Effect of NADPH–cytochrome P450 reductase on all-trans-retinoic acid efficacy and cytochrome P450 26A1 expression in human myeloid leukaemia HL-60 cells
| Autor: | Cong-Min Zhang, Hong-Hao Zhou, Jin-Feng Lv, Lei Hu, Lan Fan, Wei Zhuo |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cellular differentiation Pharmaceutical Science Apoptosis HL-60 Cells Tretinoin Biology 03 medical and health sciences CYP26A1 Cytochrome P-450 Enzyme System Downregulation and upregulation Humans Cell Proliferation NADPH-Ferrihemoprotein Reductase Pharmacology Cell growth Cell Differentiation Cell Cycle Checkpoints Retinoic Acid 4-Hydroxylase Cell cycle Molecular biology 030104 developmental biology Leukemia Myeloid Cell culture Inactivation Metabolic Cancer cell |
| Zdroj: | Journal of Pharmacy and Pharmacology. 68:1193-1202 |
| ISSN: | 2042-7158 0022-3573 |
| DOI: | 10.1111/jphp.12591 |
| Popis: | Objectives All-trans-retinoic acid (ATRA), a naturally occurring metabolite of vitamin A, has been shown to have great potential as an antitumorigenic drug to treat acute leukaemia by promoting cancer cell differentiation. Cytochrome P450 oxidoreductase (POR) is the only obligate electron donor for all of the microsomal cytochrome P450 enzymes including CYP26A1 which is highly specific for ATRA metabolism and efficacy in human myeloid leukaemia cells. In this study, we aimed to investigate the effect of POR on ATRA efficacy and CYP26A1 expression in human myeloid leukaemia HL-60 cells. Methods Stably expressed POR and POR-RNAi HL-60 cell lines were established by transfecting POR overexpression or RNAi (RNA interference) vectors mediated by lentivirus. The protein expression of POR and CYP26A1 was examined by Western blot. The potential roles of POR on ATRA efficacy in HL-60 cells were explored by cell viability assay, cell cycle distribution, cellular differentiation and apoptosis analysis. Key findings All-trans-retinoic acid treatment caused the expression of POR upregulation and CYP26A1 downregulation in dose- and time-dependent manners. POR overexpression decreased CYP26A1 expression in HL-60 cells. When POR gene was interfered, the downregulation of CYP26A1 expression by ATRA was abolished. In addition, POR overexpression in HL-60 cells significantly compromised ATRA-induced cell proliferation inhibition, cell cycle arrest, differentiation and apoptosis, whereas downregulation of POR significantly potentiated ATRA effects. Conclusions Our study therefore suggested that POR played an important role in regulating ATRA efficacy and CYP26A1 expression in HL-60 cells. |
| Databáze: | OpenAIRE |
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