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

Cancer Letters
Walter MiklosP Heffeter

Abstract

Although triapine is promising for treatment of advanced leukemia, it failed against solid tumors due to widely unknown reasons. To address this issue, a new triapine-resistant cell line (SW480/tria) was generated by drug selection and investigated in this study. Notably, SW480/tria cells displayed broad cross-resistance against several known ABCB1 substrates due to high ABCB1 levels (induced by promoter hypomethylation). However, ABCB1 inhibition did not re-sensitize SW480/tria cells to triapine and subsequent analysis revealed that triapine is only a weak ABCB1 substrate without significant interaction with the ABCB1 transport function. Interestingly, in chemo-naive, parental SW480 cells short-time (24 h) treatment with triapine stimulated ABCB1 expression. These effects were based on activation of protein kinase C (PKC), a known response to cellular stress. In accordance, SW480/tria cells were characterized by elevated levels of PKC. Together, this led to the conclusion that increased ABCB1 expression is not the major mechanism of triapine resistance in SW480/tria cells. In contrast, increased ABCB1 expression was found to be a consequence of triapine stress-induced PKC activation. These data are especially of importance whe...Continue Reading

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Citations

Mar 17, 2016·Chemical Research in Toxicology·James T WilsonJoseph E Deweese
Jan 18, 2018·Antioxidants & Redox Signaling·Petra HeffeterChristian R Kowol
Nov 4, 2015·Journal of Experimental & Clinical Cancer Research : CR·Florian SeveldaWalter Berger
Oct 18, 2020·Cells·Katja Zappe, Margit Cichna-Markl
Aug 18, 2021·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Andreia ValentePetra Heffeter

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