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WO2013032231A2 - Composition pharmaceutique anti-angiogène comprenant un inhibiteur de microarn-382 - Google Patents

Composition pharmaceutique anti-angiogène comprenant un inhibiteur de microarn-382 Download PDF

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Publication number
WO2013032231A2
WO2013032231A2 PCT/KR2012/006910 KR2012006910W WO2013032231A2 WO 2013032231 A2 WO2013032231 A2 WO 2013032231A2 KR 2012006910 W KR2012006910 W KR 2012006910W WO 2013032231 A2 WO2013032231 A2 WO 2013032231A2
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microrna
cells
expression
cancer
vascular endothelial
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Korean (ko)
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WO2013032231A3 (fr
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이유미
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Industry Academic Cooperation Foundation of KNU
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Industry Academic Cooperation Foundation of KNU
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Priority claimed from KR20120094794A external-priority patent/KR20130024831A/ko
Publication of WO2013032231A2 publication Critical patent/WO2013032231A2/fr
Publication of WO2013032231A3 publication Critical patent/WO2013032231A3/fr
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    • 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
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • 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
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C12N2310/113—Antisense targeting other non-coding nucleic acids, e.g. antagomirs

Definitions

  • the present invention relates to a composition for inhibiting angiogenesis, and more particularly to a pharmaceutical composition for inhibiting angiogenesis comprising an inhibitor of microRNA-382.
  • microRNAs are small non-coding RNAs that inhibit gene expression in post-transcriptional regulation.
  • microRNA consists of an average of 18 to 25 nucleotides and forms a hairpin structure. Complementary binding to the 3 ′ UTR region of the target gene sequence inhibits mRNA degradation and translation into proteins, and more than 5,000 human genes have been identified as targets of microRNAs.
  • target genes are regulated, the functions of microRNAs in vivo are diversified into cell differentiation and proliferation, control of developmental stage and metabolism, angiogenesis and cell death, and the importance of microRNA role is emphasized more. The trend is falling.
  • microRNAs regulate the formation of neovascularization, suggesting the potential for new therapies to inhibit vascular disease and cancer using this mechanism.
  • cancer therapeutic drugs that prevent the early stage of cancer cell formation and inhibit the angiogenesis induced by cancer through the mechanism of microRNA expression regulation of cancer-associated genes is urgently needed.
  • the present inventors have discovered a specific microRNA involved in angiogenesis in a hypoxic environment without any side effects, and as a result of intensive research on an effective cancer treatment composition using the same, when inhibiting the microRNA-382 which increases expression in gastric cancer cells By confirming the angiogenesis inhibitory effect, the present invention has been completed.
  • an object of the present invention is to provide a pharmaceutical composition for inhibiting angiogenesis around cancer through inhibition of microRNA-382, which has increased expression in a hypoxic environment, and an angiogenesis suppression method using the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition for inhibiting angiogenesis comprising a microRNA-382 inhibitor.
  • the pharmaceutical composition for inhibiting angiogenesis is characterized in that it is used to treat cancer by inhibiting cancer cell proliferation.
  • the cancer cell includes gastric cancer cells.
  • the present invention also provides a method for inhibiting angiogenesis, comprising administering to the individual a pharmaceutically effective amount of the pharmaceutical composition.
  • composition of the present invention may inhibit angiogenesis and proliferation of cancer cells by inhibiting microRNA-382 and ultimately may be usefully used for the treatment of cancer.
  • Figure 1 shows the results of comparing the expression pattern of the microRNAs changed compared to normal oxygen conditions when cultured gastric cancer cell line MKN1 cells in the hypoxic condition through a microarray experiment. It was found that there was a change in the amount of expression of a plurality of microRNAs under two conditions, among which the expression of microRNA-382 increased under hypoxic conditions.
  • Figure 2 shows the expression level of microRNA-382 through real-time PCR after incubating the gastric cancer cell line MKN1 cells in hypoxic conditions by time. It was confirmed that the expression of microRNA-382 was increased in the hypoxic condition compared to normal oxygen, and it was found that the microRNA-382 was most expressed in the culture for 24 hours.
  • Figure 3 shows the result of suppressing the proliferation of the cells when cultured vascular endothelial cells in the conditioned medium in which the expression of the microRNA-382 increased in hypoxic conditions reduced by treatment with the inhibitor.
  • Figure 4 shows the results of suppression of cell migration ability when vascular endothelial cells were cultured in a condition medium in which microRNA-382 with increased expression in hypoxic conditions was reduced by treatment with an inhibitor.
  • FIG. 5 shows the results of suppressing angiogenesis of cells when vascular endothelial cells were cultured in a condition medium in which microRNA-382 with increased expression in hypoxic condition was reduced by treatment with an inhibitor.
  • Figure 6 shows the results of improved cell proliferation when cultured vascular endothelial cells in a condition medium that increased the expression of microRNA-382 under normal oxygen conditions.
  • Figure 7 shows the results of improved cell mobility when cultured vascular endothelial cells in a condition medium that increased the expression of microRNA-382 under normal oxygen conditions.
  • Figure 8 shows the results of improved cell vascular formation ability when cultured vascular endothelial cells in a condition medium that increased the expression of microRNA-382 under normal oxygen conditions.
  • Figure 9 shows the results confirmed that the expression level of PTEN is reduced in cancer cells of hypoxic conditions.
  • 10 is a diagram showing a binding site of 3'UTR of microRNA-382 and PTEN.
  • FIG. 11 illustrates a recombinant vector fused with luciferase protein containing 3'UTR of PTEN to confirm microRNA-382 binding to PTEN 3'-UTR, and microRNA- into a cell line transduced with the vector. After treating 382, a graph showing the activity of luciferase expressed in cells.
  • the present invention provides a pharmaceutical composition for inhibiting angiogenesis comprising a microRNA-382 inhibitor.
  • the present inventors confirmed the angiogenesis of microRNA-382 and the regulation of proliferation of vascular endothelial cells in the hypoxic environment of cancer cells through experiments. In addition, it was confirmed that the expression of microRNA-382 increased when hypoxic conditions were formed in gastric cancer cells, and it was confirmed through experiments that the inhibition of proliferation, migration, and angiogenesis of peripheral vascular endothelial cells was reduced after suppressing the inhibitor. It was.
  • microRNA-382 is involved in cancer cell proliferation and may be a target of cancer therapy.
  • the present invention provides a pharmaceutical composition, which is used for treating cancer by inhibiting microRNA-382 to inhibit angiogenesis and proliferation of vascular endothelial cells around cancer.
  • the cancer includes gastric cancer.
  • microRNAs showing different expression levels when hypoxic in gastric cancer cell line MKN1 cells were confirmed through microarray experiments (see FIG. 1), among which microRNA-382 was 24 hours under hypoxic conditions. The highest expression was confirmed by real-time PCR (see FIG. 2).
  • microRNA-382 whose expression is increased in hypoxic gastric cancer cells, was reduced by inhibitors.
  • vascular endothelial cells were cultured in the conditioned medium extracted after 6 hours, 12 hours, and 24 hours, cell proliferation was reduced (see FIG. 3). It was confirmed to decrease (see FIGS. 4 and 5).
  • microRNA-382 the target gene of the microRNA-382 is PTEN, and the microRNA-382 binds to the 3'-UTR of the PTEN (see FIGS. 9 to 12).
  • the CAM assay and the tube formation assay were performed to in vivo.
  • the angiogenic effect was shown by microRNA-382 (see FIGS. 13 to 15).
  • microRNA-382 plays a role in promoting angiogenesis and proliferation of vascular endothelial cells.
  • the results suggest that by inhibiting microRNA-382, cancer cell metastasis, proliferation, and angiogenesis can be inhibited, and furthermore, it can be effectively used for cancer treatment.
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may include physiological saline, polyethylene glycol, ethanol, vegetable oil, isopropyl myristate, and the like, but is not limited thereto.
  • the present invention also provides a method of treating cancer by administering to a subject a pharmaceutically effective amount of a composition for inhibiting angiogenesis comprising a microRNA-382 inhibitor.
  • a pharmaceutically effective amount of a composition for inhibiting angiogenesis comprising a microRNA-382 inhibitor.
  • “individual” means a subject in need of treatment for a disease, and more specifically human, or non-human primates, mice, rats, dogs, cats, horses, and cattle Means such mammals.
  • the "pharmaceutically effective amount” may be adjusted in various ways depending on the weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease of the patient. It is obvious to
  • the preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration, and the duration, and may be appropriately selected by those skilled in the art. However, preferably, it is administered at 0.001 to 100 mg / kg body weight per day, more preferably 0.01 to 30 mg / kg body weight. Administration may be administered once a day or may be divided several times.
  • the microRNA-382 inhibitor of the present invention may be present in an amount of 0.0001 to 10% by weight, preferably 0.001 to 1% by weight, based on the total weight of the total composition.
  • the pharmaceutical composition of the present invention can be administered to mammals such as mice, mice, livestock, humans, and the like by various routes.
  • the method of administration is not limited, and may be administered by oral, rectal, or intravenous, intramuscular, subcutaneous, intrauterine dural, or intra cerbroventricular injection.
  • BAEC cells bovine aortic endothelial cells
  • DMEM medium containing 10% fetal calf serum
  • Human gastric cancer cells were put together in RPMI-1640 medium containing 10% fetal calf serum and cultured in a 37 ° C thermostat with 5% carbon dioxide.
  • the cells were cultured in a 10 cm 2 dish for RNA extraction and protein isolation.
  • adherent cells were removed from the culture vessel using trypsin-EDTA, centrifuged at 1000 rpm for 5 minutes, and then transferred to the new culture vessel in the same manner as the adherent cells.
  • the hypoxic state was maintained, the culture was carried out in an incubator maintaining 1% O 2 concentration.
  • hypoxic state is formed around the cancer, and in such an environment, changes in the expression level of various factors that control mechanisms such as cell proliferation and angiogenesis occur.
  • MKN1 cells were incubated for 24 hours at 1% oxygen concentration. After 24 hours, the medium was rapidly removed and the RNA extract was processed to separate RNA. Compared to RNA isolated from MKN1 cells cultured under normal oxygen conditions, microarray and real-time PCR were performed to confirm that the expression of microRNA-382 was increased in hypoxic conditions among microRNAs with varying expression levels (FIG. 1). And FIG. 2).
  • RNA of MKN1 cells were extracted using Purelink miRNA kit (Invitrogen) according to TRIzol reagent and manufacturer's protocol, and then GenoExplorer TM miRNA First-Strand cDNA Core Kit (Genosensor) Complementary DNA (cDNA) was generated with 500ng total RNA.
  • Real-time PCR was performed with the Biosystems 7300 Real-Time PCR system using SYBR Green PCR Master Mix (Applied Biosystems) and GenoExplorer TM miRNA qPCR Primer Sets (Genosensor). Mature microRNAs in U6 RNA (internal control MKN1 cells) were calculated.
  • Figure 1 shows the results of comparing the expression pattern of the microRNAs changed compared to normal oxygen conditions when cultured gastric cancer cell line MKN1 cells in the hypoxic condition through a microarray experiment. As shown in FIG. 1, it was found that there was a change in the amount of expression of a plurality of microRNAs under two conditions, among which the expression of microRNA-382 increased under hypoxic conditions.
  • Figure 2 shows the expression level of microRNA-382 through real-time PCR after incubating the gastric cancer cell line MKN1 cells in hypoxic conditions by time. As shown in Figure 2, it was confirmed by real-time PCR that the microRNA-382 shows the highest expression at 24 hours in the hypoxic state. That is, it was confirmed that the expression of microRNA-382 was increased in the hypoxic condition compared to normal oxygen, and it was found that the microRNA-382 was most expressed in the culture for 24 hours.
  • microRNA-382 may play a role in regulating the phenomenon of hypoxia formed in cancer cells.
  • proliferation may be accelerated by surrounding vascular endothelial cells affected by various growth factors secreted by cancer cells.
  • microRNA-382 which is increased in hypoxic cancer cells, will also affect peripheral vascular endothelial cells.
  • MKN1 cells which are gastric cancer cell lines, were cultured in an antibiotic-free medium for one day, and then transfected with PNAs TM microRNA-382 inhibitor (PANAGENE). After 20 hours of incubation in normal oxygen, the cells were transferred to 1% oxygen and incubated for 6 hours, 12 hours, and 24 hours, respectively. After culturing each time, the culture medium was extracted and concentrated, and then treated with vascular endothelial cells to observe the proliferative capacity.
  • PNAs TM microRNA-382 inhibitor PANAGENE
  • vascular endothelial cells were cultured in DMEM medium containing 10% FBS in a 48-well plate for about 24 hours, and then cultured for 20 hours after changing to medium containing only 1% FBS. Incubated for 24 hours.
  • [3 H] -cymidine was treated with 1 uCi per well for 4 hours and then washed three times with PBS. After fixing for 5 minutes in methanol at 4 °C, washed three times with distilled water.
  • vascular endothelial cells reduced the proliferative capacity of vascular endothelial cells by treating the vascular endothelial cells with reduced expression of microRNA-382 with increased inhibitory activity in hypoxic cancer cells.
  • microRNA-382 could be expected to play a role in promoting the proliferative capacity of vascular endothelial cells, and to reconfirm this, the effect of overexpression of microRNA-382 in normal oxygen state on the proliferative capacity of vascular endothelial cells was examined. .
  • mature microRNA-382 cloned into pENTR TM / H1 / T0 vector was transfected into gastric cancer cell line MKN1 cells to induce overexpression. After culturing for 24 hours, the medium was extracted, concentrated, and treated with vascular endothelial cells to observe proliferative activity. The results are shown in FIG. 6.
  • microRNA-382 improves the proliferative capacity of vascular endothelial cells around cancer cells.
  • microRNA-382 which has increased expression in hypoxic cancer cells in order to confirm that vascular endothelial cells may be affected by various growth factors secreted by cancer cells, may be improved, The effect on endothelial cell migration was examined.
  • MKN1 cells which are gastric cancer cell lines, were cultured in an antibiotic-free medium for one day, and then transfected with PNAs microRNA-382 inhibitor (PANAGENE). After 20 hours of incubation in normal oxygen, the cells were transferred to 1% oxygen and incubated for 6 hours, 12 hours, and 24 hours, respectively. After culturing each time, the culture medium was extracted and concentrated, and then treated with vascular endothelial cells.
  • PNAs microRNA-382 inhibitor PNAs microRNA-382 inhibitor
  • 24-well transwells with 8 um porosity polycarbonate filters were coated with type 1 collagen and dried for 1 hour at room temperature.
  • the extracted medium was put in the same number of cells with a serum-free medium on the top of the chamber and incubated for 20 hours, and the number of cells passing through the membrane was counted.
  • the separated cells were separated by methanol fixation, hematoxylin 10-minute staining, eosin 1-minute staining, and the cells on the unmoved membrane were removed with a cotton swab, and the cells stained under a microscope were counted.
  • the results are shown in FIG. 4. It was.
  • vascular endothelial cell migration ability was reduced by treating the vascular endothelial cells with reduced conditions of microRNA-382 with increased expression in hypoxic cancer cells through inhibitors.
  • microRNA-382 was expected to play a role in promoting vascular endothelial cell migration, and to reconfirm this, the effects of overexpression of microRNA-382 under normal oxygen on the vascular endothelial cell migration were discussed. .
  • mature microRNA-382 cloned into pENTR TM / H1 / T0 vector was transfected into gastric cancer cell line MKN1 cells to induce overexpression. After culturing for 24 hours, the medium was extracted, concentrated, and treated with vascular endothelial cells to observe the migration ability, and the results are shown in FIG. 7.
  • microRNA-382 improves the ability of vascular endothelial cells around cancer cells.
  • Example 5 Confirmation of vascular endothelial cell production capacity according to expression of microRNA-382
  • microRNA-382 which is expressed in hypoxic cancer cells, is increased in order to confirm that vascular endothelial cells may be affected by various growth factors secreted by cancer cells. The effect on the blood vessel formation ability of vascular endothelial cells was examined.
  • Matrigel was first coated on a 48-well plate at 37 ° C. for 30 minutes, and then the microRNA-382 having increased expression in the hypoxic state was extracted from the medium of cancer cells in which the inhibitor was reduced through an inhibitor. After culturing vascular endothelial cells together with the medium, the tube formation was confirmed under a microscope 12 hours later, and the results are shown in FIG. 5.
  • microRNA-382 was expected to play a role in promoting angiogenesis, and to reconfirm this, the effect on the angiogenesis when overexpression of microRNA-382 in normal oxygen state was considered.
  • microRNA-382 improves the blood vessel formation ability of vascular endothelial cells around cancer cells.
  • the present inventors performed the following experiment to identify the target gene of the microRNA-382 is increased expression in cancer cells of hypoxic conditions.
  • PTEN was selected from target genes through Target Scan, miRanda, and Sanger miRbase Target, which are programs for predicting target genes and binding sites of microRNAs. First, PTEN expression levels in cancer cells under hypoxic conditions were confirmed. .
  • PTEN which decreases expression in hypoxic cancer cells
  • miR-130a and miR-495 bind to 3'-UTR portion of PTEN through miRanda program. The site was found. And it was confirmed that the binding site with the microRNA-382 in the 3'-UTR of PTEN mRNA is preserved in various species (see Fig. 10).
  • the 3'-UTR portion of PTEN including the binding site of microRNA-382 was cloned into a luciferase reporter vector, and pGL3-luciferase-PTEN 3 '-UTR-vector was constructed. Thereafter, the prepared vector was transduced into cells, microRNA-382 was treated to cells transfected with the vector, and luciferase activity in the cells was measured.
  • microRNA-382 binds directly to the 3'UTR of the target gene PTEN.
  • miRNA mimic MSY0000737
  • miRNA inhibitor that can inhibit microRNA (Qiagen miScript miRNAs).
  • the present inventors performed chick chorioallantoic membrane (CAM) assay to confirm the angiogenic effect of microRNA-382 in vivo.
  • CAM chick chorioallantoic membrane
  • CAM assay was performed as follows.
  • the fertilized eggs were incubated in an incubator maintained at a temperature of 37-38 ° C. and a humidity of 90% or higher.
  • the cut ends of the fertilized eggs were injured with a knife, then the holes were sealed and incubated again with the holes facing down. Thereafter, a circular window having a diameter of 2-3 cm toward the air sac of the fertilized egg (the opposite side of the syringe hole) was cut out, and only the one identified as the fertilized egg was blocked with a wide glass tape and cultured again to induce the production of CAM.
  • the negative control and microRNA-382 mimic were transduced into cells under normal oxygen conditions, and the conditioned medium obtained after 24 hr was concentrated 30 times, mixed with matrigel in a 1: 1 ratio to form a mixture. This was processed on CAM.
  • the negative control and the microRNA-382 inhibitor were transduced into the cells and subjected to hypoxic condition after 16 hr, and after 24 hr, the medium was separated / concentrated and mixed with matrigel in a 1: 1 ratio. A mixture was made, which was processed on CAM and photographed close by camera after 4 days.
  • CAM treated with the conditioned medium mixture containing microRNA-382 increased the number of branches of microvessels compared to the negative control, whereas treated conditioned medium containing microRNA-382 inhibitors under hypoxic conditions.
  • mirroRNA-382 has an effect of promoting angiogenesis in vivo.
  • the present inventors confirmed whether angiogenesis-promoting effect can be suppressed by treatment with PTEN protein, a target gene of miroRNA-382.
  • tube formation assay was performed using a condition medium obtained from cells transduced with PTEN so that the PTEN protein was overexpressed. As a result, tube formation induced by microRNA-382 was inhibited by PTEN treatment. It was confirmed (see FIG. 14).
  • CAM assay confirmed that angiogenesis increased by microRNA-382 was decreased by PTEN, and angiogenesis was reduced by treatment with microRNA-382 inhibitor in hypoxic condition than in hypoxic state (see FIG. 15). ).

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Abstract

L'invention concerne une composition anti-angiogène et plus particulièrement une composition pharmaceutique anti-angiogène comprenant un inhibiteur de microARN-382. Les inventeurs de la présente invention ont confirmé que le micro-ARN-382 dont l'expression est élevée dans les cellules du cancer de l'estomac dans des environnements pauvres en oxygène, modifie la promotion de l'angiogenèse induite par un environnement pauvre en oxygène. Ainsi, la composition pharmaceutique de l'invention inhibe le microARN-382 et donc l'angiogenèse et la prolifération cellulaire, et peut finalement être utilisé de manière avantageuse dans le traitement du cancer.
PCT/KR2012/006910 2011-08-30 2012-08-29 Composition pharmaceutique anti-angiogène comprenant un inhibiteur de microarn-382 Ceased WO2013032231A2 (fr)

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US14/240,539 US9012426B2 (en) 2011-08-30 2012-08-29 Pharmaceutical anti-angiogenic composition including a MicroRNA-382 inhibitor

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KR10-2011-0086987 2011-08-30
KR20110086987 2011-08-30
KR10-2012-0094794 2012-08-29
KR20120094794A KR20130024831A (ko) 2011-08-30 2012-08-29 ｍｉｃｒｏＲＮＡ－382의 억제제를 포함하는 혈관신생억제용 약학적 조성물

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WO2008014008A2 (fr) * 2006-07-28 2008-01-31 The Johns Hopkins University Compositions et procédés pour moduler l'angiogenèse
CN102046810B (zh) * 2008-04-07 2014-11-19 康奈尔研究基金公司 血管生成抑制
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