4.6 Article

Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

期刊

CANCERS
卷 11, 期 9, 页码 -

出版社

MDPI
DOI: 10.3390/cancers11091224

关键词

testicular germ cell tumors; embryonal carcinoma; chemoresistance; cisplatin; cancer stem cell markers

类别

资金

  1. Slovak Research and Development Agency [APVV-15-0086, APVV-15-0697, APVV-16-0178]
  2. Scientific Grant Agency of The Ministry of Education, Science, Research and Sport of the Slovak Republic [VEGA 1/0043/18]
  3. Ministry of Health of the Slovak Republic [2018/39-LFUK-13]
  4. Cancer Research Foundation
  5. League against Cancer

向作者/读者索取更多资源

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.

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