Nongenotoxic ABCB1 activator tetraphenylphosphonium can contribute to doxorubicin resistance in MX-1 breast cancer cell line.

Abstract

Hyperactivation of ABC transporter ABCB1 and induction of epithelial-mesenchymal transition (EMT) are the most common mechanism of acquired cancer chemoresistance. This study describes possible mechanisms, that might contribute to upregulation of ABCB1 and synergistically boost the acquisition of doxorubicin (DOX) resistance in breast cancer MX-1 cell line. DOX resistance in MX-1 cell line was induced by a stepwise increase of drug concentration or by pretreatment of cells with an ABCB1 transporter activator tetraphenylphosphonium (TPP+) followed by DOX exposure. Transcriptome analysis of derived cells was performed by human gene expression microarrays and by quantitative PCR. Genetic and epigenetic mechanisms of ABCB1 regulation were evaluated by pyrosequencing and gene copy number variation analysis. Gradual activation of canonical EMT transcription factors with later activation of ABCB1 at the transcript level was observed in DOX-only treated cells, while TPP+ exposure induced considerable activation of ABCB1 at both, mRNA and protein level. The changes in ABCB1 mRNA and protein level were related to the promoter DNA hypomethylation and the increase in gene copy number. ABCB1-active cells were highly resistant to DOX and showed morphological and molecular features of EMT. The study suggests that nongenotoxic ABCB1 inducer can possibly accelerate development of DOX resistance.

• Authors: Raimonda Kubiliute, Indre Januskeviciene, Ruta Urbanaviciute, Kristina Daniunaite, Monika Drobniene, Valerijus Ostapenko, Rimantas Daugelavicius, Sonata Jarmalaite
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 6556 (03 22 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33753859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Onium Compounds
• Organophosphorus Compounds
• Doxorubicin
• tetraphenylphosphonium

Topics

• ATP Binding Cassette Transporter, Subfamily B (agonists)
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (genetics, pathology)
• Cell Line, Tumor
• Computational Biology (methods)
• DNA Methylation
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Epigenesis, Genetic (drug effects)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Female
• Gene Dosage
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Humans
• Models, Biological
• Onium Compounds (pharmacology)
• Organophosphorus Compounds (pharmacology)
• Transcriptome