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Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof

a technology of autophagy and pharmaceutical compositions, applied in drug compositions, metabolic disorders, cardiovascular disorders, etc., can solve problems such as maladaptive tissue remodeling

Inactive Publication Date: 2016-09-01
INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM) +6
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that acetyl CoA (AcCoA) plays a crucial role in regulating starvation-induced autophagy, a process of self-digestion. The inventors found that nutrient starvation causes rapid depletion of AcCoA, preceding that of ATP or NADH. Increasing or maintaining high AcCoA levels inhibits maladaptive autophagy and induces zimophagy, a beneficial form of autophagy. The invention provides novel methods for modulating autophagy and treating autophagy-related diseases, including pancreatitis. The use of AcCoA depleting agents such as hydroxycitric acid can trigger zimophagy and improve the symptomatology of the disease.

Problems solved by technology

Although autophagy plays a major role in antagonizing degenerative processes and unwarranted cell death, its excessive induction may result in maladaptive tissue remodeling (Cao et al., 2013; Choi et al., 2013; Levine and Kroemer, 2008; Zhu et al., 2007).

Method used

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  • Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof
  • Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof
  • Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof

Examples

Experimental program
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Effect test

example 1

Chemicals, Cell Lines and Culture Conditions

[0110]Unless otherwise specified, chemicals were purchased from Sigma-Aldrich (St. Louis, USA), culture media and supplements for cell culture from Gibco-Invitrogen (Carlsbad, USA) and plastic ware from Corning (Corning, USA). Human colon carcinoma HCT 116 cells were cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 mg / L sodium pyruvate, 10 mM HEPES buffer, 100 units / mL penicillin G sodium and 100 μg / mL streptomycin sulfate (37° C., 5% CO2). Human osteosarcoma U2Os cells, their GFP-LC3-expressing derivatives, human neuroblastoma H4 GFP-LC3 (gift from Prof J. Yuan) cells and human GFP-LC3-expressing HeLa cells were cultured in DMEM medium containing 10% fetal bovine serum, 100 mg / L sodium pyruvate, 10 mM HEPES buffer, 100 units / mL penicillin G sodium and 100 μg / mL streptomycin sulfate (37° C., 5% CO2). Mouse embryo fibroblasts (MEFs) were cultured in the same DMEM with additional supplementation of non-essential amino-aci...

example 2

Results

[0154]Inhibition of Autophagy by Acetyltransferases and Acetylproteins.

[0155]One of the best-studied physiological inducers of autophagy is energy depletion, as it results from exposing cells to nutrient-free media or by subjecting mice to starvation (Mizushima and Komatsu, 2011). Mass spectrometric metabolomic profiling of starved cells (in vitro) or organs (in vivo) revealed the intracellular depletion of very few common metabolites including acetyl CoA (AcCoA). Starvation-induced AcCoA depletion could be confirmed in murine and human cell lines, both in total cellular homogenates and cytosolic fractions, with a stronger effect observed in the latter. Interestingly, the starvation-induced decrease of AcCoA was not accompanied by the depletion of neither ATP nor NADH at the analyzed incubation times. In mice, heart and muscle tissues respond to nutrient depletion by mounting a strong autophagic response (Mizushima et al., 2004), which we found to be commensurated with a dras...

example 3

Results

[0180]Starvation Induces Depletion of Acetyl-CoA and Protein Deacetylation

[0181]Autophagy can be potently induced by exposing cells to nutrient-free media or by subjecting mice to starvation (Mizushima and Komatsu, 2011). Mass spectrometric metabolomic profiling of starved cells (in vitro) or organs (in vivo) revealed the intracellular depletion of very few common metabolites, one of which was AcCoA. Starvation-induced AcCoA depletion could be confirmed in murine and human cell lines, both in total cellular homogenates and in cytosolic fractions. At the analyzed short (<6 hr) incubation times, the starvation-induced decrease of AcCoA was not accompanied by the depletion of ATP or NADH. In mice, heart and muscle tissues responded to nutrient depletion by mounting a strong autophagic response (Mizushima et al., 2004), which we found to be commensurate with a reduction in AcCoA levels and a decrease in cytoplasmic protein acetylation. In contrast, brain tissue, in which autophag...

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Abstract

The present invention provides novel methods for the modulation of autophagy and the treatment of autophagy-related diseases, including cancer, neurodegenerative diseases, liver diseases, muscle diseases and pancreatitis.

Description

FIELD OF THE INVENTION[0001]The present inventions relates to methods and pharmaceutical compositions for modulating (i.e. inducing or inhibiting) autophagy in a subject in need thereof.BACKGROUND OF THE INVENTION[0002]Macroautophagy (“autophagy”) involves the highly regulated sequestration of cytoplasmic organelles or portions of the cytosol in double-membrane vesicles, called autophagosomes, which fuse with lysosomes resulting in the degradation of the inner autophagosomal membrane and luminal content (Mizushima and Komatsu, 2011). Autophagy plays an essential role in cellular adaptation to multiple types of stress, recycling of superfluous or damaged cellular material, quality control of organelles, removal of protein aggregates, and destruction of intracellular pathogens (Kroemer et al., 2010). Disabled or insufficient autophagy participates in the pathogenesis of multiple infectious diseases, autoimmune or autoinflammatory states, malignant transformation, neuro- or myodegenera...

Claims

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Application Information

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IPC IPC(8): A61K31/7076A61K31/4458A61K31/235A61K45/06A61K31/4155A61K31/22A61K31/385A61K31/19A61K31/405A61K31/225
CPCA61K31/7076A61K31/405A61K31/4458A61K31/235A61K45/06A61K31/4155A61K31/22A61K31/385A61K31/19A61K31/225A61K31/194A61K31/216A61K31/7008A61P3/00A61P9/00A61P25/00A61P29/00A61P31/00A61P35/00
Inventor KROEMER, GUIDOMARINO, GUILLERMOPIETROCOLA, FEDERICO
Owner INST NAT DE LA SANTE & DE LA RECHERCHE MEDICALE (INSERM)
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