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Disulfiram Overcomes Cisplatin Resistance in Human Embryonal Carcinoma Cells

Silvia Schmidtova1, Katarina Kalavska2,3,4, Katarina Gercakova2

  • 1Cancer Research Institute, Biomedical Research Center, University Science Park for Biomedicine, Slovak Academy of Sciences, Dubravska cesta 9, 845 05 Bratislava, Slovakia. silvia.schmidtova@savba.sk.

Cancers
|August 25, 2019
PubMed

Insights

Cisplatin resistance in testicular germ cell tumors is a challenge. Researchers identified ALDH1A3 as a therapeutic target and found disulfiram effective in overcoming chemoresistance in these cancers.

Area of Science:

  • Oncology
  • Cancer Research
  • Pharmacology

Background:

  • Cisplatin resistance presents a significant clinical challenge in treating testicular germ cell tumors (TGCTs).
  • Cancer stem cell (CSC) markers are implicated in chemoresistance, necessitating investigation into novel therapeutic strategies.
  • Understanding the mechanisms of chemoresistance is crucial for developing effective treatments for refractory TGCTs.

Purpose of the Study:

  • To investigate mechanisms of cisplatin resistance in TGCTs, focusing on cancer stem cell markers.
  • To identify potential therapeutic targets and modalities to overcome chemoresistance in TGCTs.
  • To evaluate disulfiram as a chemosensitizing agent in cisplatin-resistant TGCT models.

Main Methods:

  • Development and characterization of cisplatin-resistant (CisR) TGCT cell lines (NTERA-2, NCCIT) using flow cytometry, gene expression, and protein arrays.
  • Assessment of tumorigenicity in immunodeficient mouse models.
  • Evaluation of ALDH1A3 expression via immunohistochemistry in 216 patient samples and in vitro assays.
  • Testing the synergistic effect of disulfiram and cisplatin on resistant cells and xenografts.

Main Results:

  • CisR cells exhibited significantly increased resistance to platinum-based chemotherapeutics (cisplatin, carboplatin, oxaliplatin).
  • NTERA-2 CisR cells showed altered morphology, increased tumorigenicity, high ALDH1A3 expression, and elevated ALDH activity.
  • Disulfiram combined with cisplatin demonstrated synergistic effects in resistant cell lines and inhibited xenograft growth.
  • Elevated ALDH1A3 expression was observed in TGCT patient tissues compared to normal testicular tissue.

Conclusions:

  • A novel, clinically relevant model of chemoresistant TGCTs was characterized.
  • ALDH1A3 was identified as a potential therapeutic target for overcoming cisplatin resistance in TGCTs.
  • Disulfiram represents a promising treatment option for patients with refractory TGCTs, particularly in combination with cisplatin.
Keywords:
cancer stem cell markerschemoresistancecisplatinembryonal carcinomatesticular germ cell tumors

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