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

Chung-Pu Wu1, Sung-Han Hsiao2, Megumi Murakami3

  • 1Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan.

Cancer Letters
|September 13, 2017
PubMed

Insights

Tyrphostin RG14620, an EGFR inhibitor, effectively reverses multidrug resistance (MDR) in cancer cells overexpressing ABCG2. This selective compound enhances chemotherapy efficacy by targeting ABCG2, offering a potential strategy against drug-resistant tumors.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Research

Background:

  • Multidrug resistance (MDR) in cancer is often caused by ATP-binding cassette (ABC) transporters like ABCB1, ABCC1, and ABCG2.
  • Epidermal growth factor receptor (EGFR) inhibitors can reverse MDR, but lack specificity for ABCG2.
  • Developing selective modulators for ABCG2 is crucial for overcoming chemotherapy resistance.

Purpose of the Study:

  • To investigate the interaction between ABCG2 and tyrphostin RG14620, an EGFR inhibitor.
  • To evaluate the efficacy and selectivity of tyrphostin RG14620 in reversing ABCG2-mediated MDR.
  • To explore the potential of tyrphostin RG14620 as a therapeutic agent against drug-resistant cancers.

Main Methods:

  • Utilized multidrug-resistant cancer cell lines overexpressing ABCG2.
  • Assessed the effect of tyrphostin RG14620 on drug-induced apoptosis and chemosensitivity.
  • Performed biochemical assays, including ATP hydrolysis and photoaffinity labeling inhibition.
  • Conducted docking analysis to study the binding of tyrphostin RG14620 to ABCG2.

Main Results:

  • Tyrphostin RG14620 enhances drug-induced apoptosis and restores chemosensitivity in ABCG2-overexpressing cells at non-toxic concentrations.
  • Tyrphostin RG14620 demonstrates selectivity for ABCG2 over ABCB1 and ABCC1.
  • Biochemical assays confirmed tyrphostin RG14620's interaction with ABCG2, stimulating ATP hydrolysis and inhibiting photoaffinity labeling.
  • Docking analysis supported the binding of tyrphostin RG14620 within the ABCG2 drug-binding pocket.

Conclusions:

  • Tyrphostin RG14620 is a potent and selective modulator of the ABCG2 transporter.
  • This compound can overcome chemoresistance mediated by ABCG2.
  • Tyrphostin RG14620 holds promise for improving treatment outcomes in patients with drug-resistant tumors.
Keywords:
ABC transporterABCG2EGFR inhibitorMultidrug resistanceTyrphostin RG14620

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