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DCPIP (2,6-dichlorophenolindophenol) as a genotype-directed redox chemotherapeutic targeting NQO1*2 breast carcinoma
Christopher M Cabello1, Sarah D Lamore, Warner B Bair
1Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
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.
Insights
This study shows that the pro-oxidant DCPIP effectively targets breast cancer cells with a specific genetic mutation (NQO1*2). This targeted approach induces cancer cell death and reduces tumor growth in preclinical models, offering a new strategy for personalized redox chemotherapy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Chemotherapy can be personalized by targeting cellular oxidative stress.
- NAD(P)H:quinone oxidoreductase (NQO1) expression influences the efficacy of pro-oxidant drugs.
- The NQO1*2 genotype encodes a functionally impaired NQO1 protein, common in some breast cancers.
Purpose of the Study:
- To evaluate 2,6-dichlorophenolindophenol (DCPIP) as a genotype-directed redox chemotherapeutic.
- To target breast cancer cells with the homozygous NQO1*2 genotype.
Main Methods:
- Utilized breast carcinoma cell lines and NQO1-transfectants with varying NQO1 expression.
- Assessed DCPIP sensitivity, oxidative stress markers, and gene expression.
- Tested DCPIP efficacy in a murine xenograft model of NQO1*2 breast carcinoma.
Main Results:
- Homozygous NQO1*2 breast carcinoma cells showed hypersensitivity to DCPIP.
- DCPIP induced caspase-independent cell death, oxidative stress, glutathione depletion, and genomic instability.
- Upregulation of oxidative, heat shock, and genotoxic stress response genes was observed.
- DCPIP demonstrated significant anti-tumour activity in a murine xenograft model.
Conclusions:
- DCPIP is a feasible genotype-directed redox chemotherapeutic agent for NQO1*2 breast carcinoma.
- Targeting NQO1*2 genotype offers a personalized approach to breast cancer treatment.
- Modulating cellular oxidative stress is a promising strategy for cancer therapy.
