WO2002057473A1 - Procede relatif a l'inhibition de l'expression des genes du facteur de croissance vasculaire endotheliale (vegf) et de l'erythropoietine (epo) par le biais de la quercetine - Google Patents

Procede relatif a l'inhibition de l'expression des genes du facteur de croissance vasculaire endotheliale (vegf) et de l'erythropoietine (epo) par le biais de la quercetine Download PDF

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Publication number
WO2002057473A1
WO2002057473A1 PCT/KR2001/000065 KR0100065W WO02057473A1 WO 2002057473 A1 WO2002057473 A1 WO 2002057473A1 KR 0100065 W KR0100065 W KR 0100065W WO 02057473 A1 WO02057473 A1 WO 02057473A1
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Prior art keywords
quercetin
expression
cells
vegf
tumor cells
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PCT/KR2001/000065
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English (en)
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Young-Mee Park
Sun-Hee Baek
Mi-Young Han
Eun-Mi Choi
Chang-Won Lee
Jae-Won Kim
Jong-Hoon Park
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Young-Mee Park
Sun-Hee Baek
Mi-Young Han
Eun-Mi Choi
Chang-Won Lee
Jae-Won Kim
Jong-Hoon Park
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Application filed by Young-Mee Park, Sun-Hee Baek, Mi-Young Han, Eun-Mi Choi, Chang-Won Lee, Jae-Won Kim, Jong-Hoon Park filed Critical Young-Mee Park
Priority to PCT/KR2001/000065 priority Critical patent/WO2002057473A1/fr
Priority to JP2002558525A priority patent/JP2004517631A/ja
Publication of WO2002057473A1 publication Critical patent/WO2002057473A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

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  • the present invention relates ' to a method for inhibiting the expression of vascular endothelial growth factor (hereinafter referred to as 'VEGF') and erythropoietin (hereinafter referred to as 'EPO') genes by quercetin, more particularly, to a method for inhibiting the expression of VEGF and EPO genes in hypoxic tumor cells by quercetin treatment.
  • 'VEGF' vascular endothelial growth factor
  • 'EPO' erythropoietin
  • hypoxic tumors contain a lot of hypoxic cells due to an inadequate vasculature (see: Moulder and Rockwell, Cancer Metastasis Rev., 5:313-341, 1987; Vaupel et al., Cancer Res., 49:6449-6465, 1989) or changes in a supply of red blood cells in intratumoral microvessels (see: Kimura et al., Cancer Res., 56:5522-5528, 1996) . Although some of these hypoxic tumor cells may be converted into normoxic cells by reoxygenation attainable by reopening of temporally closed or clogged microvessels not to inhibit tumor cell growth (see: Brown, J. M., Br . J.
  • hypoxia has been known to affect the patterns of gene expression in tumor cells (see: Brown and Giaccia, Int. J. Radiat. Biol., 65:95-102, 1994) and it has been reported that stress reaction of normal cells is induced by low-oxygen environment and, in consequence, syntheses of stress proteins are induced in vivo and in vitro (see: Guttman et al., Cell, 22:229-307, 1980; Heacock and Sutherland, Br. J. Cancer, 62:217-225, 1990; Iwaki et al., Circulation, 87:2023-2032, 1993). For example, Baek et al.
  • heat shock proteins such as hsp70 and hsp25 are upregulated in mouse radiation induced fibrosarcoma (RIF) cells by hypoxia, and hypoxic tumor cells with increased level of heat shock proteins are more resistant to hypoxia than normoxic cells (see: Baek et al., J. Biochem. & Mol. Biol., 32:112-118, 1999).
  • VEGF vascular endothelial growth factor
  • EPO see: Wang and Semenza, Blood, 82:3610- 3615, 1993
  • TGF ⁇ -1 transforming growth factor ⁇ - 1
  • hypoxic tumor cells In order to overcome problems caused by hypoxic tumor cells, the following three methods are mostly employed in the art: i) oxygenation of tumor cells, ii) attenuation of hypoxic cells with radiation or chemotherapy, iii) induction of hypoxic cell death using the cytotoxin obtained from hypoxic cells (see: Brown and Koong, J. Intl. Cancer Inst., 83:178-185, 1991).
  • hypoxic tumor cells are resistant to both radiation and chemotherapy, there is a continuing need to increase curative efficiency for tumor cells by inhibiting protein syntheses required for tumor cell survival and angiogenesis using the methods other than described above .
  • the present inventors have made an effort to increase curative efficiency for tumor cells, and discovered that treatment of hypoxic tumor cells with quercetin, which has been known to have inhibitory effect on expression of heat shock proteins, is able to inhibit expression of angionenesis-associated factors, VEGF and EGF, subsequently, increasing curative efficiency for tumor cells by inhibiting angiogenesis.
  • the primary object of the present invention is, therefore, to provide a method for inhibiting expression of VEGF and EPO genes by quercetin.
  • Figure 1 is a graph showing protein synthesis rate with culture time.
  • Figure 2a is a graph showing the expression of VEGF gene .
  • Figure 2b is a graph showing the expression of EPO gene .
  • Figure 3a is a photograph of western blot of VEGF protein.
  • Figure 3b is a photograph of western blot of EPO protein.
  • Figure 4 is a graph showing the inhibition of angiogenesis in fertilized eggs depending on quercetin concentration.
  • Figure 5 is a photograph of X-ray film representing HIF-1 gene activity.
  • Figure 6a is a photograph of western blot representing expression of PKC ⁇ in cytoplasmic fraction.
  • Figure 6b is a photograph of western blot representing expression of PKC ⁇ in particulate fraction.
  • the expression of angiogenesis-associated factors is inhibited by treating hypoxic tumor cells with quercetin. That is, treatment of the tumor cells with the quercetin inhibits activity of protein kinase C delta (hereinafter referred to as 'PKC ⁇ '), subsequently, the activity of hypoxia inducible factor-1 (hereinafter referred to as 'HIF-1') which is controlled by the PKC ⁇ becomes inhibited, and finally, the expression of genes for angiogenesis- associated factors, i.e., VEGF and EPO of which expression is regulated by the HIF-1 is inhibited.
  • 'PKC ⁇ ' protein kinase C delta
  • 'HIF-1' hypoxia inducible factor-1
  • the present invention is further illustrated as follows .
  • quercetin which inhibits heat shock protein expression in tumor cells can be applied to the treatment of cancer, to find out alternative mechanism, mouse tumor cells- were treated with quercetin, hypoxia was induced by incubating the cells in a hypoxic chamber, total RNA and protein were isolated from the cells and the gene expression pattern of angiogenesis relating factors, VEGF and EPO was examined. As a result, it has been proved that quercetin plays a role in angiogenesis by verifying inhibition of the expression of angiogenesis relating genes in quercetin- treated tumor cells.
  • angiogenesis was assayed employing CAM assay method in fertilized eggs with or without quercetin treatment, and the angiogenesis on the chorioallantoic membrane with quercetin treatment decreased compare to that without quercetin treatment.
  • hypoxia in vitro which is a physiological characteristic of tumor cells
  • the tumor cells were cultured under a condition of oxygen-glucose depletion in a hypoxic chamber (Forma Scientific, U.S.A.) at 37°C.
  • a hypoxic chamber Forma Scientific, U.S.A.
  • RIF tumor cells grown in a glucose-supplemented medium were incubated in a glucose-depleted medium (GIBCO-BRL, U.S.A.) with three times of medium changes which was preequilibrated with a low-oxygen gas mixture of 5% C0 2 - 85% N 2 -10% H 2 at 37°C to maintain partial oxygen pressure at 0.02%.
  • Hypoxia in RIF cells was discontinued by feeding the cells with a glucose-supplemented medium and incubating in a normoxic incubator.
  • Example 2 Determination of effective concentration of quercetin on tumor cells
  • RIF cells in a logarithmic phase were treated with quercetin at the concentrations of 0.05,
  • Example 3 Determination of exposure time of tumor cells to hypoxic condition
  • FIG. 1 is a graph showing the protein biosynthesis rate with time, where protein biosynthesis rate is defined as radioactivity incorporated into l ⁇ g of protein.
  • RT-PCR was performed on the said genes.
  • RIF cells with or without quercetin treatment were exposed to a hypoxic condition for 0, 1, 4 and 8 hours and then total RNA was isolated from the cells respectively.
  • One microgram of total RNA, 500 ng of random hexamer, 0.5mM each of dNTP, 10X reaction buffer and 400 unit of MMLV (Moloney murine leukemia virus) reverse transcriptase were mixed and the mixture was incubated at 37 °C for 1 hour.
  • PCR was performed in a mixture containing 0.2mM each of VEGF primer 1: 5'- tgcactggaccctggcttta-3' (SEQ ID NO: 1) and primer 2: 5'- tttgcaggaacatttacacg-3' (SEQ ID NO: 2) or EPO primer 3: 5'- agccctgcgtctaatgtttc-3 ' (SEQ ID NO: 3) and primer 4: 5'- cgaccaccagagacccttca-3' (SEQ ID NO: 4), 10X PCR buffer solution (50mM KC1, 1.5mM MgCl 2 , 0.01% gelatin, lOmM Tris, pH 8.3) and AmpliTaq DNA polymerase (Perkin Elmer, U.S.A.).
  • Figures 2a and 2b are graphs showing the expression of VEGF gene and EPO gene, respectively. As shown in Figures 2a and 2b, the mRNA expression of VEGF and EPO genes was inhibited in quercetin-treated cells compare to that in quercetin- untreated cells.
  • Example 5 Effect of quercetin on the expression of VEGF and EPO genes
  • RIF cells with or without quercetin treatment were exposed to a hypoxic condition for 0, 1, 4 and 8 hours, washed with cold phosphate buffer solution three times, resuspended in a solution of SDS-gel sample buffer (0.1% (w/v) bromophenol blue, 20% glycerol (v/v) , 4% sodium dodecyl sulfate (w/v) , 10% ⁇ -mercaptoethanol (v/v) ) and then heated at 100°C for 5 minutes.
  • Figure 3a and 3b are photographs of western blot of VEGF protein and EPO protein. As shown in Figures 3a and 3b, in cells without quercetin treatment, expression level of VEGF and EPO genes stayed same with time, while the expression of VEGF and EPO genes of quercetin-treated cells was found to be inhibited with time.
  • FIG. 4 is a graph showing the inhibition of angiogenesis in fertilized eggs depending on quercetin concentration. As shown in Figure 4, inhibition of angiogenesis reached up to 70 to 80% when cells were treated with 5 to lO ⁇ g of quercetin.
  • Example 7 Inhibitory effect of quercetin on HIF-1 activity
  • HIF-1 gene which is known to control VEGF and EPO gene expression
  • EMSA method that is, RIF cells with or without quercetin treatment were exposed to a hypoxic condition for 0, 0.5 and 1.5 hours, washed with phosphate buffer solution 3 times, resuspended in 1ml of buffer solution (1.5mM MgCl 2 , lOmM HEPES, pH 7.9), incubated on ice for 15 minutes, and then centrifuged at 3000 x g for 15 minutes at 4°C to obtain nuclei pellet respectively.
  • buffer solution 1.5mM MgCl 2 , lOmM HEPES, pH 7.9
  • the nuclei pellet was resuspended in 200 ⁇ l of buffer solution (1.5mM MgCl 2 , 0.2mM DTT, ImM PMSF, l ⁇ g/ml Aprotinin, ImM Leupeptin, lOOmM KC1, 10% (v/v) glycerol, lOmM HEPES, pH 7.9), incubated on ice for 15 minutes and then centrifuged at 12000 xg for 15 minutes at 4°C to obtain supernatant.
  • buffer solution 1.5mM MgCl 2 , 0.2mM DTT, ImM PMSF, l ⁇ g/ml Aprotinin, ImM Leupeptin, lOOmM KC1, 10% (v/v) glycerol, lOmM HEPES, pH 7.9
  • Example 8 Inhibitory effect of quercetin on PKC ⁇
  • the said cytoplasmic fraction was mixed with 70 ⁇ l of buffer solution containing Triton X-100(10% SDS (w/v), 5% ⁇ - mercaptoethanol (v/v) , 10% glycerol (v/v) , 1% triton X-100, 25mM Tris-Cl, pH 6.8), incubated at 4°C for 30 minutes and centrifuged at 100,000 xg for 30 minutes at 4°C to obtain particulate fraction in supernatant. Equal amounts of the cytoplasmic fraction and the particulate fraction were subjected to electrophoresis and expression of PKC ⁇ was examined using PKC ⁇ antibody (see: Figures 6a and 6b).
  • Figures 6a and 6b are photographs of western blot representing expression of PKC ⁇ in the cytoplasmic fraction and PKC ⁇ in the particulate fraction, where c respresents positive control.
  • the level of PKC ⁇ expression was maintained both in the cytoplasmic fraction and in the particulate fraction, while in cells with quercetin treatment, the level of PKC ⁇ expression in the cytoplasmic fraction was maintained but the level of PKC ⁇ expression in the particulate fraction was decreased.
  • the inhibition of VEGF and EPO gene expression was caused by decrease in the expression of PKC ⁇ gene.
  • the present invention provides a method for inhibiting the expression of angiogenesis-associated factors, VEGF and EPO genes by treating hypoxic tumor cells with quercetin.
  • quercetin since quercetin is able to inhibit the expression of genes for angiogenesis-associated factors, VEGF and EPO in solid tumor cells, it would be practically applied for the elevation of therapeutic efficiency against hypoxic tumor cells and the inhibition of metastasis of cancer cells.

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Abstract

L'invention concerne un procédé relatif à l'inhibition de l'expression des gènes du facteur de croissance VEGF et de l'EPO à travers un traitement des cellules tumorales hypoxiques à base de quercétine. Par sa capacité d'inhibition de l'expression des gènes liés à l'angiogenèse (à savoir, gènes du facteur de croissance VEGF et de l'EPO), la quercétine aurait un champ d'application pratique pour l'inhibition de la métastase des cellules cancéreuses et l'optimisation de la thérapie contre les cellules tumorales hypoxiques.
PCT/KR2001/000065 2001-01-17 2001-01-17 Procede relatif a l'inhibition de l'expression des genes du facteur de croissance vasculaire endotheliale (vegf) et de l'erythropoietine (epo) par le biais de la quercetine WO2002057473A1 (fr)

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PCT/KR2001/000065 WO2002057473A1 (fr) 2001-01-17 2001-01-17 Procede relatif a l'inhibition de l'expression des genes du facteur de croissance vasculaire endotheliale (vegf) et de l'erythropoietine (epo) par le biais de la quercetine
JP2002558525A JP2004517631A (ja) 2001-01-17 2001-01-17 クエルセチンにより血管内皮成長因子及びエリスロポエチンの遺伝子発現を阻害する方法

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006010628A1 (fr) * 2004-07-29 2006-02-02 Creabilis Therapeutics S.P.A. Emploi de k-252a et d'inhibiteurs de kinase pour la prevention ou le traitement de pathologies associees a hmgb1
EP1626712A2 (fr) * 2003-05-08 2006-02-22 The University Of Mississippi Composes de saururus cernuus pouvant inhiber des reponses cellulaires a l'hypoxie
WO2010005527A1 (fr) 2008-06-30 2010-01-14 Angioblast Systems, Inc. Traitement de maladies oculaires et d’une néovascularisation excessive utilisant un traitement combiné
WO2013164512A3 (fr) * 2012-05-04 2014-03-20 Universidad De Valladolid Composition utilisée dans le traitement et/ou la prévention d'inflammation, de stress oxydant et de néovascularisation oculaire
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10308943B2 (en) 2016-02-08 2019-06-04 Vitrisa Therapeutics, Inc. Compositions with improved intravitreal half-life and uses thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0808974D0 (en) * 2008-05-16 2008-06-25 Veritron Ltd Plant extract and its therapeutic use
JP2013234148A (ja) * 2012-05-09 2013-11-21 Oriza Yuka Kk 血管新生抑制剤

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1626712A2 (fr) * 2003-05-08 2006-02-22 The University Of Mississippi Composes de saururus cernuus pouvant inhiber des reponses cellulaires a l'hypoxie
EP1626712A4 (fr) * 2003-05-08 2009-04-01 Univ Mississippi Composes de saururus cernuus pouvant inhiber des reponses cellulaires a l'hypoxie
WO2006010628A1 (fr) * 2004-07-29 2006-02-02 Creabilis Therapeutics S.P.A. Emploi de k-252a et d'inhibiteurs de kinase pour la prevention ou le traitement de pathologies associees a hmgb1
US9884014B2 (en) 2004-10-12 2018-02-06 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
WO2010005527A1 (fr) 2008-06-30 2010-01-14 Angioblast Systems, Inc. Traitement de maladies oculaires et d’une néovascularisation excessive utilisant un traitement combiné
WO2013164512A3 (fr) * 2012-05-04 2014-03-20 Universidad De Valladolid Composition utilisée dans le traitement et/ou la prévention d'inflammation, de stress oxydant et de néovascularisation oculaire
US10308943B2 (en) 2016-02-08 2019-06-04 Vitrisa Therapeutics, Inc. Compositions with improved intravitreal half-life and uses thereof

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