Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Kusne, Yael; Goldberg, Emily L.; Parker, Sara S.; Hapak, Sophie M.; Maskaykina, Irina Y.; Chew, Wade M.; Limesand, Kirsten H.; Brooks, Heddwen L.; Price, Theodore J.; Sanai, Nader; Nikolich-Zugich, Janko; Ghosh, Sourav

doi:10.1007/s11357-013-9572-5

Cited by 8 publications

(70 citation statements)

References 69 publications

(70 reference statements)

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“…In response to Lm-gp33 challenge, we confirmed that the memory response generated following rapa treatment conferred better protection, as mice that had been treated with rapa during their primary LCMV infection had improved bacterial clearance in the spleen on day 3 post-challenge (Supplemental Figure 2C). We further confirmed that at this dosing regimen, our mice experienced similar rapa exposure based on blood drug concentrations, which ranged from 8-15ng/ml (9), well within the range of 5-20ng/ml reported by Araki et al (3). We conclude that our experimental conditions were similar to those previously reported and that depressed CD8 T cell effector function during the primary infection is indeed a consequence of the rapa treatment.…”

Section: Resultssupporting

confidence: 89%

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Immune Memory–Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections

Goldberg

Doty

Lutes

et al. 2014

The Journal of Immunology

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Direct mTORC1 inhibition by short-term low-dose rapamycin treatment has recently been shown to improve CD8 T cell immunological memory. While these studies focused on memory development, the impact of low-dose rapamycin on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. We investigated the impact of acute rapamycin treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose rapamycin treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naïve cells and the reduced formation of short-lived effector cells (SLEC). Therefore, more than one cell type required for a protective effector immune response are impaired by rapamycin in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of rapamycin treatment as means to improve immune memory.

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Section: Resultssupporting

confidence: 89%

“…For in vitro assays, rapa was added at indicated concentrations to the cells at the outset of the assay and kept present throughout. For in vivo experiments rapa was quantified in whole blood as described previously (9), at the University of Arizona and the Texas Biomedical Research Institute (San Antonio, TX), with highly concordant results.…”

Section: Methodsmentioning

confidence: 99%

Immune Memory–Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections

Goldberg

Doty

Lutes

et al. 2014

The Journal of Immunology

Self Cite

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“…Thus, the different activity and availability of CLIC1 as active chloride channel in normal and tumoral cells, dictates the strict selectivity of metformin towards CSCs. The specificity of metformin's effects is corroborated by the observation that in diabetic patients and in experimental studies, chronic metformin treatment is not toxic to normal stem cells [ 55 , 56 ], in contrast with mTOR inhibitors [ 55 ]. The observations that CLIC1 chloride current is essential for human GBM CSC proliferation [ 32 ] and that metformin preferentially affects CSC viability [ 17 ] support this assumption.…”

Section: Discussionmentioning

confidence: 98%

Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

et al. 2014

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Epidemiological and preclinical studies propose that metformin, a first-line drug for type-2 diabetes, exerts direct antitumor activity. Although several clinical trials are ongoing, the molecular mechanisms of this effect are unknown.Here we show that chloride intracellular channel-1 (CLIC1) is a direct target of metformin in human glioblastoma cells. Metformin exposure induces antiproliferative effects in cancer stem cell-enriched cultures, isolated from three individual WHO grade IV human glioblastomas. These effects phenocopy metformin-mediated inhibition of a chloride current specifically dependent on CLIC1 functional activity. CLIC1 ion channel is preferentially active during the G1-S transition via transient membrane insertion. Metformin inhibition of CLIC1 activity induces G1 arrest of glioblastoma stem cells. This effect was time-dependent, and prolonged treatments caused antiproliferative effects also for low, clinically significant, metformin concentrations. Furthermore, substitution of Arg29 in the putative CLIC1 pore region impairs metformin modulation of channel activity.The lack of drugs affecting cancer stem cell viability is the main cause of therapy failure and tumor relapse. We identified CLIC1 not only as a modulator of cell cycle progression in human glioblastoma stem cells but also as the main target of metformin's antiproliferative activity, paving the way for novel and needed pharmacological approaches to glioblastoma treatment.

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“…The authors observed no influence in proliferation or neuronal cell differentiation in their experiments. In contrast, rapamycin, also a commonly used mTOR inhibitor, leads to a decrease in neural progenitors in mice in vitro [Kusne et al, 2014].…”

Section: Metformin Does Not Influence Sgn Survival or Outgrowthmentioning

confidence: 99%

“…However, our observation is in line with observations in the central nervous system. Kusne et al [2014] analyzed the effect of metformin on neural stem cells of mice in vitro. The authors observed no influence in proliferation or neuronal cell differentiation in their experiments.…”

Section: Metformin Does Not Influence Sgn Survival or Outgrowthmentioning

confidence: 99%

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

et al. 2015

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Metformin is a commonly used antidiabetic drug. It has been shown that this drug activates the AMP-activated protein kinase, which inhibits downstream the mammalian target of rapamycin. In addition, several studies indicate that metformin reduces intracellular reactive oxygen species. Our data, using an in vitro rat model, indicate that metformin is able to protect auditory hair cells (HCs) from gentamicin-induced apoptotic cell death. Moreover, metformin has no toxic effect on spiral ganglion neuronal survival or outgrowth in vitro. These results suggest a protective effect of metformin on auditory HC survival in gentamicin-induced HC loss in vitro.

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Contrasting effects of chronic, systemic treatment with mTOR inhibitors rapamycin and metformin on adult neural progenitors in mice

Cited by 8 publications

References 69 publications

Immune Memory–Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections

Immune Memory–Boosting Dose of Rapamycin Impairs Macrophage Vesicle Acidification and Curtails Glycolysis in Effector CD8 Cells, Impairing Defense against Acute Infections

Metformin repositioning as antitumoral agent: selective antiproliferative effects in human glioblastoma stem cells, via inhibition of CLIC1-mediated ion current

Metformin Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

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