Differential enzymatic reductions governing the differential hypoxia-selective cytotoxicities of phenazine 5,10-dioxides
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Published on: February 7, 2018
María Laura Lavaggi1, Mauricio Cabrera, Mercedes González
1Departamento de Química Orgánica, Facultad de Química-Facultad de Ciencias, Universidad de la República, Montevideo, Uruguay.
Abstract:
Some derivatives of phenazine 5,10-dioxide are selectively toxic to hypoxic cells commonly found in solid tumors. Previous studies of the phenazine 5,10-dioxide mechanism of action indicated that a bioreduction process could be involved in its selective toxicities, maybe as result of its potential H(*)-releasing capability in hypoxia. The major unresolved aspect of the mechanism of phenazine 5,10-dioxides is the identity of the reductase(s) in the cell responsible for activating the drug to its toxic form and metabolites. We have studied the metabolism in both hypoxia and oxia of some selected 2-amino and 2-hydroxyphenazine 5,10-dioxides, 1- 5, using rat liver microsomal and cytosol fractions. Differential hypoxic/oxic metabolism was found to be correlated to a compound's cytotoxic selectivity but, in general, without metabolic differences between liver microsomal or cytosolic enzymes. Dicoumarol and ketoconazole were found to inhibit the hypoxic metabolism of the most selective phenazine 5,10-dioxide, 1, inferring a role for DT-diaphorase and cytochrome P450. The least hypoxic selective agents, 4 and 5, possess different hypoxia-metabolic profiles as compared to derivative 1, explaining the differential cytotoxic biological behavior. The nonselective derivative, 2, suffered bioreduction in both conditions and, according to the inhibition studies with dicoumarol and ketoconazole, involves both DT-diaphorase and cytochrome P450. The nontoxic derivative, 3, showed poor bioreductive behavior.
Insights
Phenazine 5,10-dioxide derivatives show selective toxicity to hypoxic tumor cells. Researchers identified DT-diaphorase and cytochrome P450 as key enzymes involved in activating these compounds, explaining their varying efficacies.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Phenazine 5,10-dioxide derivatives exhibit selective toxicity towards hypoxic tumor cells.
- Bioreduction is a potential mechanism underlying this selective toxicity, possibly linked to H(*)-releasing capabilities in hypoxia.
- Identifying the specific cellular reductases responsible for activating these drugs remains a key unresolved question.
Purpose of the Study:
- To investigate the hypoxic and oxic metabolism of selected 2-amino and 2-hydroxyphenazine 5,10-dioxides (compounds 1-5).
- To correlate metabolic profiles with the cytotoxic selectivity of these phenazine derivatives.
- To identify the specific enzymes involved in the bioreduction and activation of these compounds.
Main Methods:
- Metabolic studies were conducted using rat liver microsomal and cytosol fractions under both hypoxic and oxic conditions.
- Differential metabolism was assessed and correlated with cytotoxic selectivity.
- Enzyme inhibition studies were performed using dicoumarol and ketoconazole to infer the roles of DT-diaphorase and cytochrome P450.
Main Results:
- Hypoxic/oxic metabolism differences correlated with cytotoxic selectivity, generally without significant differences between liver microsomal or cytosolic enzymes.
- Hypoxic metabolism of the most selective derivative (1) was inhibited by dicoumarol and ketoconazole, suggesting roles for DT-diaphorase and cytochrome P450.
- Less selective agents (4, 5) and the nonselective derivative (2) exhibited distinct hypoxia-metabolic profiles, explaining their differential cytotoxic effects. Derivative 2 involved both DT-diaphorase and cytochrome P450.
Conclusions:
- The study elucidates the metabolic pathways and enzymatic basis for the selective toxicity of phenazine 5,10-dioxide derivatives.
- DT-diaphorase and cytochrome P450 are implicated in the bioreduction and activation of these anticancer agents.
- Understanding these mechanisms provides insights into optimizing the therapeutic potential of phenazine derivatives against solid tumors.
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