title: Downregulation of BCRP and anti-apoptotic proteins by proadifen (SKF-525A) is responsible for the enhanced mitoxantrone accumulation and toxicity in mitoxantrone-resistant human promyelocytic leukemia cells.
abstract: Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. Drugs inhibiting these transporters have been shown to increase the anti-proliferative properties of chemotherapeutics. As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). Because mitoxantrone (MTX) is a strong BCRP substrate and is often used in the treatment of leukemia, we investigated the effect of 24 h proadifen pre-treatment on the cytotoxicity of MTX in leukemic cell lines that are sensitive to MTX (HL-60) and MTX-resistant ABCG2-overexpressing subclone (cBCRP). We show for the first time that proadifen is able to enhance the cytotoxic properties of MTX in cBCRP cells, particularly through the inhibition of BCRP expression and activity. This proadifen-MTX synergism was also mediated by the inhibition of various cellular proteins engaged in apoptosis, including Mc-1, Bcl-xL, survivin and activation of procaspase-3. Proadifen also decreased the expression of γH2AX, which is involved in the recruitment of reparation proteins. Moreover, the inhibition of DNA damage repair proteins Ku86 and B23 after proadifen treatment indicate a possible role of proadifen in DNA repair blockage, thus suppressing the reparation rate of MTX-induced DSBs.
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, SK-040 01 Košice, Slovak Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Hiľovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, SK-040 01 Košice, Slovak Republic.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Jendželovský
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, SK-040 01 Košice, Slovak Republic.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Jendželovská
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, SK-040 01 Košice, Slovak Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Kovaľ
authors.affiliation: Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Šafárik University in Košice, SK-040 01 Košice, Slovak Republic.
authors.forename: Peter
authors.initials: P
authors.lastname: Fedoročko
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008942:Mitoxantrone / Q000494:pharmacology*; D011335:Proadifen / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D051017:Apoptosis Regulatory Proteins; D004791:Enzyme Inhibitors; D011335:Proadifen; D008942:Mitoxantrone