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National Institute of Environmental Health Sciences

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Publication Detail

Title: DCPIP (2,6-dichlorophenolindophenol) as a genotype-directed redox chemotherapeutic targeting NQO1*2 breast carcinoma.

Authors: Cabello, Christopher M; Lamore, Sarah D; Bair 3rd, Warner B; Davis, Angela L; Azimian, Sara M; Wondrak, Georg T

Published In Free Radic Res, (2011 Mar)

Abstract: Accumulative experimental evidence suggests feasibility of chemotherapeutic intervention targeting human cancer cells by pharmacological modulation of cellular oxidative stress. Current efforts aim at personalization of redox chemotherapy through identification of predictive tumour genotypes and redox biomarkers. Based on earlier research demonstrating that anti-melanoma activity of the pro-oxidant 2,6-dichlorophenolindophenol (DCPIP) is antagonized by cellular NAD(P)H:quinone oxidoreductase (NQO1) expression, this study tested DCPIP as a genotype-directed redox chemotherapeutic targeting homozygous NQO1*2 breast carcinoma, a common missense genotype [rs1800566 polymorphism; NP_000894.1:p.Pro187Ser] encoding a functionally impaired NQO1 protein. In a panel of cultured breast carcinoma cell lines and NQO1-transfectants with differential NQO1 expression levels, homozygous NQO1*2 MDA-MB231 cells were hypersensitive to DCPIP-induced caspase-independent cell death that occurred after early onset of oxidative stress with glutathione depletion and loss of genomic integrity. Array analysis revealed upregulated expression of oxidative (GSTM3, HMOX1, EGR1), heat shock (HSPA6, HSPA1A, CRYAB) and genotoxic stress response (GADD45A, CDKN1A) genes confirmed by immunoblot detection of HO-1, Hsp70, Hsp70B', p21 and phospho-p53 (Ser15). In a murine xenograft model of human homozygous NQO1*2-breast carcinoma, systemic administration of DCPIP displayed significant anti-tumour activity, suggesting feasibility of redox chemotherapeutic intervention targeting the NQO1*2 genotype.

PubMed ID: 21034357 Exiting the NIEHS site

MeSH Terms: 2,6-Dichloroindophenol/pharmacology*; 2,6-Dichloroindophenol/therapeutic use; Animals; Antineoplastic Agents/pharmacology*; Antineoplastic Agents/therapeutic use; Breast Neoplasms/genetics; Breast Neoplasms/metabolism*; Breast Neoplasms/pathology*; Caspases/metabolism; Cell Death; Cell Line, Tumor; Cell Proliferation; DNA Damage; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glutathione/metabolism; Heat-Shock Proteins/genetics; Humans; Immunoblotting; Membrane Potential, Mitochondrial; Mice; NAD(P)H Dehydrogenase (Quinone)/genetics; NAD(P)H Dehydrogenase (Quinone)/metabolism*; Oxidative Stress*; Polymerase Chain Reaction; Polymorphism, Single Nucleotide; RNA, Small Interfering

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