Abstract
Cyclophosphamide (CPA) is a pro-drug commonly used in the chemotherapeutic schemes for glioma treatment but has high toxicity and the side effects include brain damage and even death. Since CPA is activated mainly by CY2B6, over-expression of the enzyme in the tumor cells has been proposed to enhance CPA activation. In this study, we explored the induction of the Cyp2b1 (homologous to CYP2B6) by nicotine in an animal rat model with glioma. Gene expression and protein levels were analyzed by RT-PCR and Western blot. Nicotine treatment increased CYP2B1 protein levels in the healthy animals’ brain tissue. In the brain tissue of animals with glioma, the CYP2B1 showed a high expression, even before nicotine treatment. Nicotine did not increase significantly the CYP2B1 protein expression in the tumor, but increased its expression in the tumor vicinity, especially around blood vessels in the cortex. We also explored CY2B6 expression in glioma samples derived from pediatric patients. Tumor tissue showed a variable expression of the enzyme, which could depend on the tumor malignancy grade. Induction of the CYP2B6 in pediatric gliomas with lower expression of the enzyme, could be an alternative to improve the antitumoral effect of CPA treatment.
Highlights
In children, central nervous system tumors (CNST) are the main cause of death due to cancer and represent the second most common type of cancer after leukemia [1,2,3]
Since it has been reported that nicotine induces Cyp2b1 expression in the brain but does not affect liver expression, we analyzed Cyp2b1 mRNA levels in a murine glioma model treated with nicotine
Brain tissue of animals with glioma, showed a higher level of Cyp2b1 expression when compared with healthy animals, and after nicotine treatment, the Cyp2b1 expression did not increase (Figure 2b)
Summary
Central nervous system tumors (CNST) are the main cause of death due to cancer and represent the second most common type of cancer after leukemia [1,2,3]. Since CYP2B6 has high hydroxylase activity for CPA, it has been proposed to sensitize tumor Since CYP2B6 has high hydroxylase activity for CPA, it has been proposed to sensitize tumor cells cells to the action of this drug by in situ expression of this enzyme with gene therapy. Chronic nicotine treatment induces CYP2B6 expression (91% homology with the human gene) in the brain of African green monkeys. This occurred in several cell types, among them, pyramidal cells of the frontal cortex, Purkinje cells of the cerebellum and neurons of the substantia nigra; its expression in the liver was not affected [23]. We found that the expression of this enzyme is high in the glioma tissue and differs between samples, probably according to malignancy grade
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