., Vernieri C; Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; IFOM, FIRC Institute of Molecular Oncology, Università degli Studi di Milano, Milan, Italy., de Braud F; Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.; Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy., Di Nicola M; Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Tagliabue E; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Castagnoli L; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy., Pupa SM; Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. serenella.pupa@istitutotumori.mi.it.
Jazyk: angličtina
Zdroj: Cellular oncology (Dordrecht) [Cell Oncol (Dordr)] 2019 Dec; Vol. 42 (6), pp. 815-828. Date of Electronic Publication: 2019 Aug 02.
DOI: 10.1007/s13402-019-00464-w
Abstrakt: Purpose: Isothiocyanates elicit anticancer effects by targeting cancer stem cells (CSCs). Here, we tested the antitumor activity of phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive tumor models.
Methods: We assessed the in vitro anticancer activity of PEITC, alone or combined with trastuzumab, in HER2-positive BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring their sphere forming efficiency (SFE). The expression of the human/rodent CSC biomarkers aldehyde-dehydrogenase (ALDH) and CD29 High /CD24 + /Sca1 Low was evaluated by cytofluorimetric analysis. The expression of wild type HER2 (WTHER2), its splice variant d16HER2 and NOTCH was analysed by quantitative RT-PCR and Western blotting. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with MI6 tumor cells transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopy and immunohistochemistry were used to assess morpho-functional and metabolic profiles of treated versus untreated mice.
Results: We found that PEITC significantly impaired the SFE of HER2-positive human cancer cells by decreasing their ALDH-positive compartments. The anti-CSC activity of PEITC was demonstrated by a reduced expression/activation of established cancer-stemness biomarkers. Similar results were obtained with MI6 cells, where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE. We also found that PEITC hampered the in vivo growth of MI6 nodules by inducing hemorrhagic and necrotic intra-tumor areas and, in combination with trastuzumab, by significantly reducing spontaneous tumor development in d16HER2 transgenic mice.
Conclusions: Our results indicate that PEITC targets HER2-positive CSCs and that its combination with trastuzumab may pave the way for a novel therapeutic strategy for HER2-positive tumors.
Databáze: MEDLINE
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