Tyrphostin RG14620 selectively reverses ABCG2-mediated multidrug resistance in cancer cell lines

Chung Pu Wu*, Sung Han Hsiao, Megumi Murakami, Ming Jie Lu, Yan Qing Li, Chia Hung Hsieh, Suresh V. Ambudkar, Yu Shan Wu

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

18 Scopus citations

Abstract

The multidrug resistance (MDR) phenotype associated with the overexpression of ATP-binding cassette (ABC) drug transporters ABCB1, ABCC1 and ABCG2 is a major obstacle in cancer chemotherapy. Numerous epidermal growth factor receptor (EGFR) inhibitors have previously been shown capable of reversing MDR in ABCG2-overexpressing cancer cells. However, most of them are not transporter-specific due to the substantial overlapping substrate specificity among the transporters. In this study, we investigated the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor of the tyrphostin family, in multidrug-resistant cancer cell lines. We found that at nontoxic concentrations, tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity to ABCG2-overexpressing multidrug-resistant cancer cells. More importantly, tyrphostin RG14620 is selective to ABCG2 relative to ABCB1 and ABCC1. Our findings were further supported by biochemical assays demonstrating that tyrphostin RG14620 stimulates ATP hydrolysis and inhibits photoaffinity labeling of ABCG2 with IAAP, and by a docking analysis of tyrphostin RG14620 in the drug-binding pocket of this transporter. Taken together, our findings indicate that tyrphostin RG14620 is a potent and selective modulator of ABCG2 that may be useful to overcome chemoresistance in patients with drug-resistant tumors.

Original languageEnglish
Pages (from-to)56-65
Number of pages10
JournalCancer Letters
Volume409
DOIs
StatePublished - 28 11 2017

Bibliographical note

Publisher Copyright:
© 2017 Elsevier B.V.

Keywords

  • ABC transporter
  • ABCG2
  • EGFR inhibitor
  • Multidrug resistance
  • Tyrphostin RG14620

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