Mutant Gly482 and Thr482 ABCG2 mediate high-level resistance to lipophilic antifolates

Cancer Chemotherapy and Pharmacology
Eran BramYehuda G Assaraf

Abstract

Cellular uptake of hydrophilic antifolates proceeds via the reduced folate carrier whereas lipophilic antifolates enter cells by diffusion. Recently we have shown that transfectant cells overexpressing the mutant G482 ABCG2 displayed 120-6,250-fold resistance to hydrophilic antifolates than untransfected cells upon 4 h drug exposure, but lost almost all their antifolate resistance upon 72 h drug exposure (Shafran et al. in Cancer Res 65:8414-8422, 2005). Here we explored the ability of the wild type (WT) R482-as well as the mutant G482-and T482 ABCG2 to confer resistance to lipophilic antifolate inhibitors of dihydrofolate reductase (trimetrexate, piritrexim, metoprine and pyrimethamine) and thymidylate synthase (AG337, AG377 and AG331). Lipophilic antifolate resistance was determined using growth inhibition assays upon 72 h drug exposure. Cells overexpressing these mutant efflux transporters displayed up to 106-fold resistance to lipophilic antifolates relative to untransfected cells; this resistance was reversed by the specific and potent ABCG2 efflux inhibitor Ko143. In contrast, cells overexpressing the WT R482 ABCG2 exhibited either no or only a low-level of lipophilic antifolate resistance. These results provide the first...Continue Reading

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Sep 15, 2014·Malaria Journal·Sanna R RijpmaJan B Koenderink
Aug 28, 2009·Expert Opinion on Drug Metabolism & Toxicology·Yi An, Weg M Ongkeko
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Jan 16, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Zhuo-Xun WuYihang Pan
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