Browsing by Author "Buc Calderon, Pedro"

Now showing 1 - 4 of 4
  • No Thumbnail Available
    Item
    Aminopyrimidoisoquinolinequinone (APIQ) redox cycling is potentiated by ascorbate and induces oxidative stress leading to necrotic-like cancer cell death
    (2012) Vasquez, David R.; Verrax, Julien; Valderrama, Jaime A.; Buc Calderon, Pedro
    Several phenylaminopyrimidoisoquinolinequinones (APIQs) were tested for their cytotoxicity against different cancer cell lines (K562, T24, HepG2) in the presence or absence of ascorbate. Ascorbate enhanced the toxic effects of quinones with first half-wave potential E-1/2(I) values in the range of -480 to -660 mV. Phenylaminoquinones that were unsubstituted at position 6 exhibited greater cytotoxic activity than did their 6-methyl-substituted analogues. Two groups of compounds were further selected, namely 8-10 and 20-22, to study the cellular mechanisms involved in quinone cytotoxicity. Indeed, these compounds have the same range of redox potentials but differed considerably in their capacity to induce cell death. In the presence of ascorbate, the cell demise induced by compounds 8-10 was not caspase-3 dependent, as shown by the lack of activation of caspase-3 and the absence of cleaved PARP fragments. In addition, an index of ER stress (eIF2 alpha phosphorylation) was activated by these compounds. Quinones 8-10 decreased the cellular capacity to reduce MTT dye and caused marked ATP depletion. Taken together, our results show that ascorbate enhances quinone redox-cycling and leads to ROS formation that inhibits cell proliferation and provokes caspase-independent cell death. Interestingly, we also observed that quinone 8 had a rather selective effect given that freshly isolated peripheral blood leukocytes from human healthy donors were more resistant than human leukemia K562 cells.
  • Thumbnail Image
    Item
    Biological evaluation of donor-acceptor aminonaphthoquinones as antitumor agents
    (ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER, 2010) Benites, Julio; Valderrama, Jaime A.; Bettega, Karina; Pedrosa, Rozangela Curi; Buc Calderon, Pedro; Verrax, Julien
    Several members of the phenylamino-1,4-naphthoquinone series were prepared in order to investigate structure-activity relationships (SAR) and to explore the antitumor effects associated with this scaffold. The cytotoxic effects of the aminoquinones (EC50) against a panel of cancer cell lines (MCF7, DU145 and T24 cells) and healthy fibroblasts (BALB/3T3) were assessed in vitro using the MTT reduction assay 48 h after drug exposure. SAR analysis of the aminonaphthoquinone series showed that insertion of a chlorine atom in the acceptor quinone nucleus and/or insertion of a methyl group at the nitrogen atom of the donor phenylamino group induced significant changes in cytotoxic activity. Quinones 7 and 9, which exhibited the highest selective indexes (5.73 and 6.29, respectively), were further characterized using the following assays: Colony formation, caspase-3 activity, and ATP content. The results showed that aminoquinone 7 strongly influenced ATP levels and impaired the proliferative capacity of T24 cells without activating caspase-3. (C) 2010 Elsevier Masson SAS. All rights reserved.
  • Thumbnail Image
    Item
    Redox-Active Quinones and Ascorbate: An Innovative Cancer Therapy That Exploits the Vulnerability of Cancer Cells to Oxidative Stress
    (BENTHAM SCIENCE PUBL LTD, 2011) Verrax, Julien; Beck, Raphael; Dejeans, Nicolas; Glorieux, Christophe; Sid, Brice; Pedrosa, Rozangela C.; Benites, Julio; Vasquez, David; Valderrama, Jaime A.; Buc Calderon, Pedro
    Cancer cells are particularly vulnerable to treatments impairing redox homeostasis. Reactive oxygen species (ROS) can indeed play an important role in the initiation and progression of cancer, and advanced stage tumors frequently exhibit high basal levels of ROS that stimulate cell proliferation and promote genetic instability. In addition, an inverse correlation between histological grade and antioxidant enzyme activities is frequently observed in human tumors, further supporting the existence of a redox dysregulation in cancer cells. This biochemical property can be exploited by using redox-modulating compounds, which represent an interesting approach to induce cancer cell death. Thus, we have developed a new strategy based on the use of pharmacologic concentrations of ascorbate and redox-active quinones. Ascorbate-driven quinone redox cycling leads to ROS formation and provokes an oxidative stress that preferentially kills cancer cells and spares healthy tissues. Cancer cell death occurs through necrosis and the underlying mechanism implies an energetic impairment (ATP depletion) that is likely due to glycolysis inhibition. Additional mechanisms that participate to cell death include calcium equilibrium impairment and oxidative cleavage of protein chaperone Hsp90. Given the low systemic toxicity of ascorbate and the impairment of crucial survival pathways when associated with redox-active quinones, these combinations could represent an original approach that could be combined to standard cancer therapy.
  • No Thumbnail Available
    Item
    Substituted 3-acyl-2-phenylamino-1,4-naphthoquinones intercalate into DNA and cause genotoxicity through the increased generation of reactive oxygen species culminating in cell death
    (2014) Farias, Mirelle Sifroni; Pich, Claus Troeger; Kviecinski, Maicon Roberto; Falcao Bucker, Nadia Cristina; Felipe, Karina Bettega; Da Silva, Fabiana Ourique; Fisher Guenther, Tania Mara; Correia, Joao Francisco; Rios, David; Benites, Julio; Valderrama, Jaime A.; Buc Calderon, Pedro; Pedrosa, Rozangela Curi
    Naphthoquinones interact with biological systems by generating reactive oxygen species (ROS) that can damage cancer cells. The cytotoxicity and the antitumor activity of 3-acyl-2-phenylamino-1,4-naphthoquinones (DPB1-DPB9) were evaluated in the MCF7 human breast cancer cell line and in male Ehrlich tumor-bearing Balb/c mice. DPB4 was the most cytotoxic derivative against MCF7 cells (EC50 15 mu M) and DPB6 was the least cytotoxic one (EC50 56 mu M). The 1,4-naphthoquinone derivatives were able to cause DNA damage and promote DNA fragmentation as shown by the plasmid DNA cleavage assay (FII form). In addition, 1,4-naphthoquinone derivatives possibly interacted with DNA as intercalating agents, which was demonstrated by the changes caused in the fluorescence of the DNA-ethidium bromide complexes. Cell death of MCF7 cells induced by 3-acyl-2-phenylamino-1,4-naphthoquinones was mostly due to apoptosis. The DNA fragmentation and subsequent apoptosis may be correlated to the redox potential of the 1,4-naphthoquinone derivatives that, once present in the cell nucleus, led to the increased generation of ROS. Finally, certain 1,4-naphthoquinone derivatives and particularly DPB4 significantly inhibited the growth of Ehrlich ascites tumors in mice (73%).