Concomitant treatment with pertussis toxin plus temozolomide increases the survival of rats bearing intracerebral RG2 glioma

Magaña-Maldonado, Roxana; Manoutcharian, Karen; Hernández‐Pedro, Norma; Rangel-López, Edgar; Cruz, Verónica Pérez-De La; Rodríguez-Balderas, Cesar; Sotelo, Julio; Pineda, Benjamín

doi:10.1007/s00432-013-1565-3

Cited by 15 publications

(14 citation statements)

References 35 publications

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“…At the moment, we cannot exclude the possibility that the autophagy pathway contributes to the CNF1-induced phenotype. A recent paper indicates the activation of the autophagy pathway following the treatment of glioma cells with pertussis toxin and TMZ [27]. Future studies are needed to clarify the possible role of autophagy in the antitumoral action of CNF1.…”

Section: Discussionmentioning

confidence: 99%

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model

et al. 2014

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BackgroundGlioblastomas are largely unresponsive to all available treatments and there is therefore an urgent need for novel therapeutics. Here we have probed the antineoplastic effects of a bacterial protein toxin, the cytotoxic necrotizing factor 1 (CNF1), in the syngenic GL261 glioma cell model. CNF1 produces a long-lasting activation of Rho GTPases, with consequent blockade of cytodieresis in proliferating cells and promotion of neuron health and plasticity.MethodsWe have tested the antiproliferative effects of CNF1 on GL261 cells and human glioma cells obtained from surgical specimens. For the in vivo experiments, we injected GL261 cells into the adult mouse visual cortex, and five days later we administered either a single intracerebral dose of CNF1 or vehicle. To compare CNF1 with a canonical antitumoral drug, we infused temozolomide (TMZ) via minipumps for 1 week in an additional animal group.ResultsIn culture, CNF1 was very effective in blocking proliferation of GL261 cells, leading them to multinucleation, senescence and death within 15 days. CNF1 had a similar cytotoxic effect in primary human glioma cells. CNF1 also inhibited motility of GL261 cells in a scratch-wound migration assay. Low dose (2 nM) CNF1 and continuous TMZ infusion significantly prolonged animal survival (median survival 35 days vs. 28 days in vehicle controls). Remarkably, increasing CNF1 concentration to 80 nM resulted in a dramatic enhancement of survival with no obvious toxicity. Indeed, 57% of the CNF1-treated animals survived up to 60 days following GL261 glioma cell transplant.ConclusionsThe activation of Rho GTPases by CNF1 represents a novel potential therapeutic strategy for the treatment of central nervous system tumors.

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Section: Discussionmentioning

confidence: 99%

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model

et al. 2014

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“…Cellular death was assessed with propidium iodide according to Magana-Maldonado et al [ 52 ]. Astrocytes were incubated with the combinations of CuSO 4 (350 μ M) with 3-HK or 3-HANA (100 μ M) in DMEM medium for 24 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

3‐Hydroxykynurenine and 3‐Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture

Ramírez-Ortega

Ramiro-Salazar

González-Esquivel

et al. 2017

Oxidative Medicine and Cellular Longevity

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Copper is an integral component of various enzymes, necessary for mitochondrial respiration and other biological functions. Excess copper is related with neurodegenerative diseases as Alzheimer and is able to modify cellular redox environment, influencing its functions, signaling, and catabolic pathways. Tryptophan degradation through kynurenine pathway produces some metabolites with redox properties as 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HANA). The imbalance in their production is related with some neuropathologies, where the common factors are oxidative stress, inflammation, and cell death. This study evaluated the effect of these kynurenines on the copper toxicity in astrocyte cultures. It assessed the CuSO4 effect, alone and in combination with 3-HK or 3-HANA on MTT reduction, ROS production, mitochondrial membrane potential (MMP), GHS levels, and cell viability in primary cultured astrocytes. Also, the chelating copper effect of 3-HK and 3-HANA was evaluated. The results showed that CuSO4 decreased MTT reduction, MMP, and GSH levels while ROS production and cell death are increasing. Coincubation with 3-HK and 3-HANA enhances the toxic effect of copper in all the markers tested except in ROS production, which was abolished by these kynurenines. Data suggest that 3-HK and 3-HANA increased copper toxicity in an independent manner to ROS production.

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“… Concomitant treatment with TMZ and PTx elicited autophagic cell death in vitro and increased the survival in RG2 glioma model. [ 122 ] …”

Section: Isocitrate Dehydrogenase 1 Mutationmentioning

confidence: 99%

Targeting autophagy to sensitive glioma to temozolomide treatment

Yan

Dai

et al. 2016

J Exp Clin Cancer Res

257

188

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Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

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Concomitant treatment with pertussis toxin plus temozolomide increases the survival of rats bearing intracerebral RG2 glioma

Abstract: We show that the concomitant use of pertussis toxin plus TMZ could represent an advantage to improve the glioma treatment.

Cited by 15 publications

References 35 publications

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model

The bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1) provides long-term survival in a murine glioma model

3‐Hydroxykynurenine and 3‐Hydroxyanthranilic Acid Enhance the Toxicity Induced by Copper in Rat Astrocyte Culture

Targeting autophagy to sensitive glioma to temozolomide treatment

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