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

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.

• Authors: 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
• Journal: Cancer letters (Cancer Lett) Vol. 361 Issue 1 Pg. 112-20 (May 28 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25749419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Pyridines
• RNA, Messenger
• RNA, Small Interfering
• Thiosemicarbazones
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
• Protein Kinase C

Topics

• ATP Binding Cassette Transporter, Subfamily B (genetics, metabolism)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, metabolism, pathology)
• Comparative Genomic Hybridization
• DNA Methylation (drug effects)
• Drug Resistance, Multiple (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Humans
• Promoter Regions, Genetic (genetics)
• Protein Kinase C (antagonists & inhibitors, genetics, metabolism)
• Pyridines (pharmacology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (pharmacology)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction
• Thiosemicarbazones (pharmacology)
• Tumor Cells, Cultured