2. Academic Validation
  3. Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation

Inhibitory effect on ovarian cancer ALDH+ stem-like cells by Disulfiram and Copper treatment through ALDH and ROS modulation

  • Biomed Pharmacother. 2019 Oct;118:109371. doi: 10.1016/j.biopha.2019.109371.
Fang Guo 1,  Zhi Yang 1,  Hagen Kulbe 1,  Andreas E Albers 2,  Jalid Sehouli 1,  Andreas M Kaufmann 3
Affiliations

Affiliations

  • 1 Clinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • 2 Department of Otolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.
  • 3 Clinic for Gynecology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany. Electronic address: [email protected].
PMID: 31545281 DOI: 10.1016/j.biopha.2019.109371
Abstract

Background: Disulfiram (DSF) is a drug used for treatment of alcoholism that has also displayed promising anti-cancer activity. It unfolds its effects by inhibiting the Enzyme activity of aldehyde dehydrogenase (ALDH) isoforms.

Methods: MTT assay, spheroid formation, clonogenicity assay, qRT-PCR, and ALDH Enzyme activity analysis were performed using ovarian Cancer cell lines IGROV1, SKOV3 and SKOV3IP1. Cell cycle analyses and measurement of intracellular Reactive Oxygen Species (ROS) were carried out by flow cytometry. ALDH+ and ALDH- cells were isolated by FACS sorting.

Results: ALDH activity was inhibited in ovarian Cancer Stem Cells (the proportion of ALDH+ cells was reduced from 21.7% to 0.391%, 8.4% to 0%, 6.88% to 0.05% in cell lines IGROV1, SKOV3, and SKOV3IP1, respectively). DSF with or without the cofactor copper (Cu2+) exhibited cytotoxicity dose- and time-dependent and enhanced cisplatin-induced Apoptosis. DSF + Cu2+ increased intracellular ROS levels triggering Apoptosis of ovarian Cancer Stem Cells (CSC). Significantly more colony and spheroid formation was observed in ALDH+ compared with ALDH- cells (P < 0.01). Moreover, ALDH+ cells were more resistant to cisplatin treatment compared with ALDH-cells (P < 0.05) and also exhibited a lower basal level of ROS. However, no significant difference in ROS accumulation nor in cellular viability was observed in ALDH + cells in comparison to ALDH- cells after pre-treatment with DSF (0.08 μM).

Conclusion: Our findings provide evidence that DSF might be employed as a novel adjuvant chemotherapeutic agent in combination with cisplatin for treatment of ovarian Cancer.

Keywords

ALDH enzyme activity; Adjuvant chemotherapy; Cellular apoptosis; Cytotoxicity; Novel chemotherapeutic agent.

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