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Antimelanoma activity of the redox dye DCPIP (2,6-dichlorophenolindophenol) is antagonized by NQO1
Christopher M Cabello1, Warner B Bair, Alexandra S Bause
1Department of Pharmacology and Toxicology, College of Pharmacy, Arizona Cancer Center, University of Arizona, 1515 North Campbell Avenue, Tucson, AZ 85724, USA.
Abstract:
Altered redox homeostasis involved in the control of cancer cell survival and proliferative signaling represents a chemical vulnerability that can be targeted by prooxidant redox intervention. Here, we demonstrate that the redox dye 2,6-dichlorophenolindophenol (DCPIP) may serve as a prooxidant chemotherapeutic targeting human melanoma cells in vitro and in vivo. DCPIP-apoptogenicity observed in the human melanoma cell lines A375 and G361 was inversely correlated with NAD(P)H:quinone oxidoreductase (NQO1) expression levels. In A375 cells displaying low NQO1 activity, DCPIP induced apoptosis with procaspase-3 and PARP cleavage, whereas G361 cells expressing high levels of enzymatically active NQO1 were resistant to DCPIP-cytotoxicity. Genetic (siRNA) or pharmacological (dicoumarol) antagonism of NQO1 strongly sensitized G361 cells to DCPIP apoptogenic activity. DCPIP-cytotoxicity was associated with the induction of oxidative stress and rapid depletion of glutathione in A375 and NQO1-modulated G361 cells. Expression array analysis revealed a DCPIP-induced stress response in A375 cells with massive upregulation of genes encoding Hsp70B' (HSPA6), Hsp70 (HSPA1A), heme oxygenase-1 (HMOX1), and early growth response protein 1 (EGR1) further confirmed by immunodetection. Systemic administration of DCPIP displayed significant antimelanoma activity in the A375 murine xenograft model. These findings suggest feasibility of targeting tumors that display low NQO1 enzymatic activity using DCPIP.
Insights
The redox dye DCPIP shows promise as a prooxidant chemotherapy for melanoma. It effectively targets cancer cells with low NQO1 expression, inducing apoptosis and reducing tumor growth in vivo.
Area of Science:
- Oncology
- Biochemistry
- Pharmacology
Background:
- Altered redox homeostasis is a key vulnerability in cancer.
- Prooxidant redox intervention offers a therapeutic strategy.
- Targeting cancer cell survival pathways is crucial.
Purpose of the Study:
- To investigate the potential of 2,6-dichlorophenolindophenol (DCPIP) as a prooxidant chemotherapeutic agent.
- To determine the role of NAD(P)H:quinone oxidoreductase (NQO1) in mediating DCPIP sensitivity in melanoma cells.
- To evaluate the efficacy of DCPIP against human melanoma in vitro and in vivo.
Main Methods:
- Assessing DCPIP-induced apoptosis in human melanoma cell lines (A375, G361) with varying NQO1 expression.
- Utilizing siRNA and dicoumarol to modulate NQO1 activity.
- Measuring oxidative stress markers, glutathione levels, and gene expression changes.
- Evaluating systemic DCPIP administration in a murine xenograft model.
Main Results:
- DCPIP induced apoptosis in A375 cells (low NQO1) but not in G361 cells (high NQO1).
- NQO1 inhibition sensitized resistant G361 cells to DCPIP, confirming NQO1's protective role.
- DCPIP treatment led to oxidative stress and glutathione depletion.
- DCPIP demonstrated significant anti-melanoma activity in vivo.
Conclusions:
- DCPIP functions as a prooxidant chemotherapeutic agent against melanoma.
- Melanoma cells with low NQO1 expression are susceptible to DCPIP-induced apoptosis.
- DCPIP holds potential for targeting NQO1-low tumors.
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