Part 1: Effect of vitamin C on the biological activity of two euryfurylbenzoquinones on TLT, a murine hepatoma cell line

Benites, Julio; Rojo, Leonel E.; Valderrama, Jaime A.; Taper, Henryk; Calderón, Pedro Buc

doi:10.1016/j.ejmech.2007.11.015

Cited by 14 publications

(11 citation statements)

References 19 publications

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“…To this end, Transplantable Liver Tumor (TLT) cells-a murine hepatocarcinoma cell line-were cultured in the absence or in the presence of tellurite and biochemical and morphological determinations were carried out in order to determine the extent and type of cell death. TLT cells have been previously used to assess both in vivo and in vitro anticancer cytotoxic effects (Duerksen and Connor 1978;Taper et al 1987;Verrax et al 2004;Crokart et al 2005;Benites et al 2008). Experimental tests included lactate dehydrogenase (LDH) leakage (cell survival), ATP levels (functional ability of cells), and caspase-3 (DEVDase) activity and cleavage of poly(ADPribose)polymerase (PARP) to assess the nature of the cell demise.…”

Section: Introductionmentioning

confidence: 99%

Tellurite-induced oxidative stress leads to cell death of murine hepatocarcinoma cells

et al. 2010

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Data regarding tellurium (Te) toxicity are scarce. Studies on its metabolism, performed mainly in bacteria, underline a major role of reactive oxygen species (ROS). We investigated whether tellurite undergoes redox cycling leading to ROS formation and cancer cell death. The murine hepatocarcinoma Transplantable Liver Tumor (TLT) cells were challenged with tellurite either in the presence or in the absence of different compounds as N-acetylcysteine (NAC), 3-methyladenine, BAPTA-AM, and catalase. NAC inhibition of tellurite-mediated toxicity suggested a major role of oxidative stress. Tellurite also decreased both glutathione (GSH) and ATP content by 57 and 80%, respectively. In the presence of NAC however, the levels of such markers were almost fully restored. Tellurite-mediated ROS generation was assessed both by using the fluorescent, oxidation-sensitive probe dichlorodihydrofluorescein diacetate (DCHF-DA) and electron spin resonance (ESR) spectroscopy to detect hydroxyl radical formation. Cell death occurs by a caspase-independent mechanism, as shown by the lack of caspase-3 activity and no cleavage of poly(ADP-ribose)polymerase (PARP). The presence of gamma-H2AX suggests tellurite-induced DNA strand breaking, NAC being unable to counteract it. Although the calcium chelator BAPTA-AM did show no effect, the rapid phosphorylation of eIF2alpha suggests that, in addition to oxidative stress, an endoplasmic reticulum (ER) stress may be involved in the mechanisms leading to cell death by tellurite.

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Section: Introductionmentioning

confidence: 99%

Tellurite-induced oxidative stress leads to cell death of murine hepatocarcinoma cells

et al. 2010

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“…Techniques leading to increased ROS formation should, therefore, reinforce the efficacy of anticancer treatments. Indeed, we have recently reported that euryfuryl benzo and naphtoquinones in the absence or presence of vitamin C, can alter the survival of hepatocarcinoma cells [10,11]. The results of the current study indicate that, in addition to the ability to induce ROS formation, other physicochemical properties may also influence the activity of quinones.…”

Section: Discussionmentioning

confidence: 60%

“…In agreement with this, we recently studied the cytotoxicity of sesquiterpene quinones, namely 2-euryfuryl-and 2-euryfuryl-3-nitro-1,4-benzoquinone, on Transplantable Liver Tumor (TLT) cells, a murine hepatoma cell line [10]. The results revealed that inactivated 2-euryfuryl-3-nitro-1,4-benzoquinone could undergo an activation process by a redox mechanism causing necrosis-like cell death, whereas 2-euryfurylbenzoquinone, which would be less able to perform bioreductive activation, seemed to induce apoptosis [10]. We subsequently focused our study on 2-euryfuryl-1,4-naphthoquinone and its 5-and 5,8-hydroxy derivatives.…”

Section: Introductionmentioning

confidence: 76%

“…A large body of evidence supports the idea that oxidative stress induced by menadione (2-methyl-1,4-naphthoquinone) leads to cell death by either necrosis or apoptosis [7][8][9]. In agreement with this, we recently studied the cytotoxicity of sesquiterpene quinones, namely 2-euryfuryl-and 2-euryfuryl-3-nitro-1,4-benzoquinone, on Transplantable Liver Tumor (TLT) cells, a murine hepatoma cell line [10]. The results revealed that inactivated 2-euryfuryl-3-nitro-1,4-benzoquinone could undergo an activation process by a redox mechanism causing necrosis-like cell death, whereas 2-euryfurylbenzoquinone, which would be less able to perform bioreductive activation, seemed to induce apoptosis [10].…”

Section: Introductionmentioning

confidence: 78%

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An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities

et al. 2010

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We describe the biological activity of some furylbenzo- and naphthoquinones (furylquinones) on hepatocarcinoma cells and healthy rat liver slices. The effects of furylquinones on cancer cells (Transplantable Liver Tumor, TLT) were assessed by measuring cell death (membrane cell lysis); intracellular contents of ATP and GSH and the activity of caspase-3 were used to determine the type of cell death. Most of the furylquinones tested (at a concentration of 25 μg/ml) induced caspase-independent cell death but compound 4 had no cytotoxic effects. The levels of both ATP and GSH were severely affected by quinones 1, 2 and 5, while no effect was observed with compound 4. These cytotoxic properties of quinones are associated with physico-chemical properties as shown by the LUMO energies and lipophilicity. Interestingly, no cytotoxic effects of furylquinones were detected when the in vitro model of precision-cut liver slices (PCLS) was used. Indeed, although CYP2E1 activity was slightly affected, ATP and GSH levels as well as protein synthesis were not modified by furylquinones. Paracetamol, a well-known hepatotoxicant, reduced these parameters by more than 80% compared to control conditions. Taking into account the considerable incidence of adverse-effects induced by most current anticancer drugs, the selective cytotoxicity shown by compounds 1, 2 and 5, in particular that of 1, represents a safety factor that encourages the further development of these quinones as new drugs in cancer therapy.

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“…As part of our current research program on sesquiterpene quinones we have recently reported a study with 2-euryfuryland 2-euryfuryl-3-nitro-1,4-benzoquinone on their cytotoxicity towards transplantable liver tumor (TLT) cells in the absence and in the presence of vitamin C. 12) Our findings revealed that inactivated 2-euryfuryl-3-nitro-1,4-benzoquinone could undergo an activation process by a redox mechanism causing cell death on TLT cells, whereas 2-euryfurylbenzoquinone, which would be less capable of bioreductive activation, seems to induce apoptosis (as shown by the increased activity of caspase-3), irrespective of the presence or the absence of vitamin C. 12) In continuation of these studies we focused our attention on 2-euryfuryl-1,4-naphthoquinone C 1 and its 5-and 5,8-hydroxyderivatives C 2 and C 3 . Our interest in these particular compounds is related to the influence of both the electronic and hydrogen bond effects of hydroxy groups located at the peri position of C 1 on the oxidative stress-mediated effects.…”

Section: )mentioning

confidence: 99%

Part 2: Influence of 2-Euryfuryl-1,4-naphthoquinone and Its peri-Hydroxy Derivatives on Both Cell Death and Metabolism of TLT Cells, a Murine Hepatoma Cell Line. Modulation of Cytotoxicity by Vitamin C

Benites

Valderrama

Taper

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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NotesCancer, second cause of mortality in the world (about 1700000 deaths in Europe in 2006) 1) is a leading life-threatening pathology characterized by a deregulation of the cell cycle which results in a progressive loss of the cellular differentiation and a non-controlled cellular growth. In spite of the enormous diversity of human cancers, cancer cells have acquired the same set of functional capabilities: self sufficiency in growth signals, insensitivity to growth signals, sustained angiogenesis, limitless replication potential, tissue invasion and metastasis, and evasion of apoptosis.2) Moreover, cancer cells are presenting an almost universal glycolytic phenotype,3) a deficiency in antioxidant enzymes like catalase and superoxide dismutase, 4,5) and a trend to accumulate vitamin C. 6)Interestingly, two vitamins, namely ascorbate (vitamin C) and menadione (vitamin K 3 ) were reported to potentiate both chemo-and radiotherapy in tumor-bearing mice. 7,8) It should be noted that the action of these compounds is not related to their action as vitamins, but rather involves a cytolytic process that takes advantage of tumor metabolism. Indeed, we have shown that the combination of ascorbate and menadione generates oxidative stress, leads to the inhibition of glycolysis and induces a necrotic cell death.9,10) This mechanism could be of particular interest in cancer therapy for several reasons. First, since many tumors exhibit defects in the apoptotic signaling pathways, there is a need for additional mechanisms to induce cell death. Second, as mentioned previously, cancer cells are expected to be more sensitive towards an oxidant stress than healthy cells because they are often deficient in antioxidant defenses. Third, due to the high energetic dependence of cancer cells on glycolysis, the impairment of such an essential pathway will be critical for their survival.We took advantage of these features to develop an original approach that consists in the exposure of cancer cells to an oxidant insult. Indeed, a redox cycle is initiated by electron transfer from ascorbate to menadione leading to the formation of a semiquinone free radical. The rapid reoxidation of the semiquinone to its quinone form by molecular oxygen leads to generation of reactive oxygen species (ROS). Among them, we have recently reported that: first, the main ROS formed is H 2 O 2 , and second, it may be formed by redox cycling between ascorbate and other quinones depending on their half-redox potentials and the stabilities of the semiquinone species. 11)As part of our current research program on sesquiterpene quinones we have recently reported a study with 2-euryfuryland 2-euryfuryl-3-nitro-1,4-benzoquinone on their cytotoxicity towards transplantable liver tumor (TLT) cells in the absence and in the presence of vitamin C. 12) Our findings revealed that inactivated 2-euryfuryl-3-nitro-1,4-benzoquinone could undergo an activation process by a redox mechanism causing cell death on TLT cells, whereas 2-euryfurylbenzoquinone, which would be less cap...

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Part 1: Effect of vitamin C on the biological activity of two euryfurylbenzoquinones on TLT, a murine hepatoma cell line

Cited by 14 publications

References 19 publications

Tellurite-induced oxidative stress leads to cell death of murine hepatocarcinoma cells

Tellurite-induced oxidative stress leads to cell death of murine hepatocarcinoma cells

An in vitro comparative study with furyl-1,4-quinones endowed with anticancer activities

Part 2: Influence of 2-Euryfuryl-1,4-naphthoquinone and Its peri-Hydroxy Derivatives on Both Cell Death and Metabolism of TLT Cells, a Murine Hepatoma Cell Line. Modulation of Cytotoxicity by Vitamin C

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