Cancers, Vol. 12, Pages 608: Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin

Cancers, Vol. 12, Pages 608: Synthetic Lethality Screening Identifies FDA-Approved Drugs that Overcome ATP7B-Mediated Tolerance of Tumor Cells to Cisplatin Cancers doi: 10.3390/cancers12030608 Authors: Marta Mariniello Raffaella Petruzzelli Luca G. Wanderlingh Raffaele La Montagna Annamaria Carissimo Francesca Pane Angela Amoresano Ekaterina Y. Ilyechova Michael M. Galagudza Federico Catalano Roberta Crispino Ludmila V. Puchkova Diego L. Medina Roman S. Polishchuk 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 cispl...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research