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posted on 2023-04-03, 15:44 authored by András Füredi, Szilárd Tóth, Kornélia Szebényi, Veronika F.S. Pape, Dóra Türk, Nóra Kucsma, László Cervenak, József Tóvári, Gergely Szakács Supplementary Figure 2. Treatment of MESSA-Dx5 cells with NSC293766 results in the loss of Pgp (green), while 8OHQ has no effect. Blue: nuclear counterstain. Scale bar is 50 µm
Funding
Hungarian Academy of Sciences
ERC
National Research, Development and Innovation
History
ARTICLE 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.
