Christophe Glorieux1, Juan Marcelo Sandoval1, Nicolas Dejeans1, Geneviève Ameye2, Hélène Antoine Poirel2, Julien Verrax1, Pedro Buc Calderon3. 1. Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium. 2. Centre de Génétique Humaine, Cliniques Universitaires Saint-Luc & de Duve Institute, Université catholique de Louvain, Brussels, Belgium. 3. Université catholique de Louvain, Louvain Drug Research Institute, Toxicology and Cancer Biology Research Group, Brussels, Belgium; Facultad de Ciencias de la Salud, Universidad Arturo Prat, Iquique, Chile. Electronic address: pedro.buccalderon@uclouvain.be.
Abstract
AIMS: Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). MAIN METHODS: FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances. Finally, the importance of NQO1 overexpression in the putative acquisition of either drug resistance or an increased sensitivity to quinones by cancer cells was investigated by immunoblotting and cytotoxicity assays. KEY FINDINGS: Genomic gain of the chromosomal band 16q22 was detected in Resox cells compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. This genomic gain was associated with amplification of the NQO1 gene in one tumor biopsy as well as in breast cancer cell lines. Using different breast cell models, we found that NQO1 overexpression was a main determinant for a potential chemotherapy resistance or an increased sensitivity to quinone-bearing compounds. SIGNIFICANCE: Because NQO1 is frequently modified in tumors at genomic and transcriptomic levels, the impact of NQO1 modulation on breast cancer cell sensitivity places NQO1 as a potential link between cancer redox alterations and resistance to chemotherapy. Thus, the NQO1 gene copy number and NQO1 activity should be considered when quinone-bearing molecules are being utilized as potential drugs against breast tumors.
AIMS: Alterations in the expression of antioxidant enzymes are associated with changes in cancer cell sensitivity to chemotherapeutic drugs (menadione and β-lapachone). Mechanisms of acquisition of resistance to pro-oxidant drugs were investigated using a model of oxidative stress-resistant MCF-7 breast cancer cells (Resox cells). MAIN METHODS: FISH experiments were performed in tumor biopsy and breast cancer cells to characterize the pattern of the NQO1 gene. SNP-arrays were conducted to detect chromosomal imbalances. Finally, the importance of NQO1 overexpression in the putative acquisition of either drug resistance or an increased sensitivity to quinones by cancer cells was investigated by immunoblotting and cytotoxicity assays. KEY FINDINGS: Genomic gain of the chromosomal band 16q22 was detected in Resox cells compared to parental breast cancer MCF-7 cells and normal human mammary epithelial 250MK cells. This genomic gain was associated with amplification of the NQO1 gene in one tumor biopsy as well as in breast cancer cell lines. Using different breast cell models, we found that NQO1 overexpression was a main determinant for a potential chemotherapy resistance or an increased sensitivity to quinone-bearing compounds. SIGNIFICANCE: Because NQO1 is frequently modified in tumors at genomic and transcriptomic levels, the impact of NQO1 modulation on breast cancer cell sensitivity places NQO1 as a potential link between cancer redox alterations and resistance to chemotherapy. Thus, the NQO1 gene copy number and NQO1 activity should be considered when quinone-bearing molecules are being utilized as potential drugs against breast tumors.
Authors: Xue Fei Han; Yuan Zhang; Liu Lin Xiong; Yang Xu; Piao Zhang; Qing Jie Xia; Ting Hua Wang; Ying Chun Ba Journal: Mol Neurobiol Date: 2016-02-12 Impact factor: 5.590
Authors: Fjodor Melnikov; Dianne Botta; Collin C White; Stefanie C Schmuck; Matthew Winfough; Christopher M Schaupp; Evan P Gallagher; Bryan W Brooks; Edward Spencer Williams; Philip Coish; Paul T Anastas; Adelina Voutchkova-Kostal; Jakub Kostal; Terrance J Kavanagh Journal: Chem Res Toxicol Date: 2019-01-07 Impact factor: 3.739