Inhibition of rat liver microsomal lipid peroxidation elicited by 2,2-dimethylchromenes and chromans containing fluorinated moieties resistant to cytochrome P-450 metabolism

Irurre, Josep; Casas, Josefina; Ramos, Isabel; Messeguer, Àngel

doi:10.1016/s0968-0896(00)82124-0

Cited by 24 publications

(13 citation statements)

References 14 publications

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“…CR‐6 is an analogue of the active component of the vitamin E complex tocopherol. Previous work has demonstrated CR‐6 capacity to scavenge both ROS and radical nitrogen intermediates (Irurre et al . 1993; Montoliu et al .…”

Section: Discussionmentioning

confidence: 99%

“…CR-6 is an analogue of the active component of the vitamin E complex tocopherol. Previous work has demonstrated CR-6 capacity to scavenge both ROS and radical nitrogen intermediates (Irurre et al 1993;Montoliu et al 1999;Sanvicens et al 2004). Moreover, while CR-6 chemical structure retains the ability to react with radical species, it lacks the hydrophobic hydrocarbonated tail present in tocopherols.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, while CR-6 chemical structure retains the ability to react with radical species, it lacks the hydrophobic hydrocarbonated tail present in tocopherols. As a result, CR-6 exhibits improved bioavailability characteristics and in vitro studies have already shown that CR-6 antioxidant activity is higher than that elicited by its natural occurring precursor (Irurre et al 1993;Sanvicens et al 2004). In the present study, we have shown CR-6 ability to reduce ROS overproduction in H 2 O 2 -treated SH-SY5Y cells in a dose-dependent manner (Fig.…”

Section: Discussionmentioning

confidence: 99%

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The radical scavenger CR‐6 protects SH‐SY5Y neuroblastoma cells from oxidative stress‐induced apoptosis: effect on survival pathways

Sanvicens

Gómez‐Vicente

Messeguer

et al. 2006

Journal of Neurochemistry

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Reactive oxygen species (ROS) and oxidative stress have long been linked to cell death of neurons in many neurodegenerative conditions. However, the exact molecular mechanisms triggered by oxidative stress in neurodegeneration are at present unclear. In the current work we have used the human neuroblastoma SH-SY5Y cell line as a model for studying the molecular events occurring after inducing apoptosis with H 2 O 2 . We show that treatment of SH-SY5Y cells with H 2 O 2 up-regulates survival pathways during early stages of apoptosis. Subsequently, the decline of anti-apoptotic protein levels leads to the activation of the calcium-dependent proteases calpains and the cysteine proteases caspases. Additionally, we demonstrate that CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) acts as a scavenger of ROS and prevents apoptosis by enhancing and prolonging up-regulation of survival pathways. Furthermore, we show that pre-treatment of SH-SY5Y cells with a cocktail containing CR-6, the pan-caspase inhibitor zVAD-fmk (zVal-Ala-Asp-fluoro-methylketone) and the calpain inhibitor SJA6017 confers almost total protection against apoptosis. In summary, the present work characterizes the molecular mechanisms involved in oxidative stress-induced apoptosis in SH-SY5Y cells. Our findings highlight the relevance of CR-6, alone or in combination with other drugs, as potential therapeutic strategy for the treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The radical scavenger CR‐6 protects SH‐SY5Y neuroblastoma cells from oxidative stress‐induced apoptosis: effect on survival pathways

Sanvicens

Gómez‐Vicente

Messeguer

et al. 2006

Journal of Neurochemistry

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“…It is therefore essential to know more about these effects, in order to restrain them. CR-6 (3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran) is an a-tocopherol analogue that has shown a potent inhibitory activity against lipid peroxidation in rat liver microsomes [16] and a neuroprotective effect related to its efficient nitric oxide and peroxynitrite scavenging capacity [17].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in Rat Retina and Hippocampus after Chronic MDMA (‘ecstasy’) Administration

et al. 2007

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The effects of MDMA administration on oxidative stress markers in rat eye and hippocampus, and the neuroprotective effects of the antioxidant 3,4-dihydro-6-hydroxy-7-methoxy-2,2-dimethyl-1(2H)-benzopyran (CR-6) have been studied. MDMA effects on liver were used for comparison with those in eye and hippocampus and to test CR-6 protective effects. Another goal was to test for apoptosis in retinal cells, as it is known that happens in liver and brain. After 1 week of ecstasy administration, malondialdehyde (MDA) concentration increased, glutathione peroxidase (GPx) activity and glutathione (GSH) content decreased in liver, as previously described. MDA concentration increased and GPx activity decreased in hippocampus; whereas no change was observed in GSH concentration. MDMA decreased ocular GSH concentration and GPx activity; no change was observed in MDA concentration. The number of TUNEL-positive nuclei increased significantly in rat retinas after 1 week of MDMA administration. CR-6 normalized the modifications in liver, hippocampus and retina mentioned above.

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“…The GP-Pharm liposomal doxorubicin is a nonpegylated (NPLD) formulation that differs from other liposomal formulations in that the active doxorubicin is located within the liposome membrane and not within the interior of the molecule. It also contains a small amount of lipochromane-6, a molecule with antioxidant properties, that is, a scavenger of radical oxygen species (ROS) that stabilizes the liposome (Casas et al, 1992;Messequer, 2006;Lipinski et al, 1997;Irurre et al, 1993). Preclinical studies have demonstrated that the liposomal formulation with the addition of lipochromane-6 has a lower cardiac toxicity than the formulation without lipochromane-6.…”

Section: Introductionmentioning

confidence: 99%

A phase I clinical and pharmacokinetic study (LIPOTEC - GP PHARM/DOXO 01) of a new liposomal doxorubicin given as 3-week schedule in patients with solid tumors

Majem¹,

Salazar²,

García³

et al. 2009

Journal of Liposome Research

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As a dose-finding phase I study of a new liposomal formulation of doxorubicin (LipD), patients (n = 39; median age: 60 years; range, 41-75; median ECOG performance status, 1; range, 0-2) with refractory cancer had a starting dose of LipD administered at 30 mg/m(2) as a 1-hour intravenous infusion. Cycle duration was 21 days. At the recommended dose (RD), patients received a first cycle of nonliposomal doxorubicin (non-LipD) to evaluate intrapatient pharmacokinetic differences between non-LipD and LipD. The most frequent diagnosis was head and neck tumor (7 patients). Tolerance and safety of dose levels of 30, 40, 50, 60, 70, 80, and 90 mg/m(2) were evaluated. A total of 131 cycles were administered (median per patient, 3; range, 1-6). Of the 39 patients, 8 completed the planned six cycles. Febrile neutropenia was dose limiting and defined the toxic dose of LipD as 70 mg/m(2). Other significant toxicities included asthenia (G2: 31%; G3: 8%), neutropenia (G3: 35%; G4: 29%), thrombopenia (G3: 15%; G4: 2%), anemia (G1-G2: 67%; G3-G4: 5%), mucositis (G1-G2: 32%, G3: 4%), and acute allergic reactions (G1-G2: 36%). Comparison of pharmacokinetic profiles of non-LipD and LipD showed that higher exposure was achieved with LipD. Stable disease was observed in 14 patients. We conclude that the LipD regimen, given as a 1-hour infusion every 3 weeks, is well tolerated and has a favorable pharmacokinetic profile. The recommended dose is 70 mg/m(2) with prophylactic antihistamines and corticoids to preempt allergic reaction.

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Inhibition of rat liver microsomal lipid peroxidation elicited by 2,2-dimethylchromenes and chromans containing fluorinated moieties resistant to cytochrome P-450 metabolism

Cited by 24 publications

References 14 publications

The radical scavenger CR‐6 protects SH‐SY5Y neuroblastoma cells from oxidative stress‐induced apoptosis: effect on survival pathways

The radical scavenger CR‐6 protects SH‐SY5Y neuroblastoma cells from oxidative stress‐induced apoptosis: effect on survival pathways

Oxidative Stress in Rat Retina and Hippocampus after Chronic MDMA (‘ecstasy’) Administration

A phase I clinical and pharmacokinetic study (LIPOTEC - GP PHARM/DOXO 01) of a new liposomal doxorubicin given as 3-week schedule in patients with solid tumors

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