Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired

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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

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W Miklos1, K Pelivan2, C R Kowol2

  • 1Department of Medicine I, Institute of Cancer Research and Comprehensive Cancer Center of the Medical University, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.

Cancer Letters
|March 10, 2015
PubMed

Insights

Triapine shows promise for leukemia but not solid tumors. New research reveals triapine resistance in cancer cells is not due to ABCB1 transporter levels but stress-induced protein kinase C activation.

Area of Science:

  • Pharmacology
  • Cancer Biology
  • Molecular Biology

Background:

  • Triapine is a promising drug for advanced leukemia.
  • Its efficacy against solid tumors remains limited due to unknown resistance mechanisms.
  • Understanding triapine resistance is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To investigate the mechanisms of triapine resistance in solid tumor cells.
  • To generate and characterize a novel triapine-resistant cell line (SW480/tria).
  • To determine the role of ABCB1 transporter and protein kinase C (PKC) in triapine resistance.

Main Methods:

  • Generation of a triapine-resistant cell line (SW480/tria) through drug selection.
  • Assessment of ABCB1 expression and substrate cross-resistance.
  • Evaluation of ABCB1 inhibition effects on triapine sensitivity.
  • Analysis of protein kinase C (PKC) activation and its role in ABCB1 expression.

Main Results:

  • SW480/tria cells exhibited cross-resistance to ABCB1 substrates due to elevated ABCB1 levels.
  • ABCB1 inhibition did not restore triapine sensitivity, indicating triapine is a weak ABCB1 substrate.
  • Triapine treatment induced ABCB1 expression via protein kinase C (PKC) activation in parental cells.
  • Elevated PKC levels were observed in resistant SW480/tria cells.

Conclusions:

  • Increased ABCB1 expression is not the primary mechanism of triapine resistance.
  • Stress-induced PKC activation by triapine leads to increased ABCB1 expression.
  • These findings are critical for selecting chemotherapeutics for combination therapy with triapine.
Keywords:
ABC transporterABCB1Multidrug resistanceProtein kinase CTriapine

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