Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance
- Author(s)
- W. Miklos, K. Pelivan, C. R. Kowol, C. Pirker, R. Dornetshuber-Fleiss, M. Spitzwieser, B. Englinger, S. van Schoonhoven, M. Cichna-Markl, G. Koellensperger, B. K. Keppler, W. Berger, P. 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 when considering the choice of chemotherapeutics for combination with triapine.
- Organisation(s)
- Department of Inorganic Chemistry, Department of Analytical Chemistry
- External organisation(s)
- Medizinische Universität Wien
- Journal
- Cancer Letters
- Volume
- 361
- Pages
- 112-120
- No. of pages
- 9
- ISSN
- 0304-3835
- DOI
- https://doi.org/10.1016/j.canlet.2015.02.049
- Publication date
- 05-2015
- Peer reviewed
- Yes
- Austrian Fields of Science 2012
- 301904 Cancer research
- Keywords
- ASJC Scopus subject areas
- Oncology, Cancer Research
- Sustainable Development Goals
- SDG 3 - Good Health and Well-being
- Portal url
- https://ucrisportal.univie.ac.at/en/publications/7f362fe1-befb-45bc-8d35-73082e81cd86