Casiopeína IIgly induced cytotoxicity to HeLa cells depletes the levels of reduced glutathione and is prevented by dimethyl sulfoxide

Alemón-Medina, Radamés; Muñoz-Sánchez, José Luis; Ruíz-Azuara, Lena; Gracia-Mora, Isabel

doi:10.1016/j.tiv.2007.11.011

Cited by 44 publications

(29 citation statements)

References 20 publications

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“…In fact, copper phen complexes have been characterized in the past three decades as agents for the oxidative modification of DNA [46][47][48]. Oxidative damage to DNA and/or other critical targets is thus a prime suspect for the toxicity of our complexes, this effect has been observed in several models where the increment of ROS is concomitant with DNA degradation [23], DNA oxidation [30], depletion of reduced glutathione [49] and/or cell death by apoptotic and non apoptotic dose-dependent mechanisms [24][25][26]. Multiple mechanisms might be involved in the production of ROS, e.g.…”

Section: Discussionmentioning

confidence: 99%

Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N–N)(acetylacetonato)]NO3 and [Cu(N–N)(glycinato)]NO3 complexes, (Casiopeínas®)

Bravo-Gómez

García‐Ramos

Gracia-Mora

et al. 2009

Journal of Inorganic Biochemistry

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Section: Discussionmentioning

confidence: 99%

Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N–N)(acetylacetonato)]NO3 and [Cu(N–N)(glycinato)]NO3 complexes, (Casiopeínas®)

Bravo-Gómez

García‐Ramos

Gracia-Mora

et al. 2009

Journal of Inorganic Biochemistry

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200

110

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“…Cas IIgly is 10- to 100-fold more active than cisplatin in culture cell models and has good therapeutic indexes in animal tumor models (Leal-García et al, 2007). Cisplatin is a DNA alkylating agent and Cas IIgly a DNA intercalating agent, yet both exert prooxidant effects in the cell and have been associated with mitochondrial dysfunction and caspase-dependent and -independent programmed cell death (apoptosis) (Marín-Hernández et al, 2003; Trejo-Solís et al, 2005; Rivero-Müller et al, 2007; Alemón-Medina et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells

et al. 2010

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Casiopeínas are a series of mixed chelate copper complexes that are being evaluated as anticancer agents. Their effects in the cell include oxidative damage and mitochondrial dysfunction, yet the molecular mechanisms leading to such effects remain unclear. We tested whether [Cu(4,7-dimethylphenanthroline)(glycinate)]NO 3 (Casiopeína IIgly or Cas IIgly) could alter cellular glutathione (GSH) levels by redox cycling with GSH to generate ROS and cellular oxidative stress. Cas IIgly induced a dramatic drop in intracellular levels of GSH in human lung cancer H157 and A549 cells, and is able to use GSH as source of electrons to catalyze the Fenton reaction. In both cell lines, the toxicity of Cas IIgly (2.5-5 μM) was potentiated by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) and diminished by the catalytic antioxidant manganese(III) meso-tetrakis(N,N′-diethylimidazolium-2-yl)porphyrin (MnTDE-1,3-IP 5+ ), thus supporting an important role for oxidative stress. Cas IIgly also caused an over-production of reactive oxygen species (ROS) in the mitochondria and a depolarization of the mitochondrial membrane. Moreover, Cas IIgly produced mitochondrial DNA damage that resulted in an imbalance of the expression of the apoproteins of the mitochondrial respiratory chain, which also can contribute to increased ROS production. These results suggest that Cas IIgly initiates multiple possible sources of ROS overproduction leading to mitochondrial dysfunction and cell death.

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“…The Copper-based drug Cas II-gly has shown its ability to promote DNA fragmentation and apoptosis in a process mediated by reactive oxygen species in a number of tumor cells tumor cells [6], [9], [15], [18], [41]. In this sense, it has been described that some metals such as Copper and some complexes of them, are cytotoxic due to their high potential to participate in redox reactions.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptosis is characterized by morphological and biochemical events such as the activation of caspases, chromatin condensation and rearrangement at the nuclear periphery, as well as DNA fragmentation, cell shrinkage, and the formation of apoptotic bodies [15]. Cell death induced by Cas II-gly is concomitant with ROS increase [15], [41] and the mechanisms involved could be related to Cas II-gly capability to activate by a Fenton-like reaction using naturally occurring cell reducing agents as the source of electrons [19], [41].…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Gene Expression Analysis Reveals Casiopeína-Induced Apoptosis Pathways

et al. 2013

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Copper-based chemotherapeutic compounds Casiopeínas, have been presented as able to promote selective programmed cell death in cancer cells, thus being proper candidates for targeted cancer therapy. DNA fragmentation and apoptosis–in a process mediated by reactive oxygen species–for a number of tumor cells, have been argued to be the main mechanisms. However, a detailed functional mechanism (a model) is still to be defined and interrogated for a wide variety of cellular conditions before establishing settings and parameters needed for their wide clinical application. In order to shorten the gap in this respect, we present a model proposal centered in the role played by intrinsic (or mitochondrial) apoptosis triggered by oxidative stress caused by the chemotherapeutic agent. This model has been inferred based on genome wide expression profiling in cervix cancer (HeLa) cells, as well as statistical and computational tests, validated via functional experiments (both in the same HeLa cells and also in a Neuroblastoma model, the CHP-212 cell line) and assessed by means of data mining studies.

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Casiopeína IIgly induced cytotoxicity to HeLa cells depletes the levels of reduced glutathione and is prevented by dimethyl sulfoxide

Cited by 44 publications

References 20 publications

Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N–N)(acetylacetonato)]NO3 and [Cu(N–N)(glycinato)]NO3 complexes, (Casiopeínas®)

Antiproliferative activity and QSAR study of copper(II) mixed chelate [Cu(N–N)(acetylacetonato)]NO3 and [Cu(N–N)(glycinato)]NO3 complexes, (Casiopeínas®)

Casiopeína IIgly-induced oxidative stress and mitochondrial dysfunction in human lung cancer A549 and H157 cells

Whole Genome Gene Expression Analysis Reveals Casiopeína-Induced Apoptosis Pathways

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