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| Cancer letters. 2015 Mar 5. pii: S0304-3835(15)00164-0. doi: 10.1016/j.canlet.2015.02.049 |
| Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance. |
| Miklos W1, Pelivan K2, Kowol CR3, Pirker C4, Dornetshuber-Fleiss R5, Spitzwieser M6, Englinger B7, van Schoonhoven S8, Cichna-Markl M9, Koellensperger G10, Keppler BK11, Berger W12, Heffeter P13 |
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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. |
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Copyright © 2015 Elsevier Ireland Ltd. All rights reserved. |
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KEYWORDS: ABC transporter, ABCB1, Multidrug resistance, Protein kinase C, Triapine |
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Publikations ID: 25749419 Quelle: öffnen |
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