title: Identification and Validation of Compounds Selectively Killing Resistant Cancer: Delineating Cell Line-Specific Effects from P-Glycoprotein-Induced Toxicity.
abstract: Despite significant progress, resistance to chemotherapy is still the main reason why cancer remains a deadly disease. An attractive strategy is to target the collateral sensitivity of otherwise multidrug resistant (MDR) cancer. In this study, our aim was to catalog various compounds that were reported to elicit increased toxicity in P-glycoprotein (Pgp)-overexpressing MDR cells. We show that the activity of most of the serendipitously identified compounds reported to target MDR cells is in fact cell-line specific, and is not influenced significantly by the function of Pgp. In contrast, novel 8-hydroxyquinoline derivatives that we identify in the National Cancer Institute (NCI) drug repository possess a robust Pgp-dependent toxic activity across diverse cell lines. Pgp expression associated with the resistance of the doxorubicin-resistant Brca1-/-;p53-/-spontaneous mouse mammary carcinoma cells could be eliminated by a single treatment with NSC57969, suggesting that MDR-selective compounds can effectively revert the MDR phenotype of cells expressing Pgp at clinically relevant levels. The discovery of new MDR-selective compounds shows the potential of this emerging technology and highlights the 8-hydroxyquinoline scaffold as a promising starting point for the development of compounds targeting the Achilles heel of drug-resistant cancer. Mol Cancer Ther; 16(1); 45-56. ©2016 AACR.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: András
authors.initials: A
authors.lastname: Füredi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Szilárd
authors.initials: S
authors.lastname: Tóth
authors.affiliation: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Kornélia
authors.initials: K
authors.lastname: Szebényi
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Veronika F S
authors.initials: VF
authors.lastname: Pape
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Dóra
authors.initials: D
authors.lastname: Türk
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Nóra
authors.initials: N
authors.lastname: Kucsma
authors.affiliation: 3rd Department of Medicine Research Laboratory, Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Cervenak
authors.affiliation: Department of Experimental Pharmacology, National Institute of Oncology, Budapest, Hungary.
authors.forename: József
authors.initials: J
authors.lastname: Tóvári
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. szakacs.gergely@ttk.mta.hu.|Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Gergely
authors.initials: G
authors.lastname: Szakács
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D062313:Databases, Pharmaceutical; D004195:Disease Models, Animal; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005260:Female; D015870:Gene Expression; D006801:Humans; D008325:Mammary Neoplasms, Experimental; D051379:Mice; D018345:Mice, Knockout; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents