Triapine-mediated ABCB1 induction via PKC induces widespread therapy unresponsiveness but is not underlying acquired triapine resistance.
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.
Department 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.
W
W
Miklos
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
K
K
Pelivan
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
C R
CR
Kowol
Department 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.
C
C
Pirker
Department 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; Department of Pharmacology and Toxicology, University of Vienna, Althanstraße 14, A-1090 Vienna, Austria.
R
R
Dornetshuber-Fleiss
Department of Analytical Chemistry, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
M
M
Spitzwieser
Department 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.
B
B
Englinger
Department 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.
S
S
van Schoonhoven
Department of Analytical Chemistry, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
M
M
Cichna-Markl
Department of Analytical Chemistry, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
G
G
Koellensperger
Institute of Inorganic Chemistry, University of Vienna, Waehringer Str. 42, A-1090 Vienna, Austria; Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
B K
BK
Keppler
Department 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; Research Platform "Translational Cancer Therapy Research", Vienna, Austria.
W
W
Berger
Department 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; Research Platform "Translational Cancer Therapy Research", Vienna, Austria. Electronic address: petra.heffeter@meduniwien.ac.at.
P
P
Heffeter
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D055028:Comparative Genomic Hybridization; D019175:DNA Methylation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D011725:Pyridines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D011493:Protein Kinase C
ABC transporter; ABCB1; Multidrug resistance; Protein kinase C; Triapine