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Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin
Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms i...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139527/ https://www.ncbi.nlm.nih.gov/pubmed/32155756 http://dx.doi.org/10.3390/cancers12030608 |
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author | Mariniello, Marta Petruzzelli, Raffaella Wanderlingh, Luca G. La Montagna, Raffaele Carissimo, Annamaria Pane, Francesca Amoresano, Angela Ilyechova, Ekaterina Y. Galagudza, Michael M. Catalano, Federico Crispino, Roberta Puchkova, Ludmila V. Medina, Diego L. Polishchuk, Roman S. |
author_facet | Mariniello, Marta Petruzzelli, Raffaella Wanderlingh, Luca G. La Montagna, Raffaele Carissimo, Annamaria Pane, Francesca Amoresano, Angela Ilyechova, Ekaterina Y. Galagudza, Michael M. Catalano, Federico Crispino, Roberta Puchkova, Ludmila V. Medina, Diego L. Polishchuk, Roman S. |
author_sort | Mariniello, Marta |
collection | PubMed |
description | Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy. |
format | Online Article Text |
id | pubmed-7139527 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-71395272020-04-10 Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin Mariniello, Marta Petruzzelli, Raffaella Wanderlingh, Luca G. La Montagna, Raffaele Carissimo, Annamaria Pane, Francesca Amoresano, Angela Ilyechova, Ekaterina Y. Galagudza, Michael M. Catalano, Federico Crispino, Roberta Puchkova, Ludmila V. Medina, Diego L. Polishchuk, Roman S. Cancers (Basel) Article Tumor resistance to chemotherapy represents an important challenge in modern oncology. Although platinum (Pt)-based drugs have demonstrated excellent therapeutic potential, their effectiveness in a wide range of tumors is limited by the development of resistance mechanisms. One of these mechanisms includes increased cisplatin sequestration/efflux by the copper-transporting ATPase, ATP7B. However, targeting ATP7B to reduce Pt tolerance in tumors could represent a serious risk because suppression of ATP7B might compromise copper homeostasis, as happens in Wilson disease. To circumvent ATP7B-mediated Pt tolerance we employed a high-throughput screen (HTS) of an FDA/EMA-approved drug library to detect safe therapeutic molecules that promote cisplatin toxicity in the IGROV-CP20 ovarian carcinoma cells, whose resistance significantly relies on ATP7B. Using a synthetic lethality approach, we identified and validated three hits (Tranilast, Telmisartan, and Amphotericin B) that reduced cisplatin resistance. All three drugs induced Pt-mediated DNA damage and inhibited either expression or trafficking of ATP7B in a tumor-specific manner. Global transcriptome analyses showed that Tranilast and Amphotericin B affect expression of genes operating in several pathways that confer tolerance to cisplatin. In the case of Tranilast, these comprised key Pt-transporting proteins, including ATOX1, whose suppression affected ability of ATP7B to traffic in response to cisplatin. In summary, our findings reveal Tranilast, Telmisartan, and Amphotericin B as effective drugs that selectively promote cisplatin toxicity in Pt-resistant ovarian cancer cells and underscore the efficiency of HTS strategy for identification of biosafe compounds, which might be rapidly repurposed to overcome resistance of tumors to Pt-based chemotherapy. MDPI 2020-03-06 /pmc/articles/PMC7139527/ /pubmed/32155756 http://dx.doi.org/10.3390/cancers12030608 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Mariniello, Marta Petruzzelli, Raffaella Wanderlingh, Luca G. La Montagna, Raffaele Carissimo, Annamaria Pane, Francesca Amoresano, Angela Ilyechova, Ekaterina Y. Galagudza, Michael M. Catalano, Federico Crispino, Roberta Puchkova, Ludmila V. Medina, Diego L. Polishchuk, Roman S. Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title | Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title_full | Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title_fullStr | Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title_full_unstemmed | Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title_short | Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin |
title_sort | synthetic lethality screening identifies fda-approved drugs that overcome atp7b-mediated tolerance of tumor cells to cisplatin |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139527/ https://www.ncbi.nlm.nih.gov/pubmed/32155756 http://dx.doi.org/10.3390/cancers12030608 |
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