Benzoxazole-based Zn(II) and Cu(II) complexes overcome multidrug-resistance in cancer

Gabriella Spengler, Annamária Kincses, Bálint Rácz, Borisz Varga, Genki Watanabe, Ryosuke Saijo, Hiroshi Sekiya, Eiji Tamai, Jun Maki, Joseph Molnár, Masami Kawase

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Abstract

Background/Aim: Multidrug resistance (MDR) represents a significant impediment to successful cancer treatment. In this study, novel metal [Zn(II), Cu(II), Mg(II), Ni(II), Pd(II), and Ag(I)] complexes of 2-trifluoroacetonyl - benzoxazole previously synthesized and characterized by our group were tested for their MDR-reversing activity in comparison with the free ligands in L5178Y mouse Tlymphoma (MDR) cells transfected with human ATP-binding cassette sub-family B member 1 (ABCB1; P-glycoprotein) gene. Materials and Methods: Cytotoxic and antiproliferative effects of the complexes were assessed by the thiazolyl blue tetrazolium bromide (MTT) method. Modulation of ABCB1 activity was measured by rhodamine 123 accumulation assay using flow cytometry. The apoptosis-inducing activity of some complexes was also tested on the multidrug resistant L5178Y mouse T-lymphoma cells, using the annexin- V/propidium iodide assay. Results: When compared to the free ligand, a remarkable enhancement in MDR reversal and cytotoxic activity was found for the Zn(II) and Cu(II) complexes. The activity of the complexes proved to be up to 29- and 5-fold higher than that of the ligands and the ABCB1 inhibitor verapamil as positive control, respectively. The complexes possessed a remarkable potential to induce apoptosis of MDR cells. Conclusion: Our results suggest that the Zn(II) and Cu(II) complexes display significant MDRreversing activity in a dose-dependent manner and possess strong cytotoxic activity and a remarkable potential to induce apoptosis in MDR L5178Y mouse T-lymphoma cells.

Original languageEnglish
Pages (from-to)6181-6187
Number of pages7
JournalAnticancer research
Volume38
Issue number11
DOIs
Publication statusPublished - Nov 2018

Keywords

  • ABCB1
  • Apoptosis
  • Benzoxazole
  • Metal complex
  • Mouse T-lymphoma
  • Multidrug resistance
  • P-glycoprotein

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Spengler, G., Kincses, A., Rácz, B., Varga, B., Watanabe, G., Saijo, R., Sekiya, H., Tamai, E., Maki, J., Molnár, J., & Kawase, M. (2018). Benzoxazole-based Zn(II) and Cu(II) complexes overcome multidrug-resistance in cancer. Anticancer research, 38(11), 6181-6187. https://doi.org/10.21873/anticanres.12971