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Open AccessArticle

Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

1
Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia
2
Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Klenova 1, 833 10 Bratislava, Slovakia
3
Translational Research Unit, Faculty of Medicine, Comenius University, Klenova 1, 833 10 Bratislava, Slovakia
4
Department of Pathology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
5
Department of Oncology, Faculty of Medicine, Comenius University and St. Elisabeth Cancer Institute, Kolarska 12, 812 50 Bratislava, Slovakia
*
Author to whom correspondence should be addressed.
These authors share the first authorship.
Both authors should be considered as senior authors.
Cancers 2019, 11(9), 1224; https://doi.org/10.3390/cancers11091224
Received: 2 July 2019 / Revised: 20 August 2019 / Accepted: 20 August 2019 / Published: 22 August 2019
Cisplatin resistance in testicular germ cell tumors (TGCTs) is a clinical challenge. We investigated the underlying mechanisms associated with cancer stem cell (CSC) markers and modalities circumventing the chemoresistance. Chemoresistant models (designated as CisR) of human embryonal carcinoma cell lines NTERA-2 and NCCIT were derived and characterized using flow cytometry, gene expression, functional and protein arrays. Tumorigenicity was determined on immunodeficient mouse model. Disulfiram was used to examine chemosensitization of resistant cells. ALDH1A3 isoform expression was evaluated by immunohistochemistry in 216 patients’ tissue samples. Chemoresistant cells were significantly more resistant to cisplatin, carboplatin and oxaliplatin compared to parental cells. NTERA-2 CisR cells exhibited altered morphology and increased tumorigenicity. High ALDH1A3 expression and increased ALDH activity were detected in both refractory cell lines. Disulfiram in combination with cisplatin showed synergy for NTERA-2 CisR and NCCIT CisR cells and inhibited growth of NTERA-2 CisR xenografts. Significantly higher ALDH1A3 expression was detected in TGCTs patients’ tissue samples compared to normal testicular tissue. We characterized novel clinically relevant model of chemoresistant TGCTs, for the first time identified the ALDH1A3 as a therapeutic target in TGCTs and more importantly, showed that disulfiram represents a viable treatment option for refractory TGCTs. View Full-Text
Keywords: testicular germ cell tumors; embryonal carcinoma; chemoresistance; cisplatin; cancer stem cell markers testicular germ cell tumors; embryonal carcinoma; chemoresistance; cisplatin; cancer stem cell markers
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Schmidtova, S.; Kalavska, K.; Gercakova, K.; Cierna, Z.; Miklikova, S.; Smolkova, B.; Buocikova, V.; Miskovska, V.; Durinikova, E.; Burikova, M.; Chovanec, M.; Matuskova, M.; Mego, M.; Kucerova, L. Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells. Cancers 2019, 11, 1224.

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