WO2009092170A1 - Utilisation d'éther lipides antitumoraux glycosylés pour induire et/ou activer l'autophagie en vue de traiter des maladies - Google Patents

Utilisation d'éther lipides antitumoraux glycosylés pour induire et/ou activer l'autophagie en vue de traiter des maladies Download PDF

Info

Publication number
WO2009092170A1
WO2009092170A1 PCT/CA2009/000083 CA2009000083W WO2009092170A1 WO 2009092170 A1 WO2009092170 A1 WO 2009092170A1 CA 2009000083 W CA2009000083 W CA 2009000083W WO 2009092170 A1 WO2009092170 A1 WO 2009092170A1
Authority
WO
WIPO (PCT)
Prior art keywords
autophagy
cells
diseases
induce
disease
Prior art date
Application number
PCT/CA2009/000083
Other languages
English (en)
Inventor
Gilbert Arthur
Robert Bittman
Original Assignee
University Of Manitoba
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University Of Manitoba filed Critical University Of Manitoba
Publication of WO2009092170A1 publication Critical patent/WO2009092170A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7008—Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages

Definitions

  • Autophagy is a normal physiological process and is one of the major degradative routes in cells (Klionsky, DJ and Emr, SD (2000), Autophagy as a regulated pathway of cellular degradation. Science 290, 1717-17201). Autophagy degrades proteins, protein complexes, and organelles along with other cytoplasmic constituents and it supplies nutrients to cells during starvation conditions. Three types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy have been identified (Cuervo, AM (2004) Autophagy: Many paths to the same end. MoI Cell Biochem 263, 55-72). They all ultimately shepherd molecules destined for degradation to the lysosomes.
  • Chaperone-mediated autophagy selectively targets proteins in the cytosol that associate with the chaperone protein Hsc73 and moves them directly across the lysosomal membrane to the lumen for digestion.
  • invaginations of the lysosomal membranes results in cytoplasmic material being taken into the lysosomal lumen.
  • the bulk of autophagy occurring in cells is macroautophagy, which is the subject of this invention.
  • macroautophagy an initiating membrane called the phagophore is formed in the cytosol which grows and encompasses cytoplasmic material.
  • a number of specific proteins produced from autophagy-related (ATG) genes are intimately involved in the various events that constitute autophagy.
  • One of the key events appears to be the conjugation of phosphatidylethanolamine to the protein LC3 (ATG8) to form LC3-II (2).
  • the formation of LC3-II is the accepted marker for autophagy (Mizushima, N, 2004, Methods for monitoring autophagy. lnt J Biochem Cell Biol 36, 2491-2502).
  • LC3 is the only ATG protein currently known to be incorporated into the autophagasome. Consequently LC3-II is used as a definitive marker for autophagosomes.
  • the autophagosome fuses with the lysosomes to form the autophagolysosome and the constituents are digested.
  • Autophagy is boosted in response to a variety of stimuli such as nutrient starvation, oxidative stress, and hypoxia.
  • Pathways regulating autophagy are not well defined but currently the best known modulator of autophagy is the mTor pathway (Rubinsztein. DC, Gestwicki, JE, Murphy, LO , Klionsky, DJ (2007) Potential therapeutic applications of autophagy. Nature Reviews Drug Discovery 6, 304-312; Pattingre, S, Espert, L, Biard-Piechaczyk, M, Codogno, P (2007), Regulation of macroautophagy by mToR and Beclin 1 complexes, Biochimie (in press)). Activation of mTor inhibits autophagy while its inhibition promotes autophagy.
  • PI3K phosphoinositide 3-kinase
  • Vps34 positively regulates autophagy through its product phosphatidylinositol 3- phosphate (PI3-P).
  • PI3-P product phosphatidylinositol 3- phosphate
  • bafilomycin which inhibits autophagy by preventing the fusion of the autophagosome with the lysosome
  • Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line H-4-II-E cells Cell Struct Fund 23, 33-42).
  • Trends Neurosci 29, 528-535 The list includes muscle and liver diseases, neurodegenerative diseases such as Parkinson's disease, Huntington's disease, spinocerebellar ataxia type 3, and certain forms of dementia involving tau mutations. It may also be relevant in heart diseases (Terman, A & Brunk, UT (2005) Autophagy in cardiac myocyte homeostasis aging and pathology. Cardiovasc Res 68, 355-365). Autophagy diminishes in the aging heart (15), the reasons for which are unclear, but may play a role in cellular damage in the aging heart. In this instance the existence of drugs that boost autophagy could be of benefit in reducing the buildup of the toxic agents.
  • rapamycin has a myriad of effects including immunosuppressive activities, discounting its use as a therapeutic agent to modulate autophagy.
  • the need to develop rapid acting agents to modulate autophagy has been recognized.
  • Recently new compounds, small-molecule enhancers of rapamycin (SMERS) have been reported that induce autophagy (Sarkar, S , Perlstein, EO, Pineau, S, Cordenier, A et al. (2007). Small molecules enhance autophagy and reduce toxicity in Huntington disease models. Nat Chem Biol 3, 331-338).
  • a method of inducing autophagy in a cell or population of cells comprising administering an effective amount of a compound selected from the group consisting of:
  • Proliferating cells were incubated with 7.5 ⁇ M GIn for 6 h (ASK1 -/-, Caspase 3 -/- WT Mef) or 24 h (A549, BT549). The cells were washed and harvested and cell lysates were prepared in the presence of protease inhibitors. Samples were run on SDS PAGE gels and subjected to Western Blot analysis with LC3 antibody.
  • FIG. 4 Effect of bafilomycin on Gin-induced LC3-II generation in ASK1 -/- .
  • the cells were washed and harvested and cell lysates were prepared in the presence of protease inhibitors. Samples were run on SDS PAGE gels and subjected to Western Blot analysis with LC3 antibody.
  • FIG. 5 Effect of 3-methyladenine and wortmannin on Gin-induced LC3-II generation in ATG5 WT cells.
  • 3-MA the cells were preincubated with 3-MA for 12 h prior to the addition of 3-MA + GIn.
  • the cells were washed and harvested and cell lysates were prepared in the presence of protease inhibitors. Samples were run on SDS PAGE gels and subjected to Western Blot analysis with LC3 antibody. DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • glycosylated antitumor ether lipids which have with a sugar residue in place of the phosphorylcholine head group at the C-3 position of the lipid (Guivisdalsky, PN, Bittman, R, Smith, Z, Blank, ML, Snyder, F, Howard, S, Salari, H. (1990).
  • the most active compounds are lipids bearing a glucosylamine (GIn) and its C-glycoside analog, both of which have an amino group at position 2 of the glucose moiety.
  • GIn glucosylamine
  • the characteristics displayed by these glycosylated ether compounds are significantly different from the prototype antitumor ether lipid ET- I 8-OCH 3 , which suggested a different mechanism of action.
  • glycosylated antitumor ether lipids are small molecules that induce and/or enhance autophagy in cells.
  • a major advantage of these compounds is the rapid manner with which they induce autophagy.
  • the reversible nature of their effects will be advantageous in that induction of autophagy would not necessarily be an event that culminates in cell death.
  • the specific use of a synthetic lipid analog to enhance or induce autophagy to treat diseases or disorders such as neurodegenerative diseases like Parkinson's and Huntington's diseases is a novel concept.
  • the ability of GAEL to induce autophagy is clearly dependent on the presence of the sugar moiety at the C3 position of the glycerol backbone since ET- I 8-OCH 3 , the prototype AEL with a phosphocholine group at the same position, does not induce autophagy.
  • the molecular mechanism of autophagy is not well understood but initiation and nucleation in starvation-induced autophagy is dependent on the activity of 2 complexes, the Beclin 1 complex and the mTORCI complex.
  • the individual components of the Beclin 1 complex are comprised of Beclin 1 , Vps34, Vps15, and UVRAG. Upon activation, the complex causes the production of phosphatidylinositol 3-phosphate (PI3P) by Vps34.
  • P3P phosphatidylinositol 3-phosphate
  • PI3P then associates with WIPI-1 to initiate nucleation.
  • the Beclin 1 complex also associates with the anti-apoptotic molecule Bcl2.
  • the association of Bcl2 with Beclin 1 inhibits the complex whereas its dissociation relieves the inhibition.
  • GAELs may induce autophagy through multiple mechanisms.
  • the compounds could inhibit the association of Bcl2 with Beclin and thereby activate the complex to generate PI3P to initiate autophagy.
  • wortmannin and 3 methyladenine which inhibit the production of PI3P but yet have no effect on GAEL-induce autophagy, indicates that the compounds can activate autophagy independently of Vps34.
  • GAELs bind to the PI3P-binding site on WIPI-1 and activate the molecule to initiate autophagy.
  • GAEL could activate class Il PI3K's, to produce PI3P, activate phosphatases to remove D4 phosphate from Pl(3,4) P2, or inhibit phosphatases that remove D3 phosphate from PI3P.
  • mTOR is a protein kinase that has been identified as a key player in regulating the initiation of starvation-induced autophagy. Under nutrient sufficient conditions, mTOR is active, leading to the phosphorylation of ATG13, a component of the ATG1 kinase complex.
  • ATG13 Phosphorylation of ATG13 causes it to dissociate from the complex and thereby inhibits the catalytic activity, leading to the inhibition of autophagy.
  • mTOR is inactive and the hypophosphorylation of ATG 17 allows it to associate with the ATG 1 complex and results in activation of ATG1.
  • GAEL initiates autophagy independently of mTOR inhibition.
  • GAEL may initiate autophagy through direct or mTOR-independent activation of ATG 1 kinase.
  • GAEL induces autophagy in ATG5-deficient cells.
  • the current theories of autophagy have identified ATG5 as a key molecule essential for vehicle expansion and completion.
  • ATG5 ATG5 as a key molecule essential for vehicle expansion and completion.
  • cells do not convert LC3-I to LC3-II and there is no insertion of LC3-II into the autophagosome.
  • the ability of GAEL to induce autophagy in cells deficient in ATG5 implies that there may be additional pathways for the expansion of the preautophagosome.
  • the conversion of LC3- 1 to LC3-II and insertion of the latter may not be absolutely required for Gin- induced autophagosome formation.
  • Gin-induced expansion of autophagosomes under certain conditions may involve novel pathways whose components have yet to be identified.
  • This invention deals with the methods of use of compounds having a formula selected from the group consisting of O-glycosylated and C-glycosylated antitumor ether lipids that are useful for inducing or enhancing autophagy for the treatment of disorders or diseases amenable to enhanced autophagy such as protein aggregation diseases, neurodegenerative diseases, Parkinson's disease, Huntington's disease, spinocerebellar ataxia type 3, and dementia involving tau mutations.
  • Other uses include, but are not limited to, protection and/or amelioration of ischemic/reperfusion injury and liver and muscular diseases.
  • a method for treating or ameliorating or treating prophylacticly a disease or disorder amenable to enhanced autophagy comprising administering to an individual in need of such treatment, for example, an individual suffering from a protein aggregation disease, a neurodegenerative disease, Parkinson's disease, Huntington's disease, spinocerebellar ataxia type 3, dementia involving tau mutations, an ischemic/reperfusion injury or a liver or muscular disease known in the art an effective amount of one of more of the compounds described below, for example, one of compounds I-VII.
  • an effective amount of any one of the compounds can be determined by routine experimentation if necessary and will depend of course on many factors, for example but by no means limited to age, weight, overall condition, disease progression and/or severity of symptoms of the individual.
  • a method of preparing a pharmaceutical composition for treating or preventing or ameliorating or treating prophylacticly a disease or disorder selected from the group consiting of: protein aggregation diseases, neurodegenerative diseases, Parkinson's disease, Huntington's disease, spinocerebellar ataxia type 3, dementia involving tau mutations, ischemic/reperfusion injury and liver and muscular diseases comprising providing a compound of Formula I-VII and mixing said compound with a pharmaceutically acceptable excipient or carrier.
  • the compounds for use in the compositions and methods provided herein have Formula I or are a compound of any one of Formulae I-VII:
  • the compound of Formula I contains a lactosyl moiety in place of the glucosyl moiety.
  • FIG. 1 shows the presence of autophagolysosomes in l-treated cells (ASK1 -/-, ATG5 Wt, ATG5 -/-, BT549).
  • the increase in levels of autophagolysosomes in l-treated cells is consistent with an increase in acridine orange accumulation in the cells, and an increase in lysosomal associated structures visualized by lysotracker red.
  • Bafilomycin inhibits the fusion of autophagosomes and lysosomes to form autophagolysosomes. Its effect on cells is to cause the accumulation of autophagosomes.
  • bafilomycin In the presence of bafilomycin, the LC3-II levels in ASK1 -/- cells and ATG5 wild-type mouse embryonic fibroblasts (MEFs) increased in I (GIn) treated cells relative to cells treated with I alone (Fig. 4).
  • GAELs induce autophagy by pathways that may be distinct from the known autophagy pathway involving ATG5 and LC3-II.
  • I a key molecule required for LC3-II formation
  • I GIn
  • LC3-II was not formed in response to treatment with I (Fig. 4) even though autophagolysosomes were produced.
  • treatment with I generated LC3-II.
  • the formation of autophagolysosomes in both ATG5 and ATG5 -/- cells is inhibited by bafilomycin.
  • Fig. 5 shows that 3MA and wortmannin did not inhibit LC3-II formation in ATG5 wild-type MEFs (Fig. 5)
  • GAELs induce autophagy through novel mechanisms.
  • ATG5 is present in cells as in the ATG5 wild type cells and ASK 1 -/- cells
  • I induced autophagosome formation via the generation of LC3-II.
  • induction is formed via a 3-MA-independent pathway.
  • I induces a novel pathway that leads to the formation of autophagolysosomes independently of LC3-II.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des éther lipides antitumoraux glycosylés (GAEL, glycosylated antitumor ether lipids) qui sont de petites molécules qui induisent et/ou activent l'autophagie dans les cellules. Un avantage majeur de ces composés est la rapidité avec laquelle ils induisent l'autophagie.
PCT/CA2009/000083 2008-01-24 2009-01-23 Utilisation d'éther lipides antitumoraux glycosylés pour induire et/ou activer l'autophagie en vue de traiter des maladies WO2009092170A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US2322408P 2008-01-24 2008-01-24
US61/023,224 2008-01-24

Publications (1)

Publication Number Publication Date
WO2009092170A1 true WO2009092170A1 (fr) 2009-07-30

Family

ID=40900751

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2009/000083 WO2009092170A1 (fr) 2008-01-24 2009-01-23 Utilisation d'éther lipides antitumoraux glycosylés pour induire et/ou activer l'autophagie en vue de traiter des maladies

Country Status (1)

Country Link
WO (1) WO2009092170A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101408A1 (fr) * 2010-02-18 2011-08-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de prévention de la métastase cancéreuse
WO2013116949A1 (fr) * 2012-02-08 2013-08-15 University Of Manitoba Éther-lipides anticancéreux glycosylés en tant que nouveaux agents cytotoxiques de cellules souches cancéreuses

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011707A1 (fr) * 1995-09-27 1997-04-03 The Liposome Company, Inc. Glyceroglycolipides d'ether modifies
WO2002060911A2 (fr) * 2000-12-11 2002-08-08 The Research Foundation Of The City University Of New York Lipides d'ether de glycolyse c

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011707A1 (fr) * 1995-09-27 1997-04-03 The Liposome Company, Inc. Glyceroglycolipides d'ether modifies
WO2002060911A2 (fr) * 2000-12-11 2002-08-08 The Research Foundation Of The City University Of New York Lipides d'ether de glycolyse c

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ERUKULLA ET AL.: "Synthesis and evaluation of the antiproliferative effects of 1-O-hexadecyl-2-O-methyl-3-O-(2'-acetamido-2'-deoxy-beta-D- glucopyranosyl)-sn-glycerol and 1-O-hexadecyl-2-O-methyl-3-0- (2'-amino-2'-deoxy-beta-D-glucopyranosyl)-sn-glycerol on epithelial cancer cell growth.", J. MED. CHEM., vol. 39, no. 7, 29 March 1996 (1996-03-29), pages 1545 - 1548 *
MARINO-ALBERNAS ET AL.: "Synthesis and growth inhibitory properties ofglycosides of 1-O-hexadecyl-2-O-methyl-sn-glycerol, analogs of the antitumor ether lipid ET 18-OCH3 (edelfosine).", J. MED. CHEM., vol. 39, no. 17, 16 August 1996 (1996-08-16), pages 3241 - 3247 *
SAMADDER ET AL.: "Glycosylated antitumor ether lipids are more effective against oncogene-transformed fibroblasts than alkyllysophospholipids.", ANTICANCER RES., vol. 18, no. 1A, January 1998 (1998-01-01), pages 465 - 470 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011101408A1 (fr) * 2010-02-18 2011-08-25 INSERM (Institut National de la Santé et de la Recherche Médicale) Procédé de prévention de la métastase cancéreuse
US9161944B2 (en) 2010-02-18 2015-10-20 Inserm (Institut National De La Sante Et De La Sante Et De La Recherche Medicale) Method for preventing cancer metastasis
WO2013116949A1 (fr) * 2012-02-08 2013-08-15 University Of Manitoba Éther-lipides anticancéreux glycosylés en tant que nouveaux agents cytotoxiques de cellules souches cancéreuses

Similar Documents

Publication Publication Date Title
Zhang et al. Multi-target design strategies for the improved treatment of Alzheimer's disease
Tusi et al. Alginate oligosaccharide protects against endoplasmic reticulum-and mitochondrial-mediated apoptotic cell death and oxidative stress
Hobbiger Inhibition of cholinesterases by irreversible inhibitors in vitro and in vivo
Rogers et al. E2020—the pharmacology of a piperidine cholinesterase inhibitor
US6953786B2 (en) Compositions comprising plant-derived polyphenolic compounds and inhibitors of reactive oxygen species and methods of using thereof
Ng et al. Potassium channel openers and prostacyclin play a crucial role in mediating the vasorelaxant activity of Gynura procumbens
PL185189B1 (pl) 2,4-disulfonylo-fenylo-butylonitron, jego sole oraz zawierające je środki farmaceutyczne
CN100375619C (zh) 改善脑功能的药物组合物及其用途
CN103980338A (zh) 蟾蜍灵衍生物、其药物组合物及用途
WO2007107846A1 (fr) Composition pharmaceutique utile en tant qu'inhibiteur de l'acétyl cholinestérase
Liu et al. 16-Hydroxycleroda-3, 13-dien-15, 16-olide inhibits the proliferation and induces mitochondrial-dependent apoptosis through Akt, mTOR, and MEK-ERK pathways in human renal carcinoma cells
Gradinaru et al. Procaine–the controversial geroprotector candidate: new insights regarding its molecular and cellular effects
EP2723345A2 (fr) Composition contenant de la phosphatidylcholine en tant que principe actif et destinée à atténuer la toxicité d'agents anticancéreux
Yoshioka et al. Cyclic AMP‐elevating agents prevent oligodendroglial excitotoxicity
US10751320B2 (en) Therapeutic agents containing cannabis flavonoid derivatives for the prevention and treatment of neurodegenerative disorders
Bodiga et al. Andrographolide suppresses cisplatin-induced endothelial hyperpermeability through activation of PI3K/Akt and eNOS–derived nitric oxide
Darmani et al. Additive antiemetic efficacy of low-doses of the cannabinoid CB1/2 receptor agonist Δ9-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva)
WO2009092170A1 (fr) Utilisation d'éther lipides antitumoraux glycosylés pour induire et/ou activer l'autophagie en vue de traiter des maladies
CZ299555B6 (cs) Farmaceutický prostredek
EP2102149B1 (fr) Dérivés de stylbène utilisés comme inhibiteurs de l'adp-ribosyl cyclase
PT2420496E (pt) Composto antiepiléptico, hipocolesterolémico e neuroprotector
Payne-Leeson et al. Use of ketorolac in the prevention of suxamethonium myalgia
JPH06510280A (ja) タンパクキナーゼｃ阻害および新規化合物バラノール
EP3463475A1 (fr) Polythérapie comprenant une cétone polyinsaturée et un inhibiteur de la calcineurine
WO2007047820A1 (fr) Methode de traitement de la douleur

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09704064

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09704064

Country of ref document: EP

Kind code of ref document: A1