Bioreduction of Idarubicin and Formation of ROS Responsible for DNA Cleavage by NADPH-Cytochrome P450 Reductase and its Potential Role in the Antitumor Effect

Celik, Haydar
Arinc, Emel
Purpose. Idarubicin is a clinically effective synthetic anthracycline analog used in the treatment of several human neoplasms. Anthracyclines have the potential to undergo bioactivation by flavoenzymes to free radicals and thus exert their cytotoxic actions. In this study, our main objective was to investigate the possible involvement of NADPH-cytochrome P450 reductase in the bioreductive activation of idarubicin to DNA-damaging species. Methods. A pBR322 plasmid DNA damage assay was used as a sensitive method for detecting strand breaks in DNA exposed to idarubicin in the presence of P450 reductase and cofactor NADPH under various incubation conditions. In addition, the rates of idarubicin reduction by P450 reductases purified from phenobarbital-treated rabbit liver, beef liver and sheep lung microsomes were determined by measuring NADPH oxidation at 340 nm. Results. The plasmid DNA experiments demonstrated that idarubicin could undergo bioreduction by P450 reductase with the resulting formation of DNA strand breaks. The antioxidant enzymes SOD and catalase, and hydroxyl radical scavengers, DMSO and thiourea, afforded significant levels of protection against idarubicin-induced DNA strand breaks. These findings suggested that DNA damage by idarubicin occurs through a mechanism which involves its redox cycling with P450 reductase to generate reactive oxygen species (ROS). The extent of DNA damage by idarubicin was found to increase with increasing concentrations of drug or enzyme as well as with increasing incubation time. The capacity of idarubicin to induce DNA damage under above incubation conditions was compared with that of a model compound, mitomycin C. Finally, enzyme assays carried out with purified P450 reductases revealed that idarubicin exhibited about two-fold higher rate of reduction than mitomycin C. Conclusion. Our findings implicated bioreduction of idarubicin by P450 reductase and subsequent redox cycling under aerobic conditions as being one mode of idarubicin action potentially contributing to its antitumor effect.


Numerical Simulation of the Storm Surge at the Sakhalin Island Southern Part on November 15, 2019
Zaytsev, A.; Pelinovsky, E. N.; Dogan, D.; Yalciner, B.; Yalçıner, Ahmet Cevdet; Kurkin, A. A.; Moskvitin, A. A. (2020-01-01)
Purpose. Investigation of the storm surge in Korsakov in the southern part of the Sakhalin Island on November 15, 2019 and comparison of the results of its numerical simulation with the data of in situ measurements constitute the aim of the article.
Drug resistant breast cancer cells overexpress ETS1 gene
Kars, Meltem Demirel; Iseri, Ozlem Darcansoy; Gündüz, Ufuk (2010-09-01)
Purpose. - Multidrug resistance (MDR) is resistance to wide range of structurally unrelated anticancer agents. MDR is a serious limitation to the effective chemotherapy. Involvement of ETS1 overexpression in upregulation of MDR1 gene expression is implicated. In the present study the aim was to assess the involvement of ETS1 and the genes, which encode the proteins interacting with ETS1 in drug resistant MCF-7 breast cancer cells.
Development of a Reconstructed Cornea from Collagen-Chondroitin Sulfate Foams and Human Cell Cultures
Vrana, N. Engin; Builles, Nicolas; Justin, Virginie; Bednarz, Jurgen; Pellegrini, Graziella; Ferrari, Barbara; Damour, Odile; Hulmes, David J. S.; Hasırcı, Vasıf Nejat (2008-12-01)
PURPOSE. To develop an artificial cornea, the ability to coculture the different cell types present in the cornea is essential. Here the goal was to develop a full-thickness artificial cornea using an optimized collagen-chondroitin sulfate foam, with a thickness close to that of human cornea, by coculturing human corneal epithelial and stromal cells and transfected human endothelial cells.
Determining and Evaluating Ideal Physics Teacher s Characteristics
Eryılmaz, Ali (Hacettepe Üniversitesi Eğitim Fakültesi, 1999-01-01)
The main purpose of this studyare; to investigate the characteristics of a prospective physics teacher, to evaluate attitudesof preservice physics teachers toward to be a physics teacher, and to evaluate preservice physics teachers' qualifications. In order to achieve the objectives of the study, literature have been searched in detail. Then, a questionnaire was developed to measure preservice physics teachers qualifications and attimdes of preservice physics teachers toward to be a physics teacher. The Que...
Reanalysis of high-resolution XMM-Newton data of V2491 Cygni using models of collisionally ionized hot absorbers
Balman, Şölen; Gamsizkan, C. (2017-02-01)
Aims. We model spectral absorption features in data of the high-resolution XMM-Newton Reflection Grating Spectrometer.
Citation Formats
H. Celik and E. Arinc, “Bioreduction of Idarubicin and Formation of ROS Responsible for DNA Cleavage by NADPH-Cytochrome P450 Reductase and its Potential Role in the Antitumor Effect,” JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, pp. 68–82, 2008, Accessed: 00, 2020. [Online]. Available: