Phenethyl isothiocyanate hampers growth and progression of HER2-positive cancer models by targeting their cancer stem cell compartment
Cellular Oncology, accepted (2019) -
Authors: Ada Koschorke, Lorenzo Castagnoli, Simona Faraci, Debora Giani, Claudia Chiodoni, Egidio Iorio Rossella Canese, Mario Paolo, Colombo Alessia, Lamolinara Manuela Iezzi Michael Ladomery ,Claudio Vernieri, M.D Filippo de Braud, M.D, Massimo Di Nicola, Elda T
Isothiocyanates produce anticancer effects by targeting cancer stem cells (CSCs). In this study we tested the antitumor activity of the phenethyl-isothiocyanate (PEITC), either alone or in combination with trastuzumab, in HER2-positive models.
We assessed the in vitro activity of PEITC and trastuzumab alone or in combination in BT474, SKBR3, HCC1954 and SKOV3 cancer cells by measuring sphere forming efficiency (SFE%). The expression of breast CSC biomarkers, ALDH and CD29High/CD24+/Sca1Low, was evaluated by FACS. Expression of full-length HER2 (WTHER2), of the d16HER2 splice variant, and NOTCH was analysed by qPCR and western blot. The in vivo activity of PEITC and trastuzumab was evaluated in mice orthotopically implanted with d16HER2-positive mammary tumor cells (MI6), transgenic for the human d16HER2 splice isoform. Magnetic resonance imaging/spectroscopyand immunohistochemistry were used to assess morphofunctional and metabolic
profiles of treated versus untreated tumors.
PEITC significantly impaired SFE% of HER2-positive human cells by decreasing their ALDH-positive compartment. The anti-BCSC activity of PEITC was demonstrated by reduced expression/activation of established cancer-stemness biomarkers including WTHER2, d16HER2, cleaved-NOTCH1 and Hes1. Similar results were observed in MI6 cells where PEITC, alone or in combination with trastuzumab, significantly inhibited their SFE%. PEITC hampered in vivo growth of MI6 nodules by increasing hemorrhagic and necrotic intra-tumor areas, and in combination with trastuzumab significantly reduced spontaneous tumor development in d16HER2 transgenic mice.
Our results provide evidence that PEITC targets HER2-positive BCSCs and that itscombination with trastuzumab