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

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Abstract

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 CD29High/CD24+/Sca1Low 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.

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Acknowledgments

The authors thank Mrs. C. Ghirelli for technical assistance, the Flow Cytometry and Cell Sorting Facility for their support in the cytofluorimetric analyses, Dr. P. Casalini for her support in the ImageJ analyses, Mrs. L. Mameli, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, for secretarial assistance and Dr. M. Borghi, Istituto Superiore di Sanità, Rome, for her contribution to the in vivo MRI study. This work was funded by grants from the Associazione Italiana Ricerca Cancro (AIRC; call 2010) 10352 to S.M. Pupa and Ministero Italiano della Salute RF-2009-1532281 to S.M. Pupa.

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Author notes

  1. Ada Koschorke, Simona Faraci, Lorenzo Castagnoli and Serenella M. Pupa contributed equally to this work.

Authors and Affiliations

  1. Molecular Targeting Unit, Department of Research, AmadeoLab, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Ada Koschorke, Simona Faraci, Debora Giani, Elda Tagliabue, Lorenzo Castagnoli & Serenella M. Pupa

  2. Molecular Immunology Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Claudia Chiodoni & Mario P. Colombo

  3. Core Facilities, NMR and MRI Unit, Istituto Superiore di Sanità, Rome, Italy

    Egidio Iorio & Rossella Canese

  4. Department of Medicine and Aging Science, Center of Excellence on Aging and Translational Medicine (CeSi-Met), G. D’Annunzio University, Chieti-Pescara, Italy

    Alessia Lamolinara & Manuela Iezzi

  5. Faculty of Health and Applied Sciences, University of the West of England, Coldharbour Lane, Frenchay, Bristol, BS16 1QY, UK

    Michael Ladomery

  6. Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Claudio Vernieri & Filippo de Braud

  7. IFOM, FIRC Institute of Molecular Oncology, Università degli Studi di Milano, Milan, Italy

    Claudio Vernieri

  8. Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy

    Filippo de Braud

  9. Unit of Immunotherapy and Anticancer Innovative Therapeutics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Massimo Di Nicola

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  1. Ada Koschorke
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  2. Simona Faraci
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Correspondence to Serenella M. Pupa.

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Supplementary Figure 1

Susceptibility of human HER2-positive BC cell lines to PEITC treatment. Cell growth of BT474, SKBR3, HCC1954, MDAMB231 and SKOV3 cell lines cultured under 2D conditions evaluated by SRB assay. MDAMB231 cell line was used as positive control for in vitro PEITC activity. Cells (3,000/well) were cultured and treated per 24, 48 and 72 h in presence of increasing concentrations of PEITC diluted in DMSO. (PDF 26 kb)

Supplementary Figure 2

Representative plots of ALDH-positive cells in BT474, SKBR3, HCC1954 and SKOV3 targets upon treatment with PEITC (12 μM) for 72 h. (PDF 231 kb)

Supplementary Figure 3

Susceptibility of MI6 cells to PEITC treatment. Cell growth of MI6 cell line cultured under 2D conditions evaluated by SRB assay. Cells (5,000/well) were cultured and treated per 24, 48 and 72 h in presence of increasing concentrations of PEITC diluted in DMSO. (PDF 102 kb)

Supplementary Figure 4

Representative images of morphology and size of MI6 mammospheres formed after 7 days in presence or not of T, PEITC and PEITC-T combination. Magnification 10X. (PDF 99 kb)

Supplementary Figure 5

Multiparametric FACS analysis of the CD29High/CD24+ SCA1Low stem cell subset in MI6 treated with DMSO, T, PEITC, and their combination (PEITC+T). (PDF 117 kb)

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Koschorke, A., Faraci, S., Giani, D. et al. Phenethyl isothiocyanate hampers growth and progression of HER2-positive breast and ovarian carcinoma by targeting their stem cell compartment. Cell Oncol. 42, 815–828 (2019). https://doi.org/10.1007/s13402-019-00464-w

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