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WO2021174995A1 - Utilisation de jq-1 dans la préparation d'un médicament pour le traitement du cancer du pancréas et méthode de vérification de l'inhibition de jq-1 sur la sécrétion d'exosomes du cancer du pancréas - Google Patents

Utilisation de jq-1 dans la préparation d'un médicament pour le traitement du cancer du pancréas et méthode de vérification de l'inhibition de jq-1 sur la sécrétion d'exosomes du cancer du pancréas Download PDF

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Publication number
WO2021174995A1
WO2021174995A1 PCT/CN2020/142371 CN2020142371W WO2021174995A1 WO 2021174995 A1 WO2021174995 A1 WO 2021174995A1 CN 2020142371 W CN2020142371 W CN 2020142371W WO 2021174995 A1 WO2021174995 A1 WO 2021174995A1
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Prior art keywords
pancreatic cancer
exosomes
secretion
pbs
protein
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PCT/CN2020/142371
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English (en)
Chinese (zh)
Inventor
肖明兵
郑文杰
顾志峰
施炜
范义辉
郭悦华
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Affiliated Hospital of Nantong University
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Affiliated Hospital of Nantong University
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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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • 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
    • C12N2503/00—Use of cells in diagnostics
    • C12N2503/02—Drug screening
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/10—Screening for compounds of potential therapeutic value involving cells

Definitions

  • the invention belongs to the technical field of biomedicine, relates to the technical field of application of JQ-1 (triphenylmethane triisocyanate), and specifically relates to the application of JQ-1 (triphenylmethane triisocyanate) in the preparation of pancreatic cancer therapeutic drugs and its inhibition Validation method for secretion of exosomes in pancreatic cancer.
  • JQ-1 triphenylmethane triisocyanate
  • pancreatic cancer plays a key role in the occurrence, development, metastasis and drug resistance of pancreatic cancer.
  • Pancreatic cancer helps its progression by secreting exosomes to shape the microenvironment of itself and other organs. Compared with normal cells and other tumors, pancreatic cancer cells secrete more exosomes, and highly malignant pancreatic cancer cells can transfer their cancerous characteristics to low-grade cancer cells through exosomes to promote their proliferation, Migration and invasion to accelerate disease progression.
  • the exosomes derived from pancreatic cancer can also be taken up by Kupffer cells in the liver, causing Kupffer cells to secrete TGF ⁇ , which in turn promotes the production of fibronectin by hepatic stellate cells, creating a microenvironment suitable for tumor growth to promote liver metastasis. It can be seen that finding effective means to inhibit exosomal secretion is of great significance for the clinical treatment of pancreatic cancer.
  • GW4869 a non-competitive inhibitor of neutral Smase (sphingomyelinase), is basically a recognized exosome inhibitor, which can inhibit the secretion of exosomes.
  • farnesyl transferase inhibitor Manumycin A
  • Ras signaling pathway Ras signaling pathway
  • hnRNP H1 Ras signaling pathway
  • the technical problem to be solved by the present invention is to provide an application of JQ-1 in the preparation of pancreatic cancer therapeutic drugs and a verification method for inhibiting the secretion of pancreatic cancer exosomes, so as to solve the problems raised in the background art.
  • the embodiment of the present invention provides an application of JQ-1 in the preparation of a pancreatic cancer therapeutic drug.
  • pancreatic cancer drug is used to inhibit the secretion of pancreatic cancer cell exosomes.
  • the embodiment of the present invention provides an anti-pancreatic cancer pharmaceutical composition, characterized in that the pharmaceutical composition contains at least JQ-1.
  • the pharmaceutical composition also includes medical auxiliary components added according to the requirements of the pharmaceutical preparation and dosage form.
  • the embodiment of the present invention also provides a method for verifying the inhibitory effect of JQ-1 on the secretion of pancreatic cancer cells exosomes, which is characterized by including the following processes: (1) Establishing a pancreatic cancer cell group after JQ-1 treatment and a control In the pancreatic cancer cell group, the cell supernatant exosomes were extracted by low-temperature ultracentrifugation; (2) Transmission electron microscopy was used to verify the goblet structure of exosomes wrapped in a double lipid membrane; (3) NTA was used to detect the concentration of exosomes; 4) After lysing the collected exosomes, use the BCA kit to quantify the protein, and use the measured protein amount to reflect the amount of exosomes; (5) Use the untreated CFPAC-1 cell line to construct subcutaneous tumors in nude mice Model, collect pancreatic cancer tissues, use PCR to detect the mRNA levels of CD63 and Rab27a.
  • step (1) specifically includes the following process: the step (1) specifically includes the following process:
  • pancreatic cancer cell group and the control pancreatic cancer cell group were to collect 80 mL of cell supernatant under the standard of the same number of cells;
  • step (2) specifically includes the following process:
  • step (3) specifically includes the following process:
  • step (4) specifically includes the following process:
  • step (5) specifically includes the following process:
  • the nude mouse models are divided into experimental group nude mice and control group nude mice, each group contains 3 nude mice, and the experimental group nude mice are injected intraperitoneally with 30mg/kg/d JQ-1 every day, first and third , 5, 6 days for injection;
  • JQ-1 has the effect of inhibiting the secretion of pancreatic cancer cells.
  • JQ-1 is applied to the preparation of pancreatic cancer therapeutic drugs , Provide a new theoretical basis for clinical patients to find potential drug targets; validated by the verification method of JQ-1 inhibiting the secretion of pancreatic cancer exosomes, thus confirming that JQ-1 has the effect of inhibiting the secretion of pancreatic cancer cells, further verifying The reliability of JQ-1 used in the preparation of therapeutic drugs for pancreatic cancer.
  • Figure 1 is a diagram of the morphology and number of pancreatic cancer cell exosomes in the control group and JQ-1 treatment group observed by transmission electron microscope in the present invention
  • Figure 2 is a graph of the concentration of exosomes in pancreatic cancer cells in the NTA detection control group and the JQ-1 treatment group of the present invention
  • Figure 3 is a graph showing the concentration of exosomal protein in pancreatic cancer cells detected by the BCA method in the control group and the JQ-1 treatment group in the present invention
  • Fig. 4 shows the mRNA levels of CD63 and Rab27a in pancreatic cancer tissues of the control group and JQ-1 treatment group after the subcutaneous tumor formation of nude mice CFPAC-1 cells is detected by PCR in the present invention
  • Figure 4A is a statistical diagram of CD63 mRNA levels in pancreatic cancer tissues of the control group and JQ-1 treatment group detected by PCR
  • Figure 4B is the statistics of Rab27a mRNA levels in pancreatic cancer tissues of the control group and JQ-1 treatment group detected by PCR picture.
  • pancreatic cancer drug is used to inhibit the secretion of pancreatic cancer cell exosomes.
  • the embodiment of the present invention provides a pharmaceutical composition for anti-pancreatic cancer, the pharmaceutical composition at least containing JQ-1.
  • the pharmaceutical composition is applied to inhibit exosomes secreted by pancreatic cancer cells.
  • the embodiment of the present invention also provides a method for verifying the inhibitory effect of JQ-1 on pancreatic cancer cells secreting exosomes, including the following processes: (1) Establishing a pancreatic cancer cell group after JQ-1 treatment and a control pancreatic cancer cell group , The use of low-temperature ultracentrifugation to extract exosomes from the cell supernatant; (2) Transmission electron microscopy to verify the cup-shaped structure of the exosomes wrapped in a double lipid membrane; (3) NTA method to detect the concentration of exosomes; (4) After the collected exosomes were lysed, the protein was quantified with the BCA kit, and the measured protein amount was used to reflect the amount of exosomes; (5) The untreated CFPAC-1 cell line was used to construct a nude mouse subcutaneous tumor model and collect In pancreatic cancer tissues, the mRNA levels of CD63 and Rab27a were detected by PCR.
  • a method for verifying the inhibitory effect of JQ-1 on the secretion of exosomes of pancreatic cancer cells specifically includes the following steps: extracting cell supernatant exosomes using a low-temperature ultracentrifugation method.
  • the detailed method is as follows: After JQ-1 treatment, the pancreatic cancer cell group and the control pancreatic cancer cell group are treated with the same number of cells and 80 mL of the cell supernatant is collected, centrifuged at 300 ⁇ g for 15 min at 4°C, and centrifuged at 2000 ⁇ g for 30 min. After centrifugation at 16,500 ⁇ g for 30 minutes, the precipitation was removed.
  • the supernatant was filtered through a 0.22 ⁇ m filter and then ultracentrifuged at 150,000 ⁇ g for 120 minutes at low temperature. The precipitate was collected and resuspended in 100 ⁇ L PBS and stored in aliquots at -80°C.
  • Transmission electron microscopy verified the cup-shaped structure of exosomes wrapped in a double lipid membrane. Take 10 ⁇ L of the collected exosomes and fix them with 2.5% glutaraldehyde for 2h, wash the exosomes with PBS and resuspend them in 100 ⁇ L PBS, take 20 ⁇ L drop on a small copper plate, and stain with 3% phosphotungstic acid in water for 1min, observe by transmission electron microscope .
  • the NTA method detects the concentration of exosomes.
  • Detailed method draw 8 ⁇ L of collected exosomes, add PBS to dilute to 4mL, the dilution factor is 500 times. After the two are blown evenly, they are driven into the nanoparticle tracking analysis instrument to detect the concentration and particle size of exosomes.
  • Vehicle is the control pancreatic cancer cell group
  • JQ-1 is the pancreatic cancer cell group after JQ-1 treatment.
  • the BCA kit was used to quantify the protein, and the measured amount of protein was used to reflect the amount of exosomes.
  • nude mouse experiment was carried out in the present invention, which specifically includes the following steps: S1, nude mouse model preparation: collect untreated CFPAC-1 cells and prepare them with 100 ⁇ L PBS The cell suspension was injected subcutaneously into nude mice to construct a nude mouse subcutaneous tumor model, the model forming time was 20 days; S2, the nude mouse model was divided into experimental group nude mice and control group nude mice, each group had 3 nude mice , The experimental group of nude mice were injected with 30mg/kg/d JQ-1 daily, and injected on the 1, 3, 5, and 6 days; after S3, 7 days, the nude mice were collected subcutaneously tumor-forming pancreatic cancer tissues, and the RNA was extracted and reversed It was recorded as cDNA, and RT-PCR was performed to detect the mRNA levels of exosomal surface markers CD63 and Rab27a to reflect the number of exosomes.
  • Figure 4A is a statistical graph of CD63 and Rab27a mRNA levels in pancreatic cancer tissues of nude mice in the control group and JQ-1 treatment group
  • Figure 4B is a statistical graph of Rab27a mRNA levels in pancreatic cancer tissues of nude mice in the control group and JQ-1 treatment group
  • Control is the mRNA levels of CD63 and Rab27a in pancreatic cancer tissues of nude mice in the control group
  • JQ-1 is the mRNA levels of CD63 and Rab27a in pancreatic cancer tissues of nude mice in the experimental group
  • the test results show that: The number of exosomes secreted by pancreatic cancer cells in the experimental group of nude mice, that is, the group injected with JQ-1 into the abdominal cavity, decreased significantly.
  • the reagents in the embodiment of the present invention are prepared as follows:
  • 1 ⁇ PBST buffer Dissolve 0.24g KH2PO4, 0.2g KCl, 1.44g Na2HPO4 ⁇ 12H2O and 1mLTween-20 in deionized water, dilute to 1000mL, and store at room temperature.
  • JQ-1-a bromodomain and extraterminated domain (BET) inhibitor has anti-proliferation and apoptosis activity against many cancers.
  • JQ1 is a BET bromodomain inhibitor that acts on BRD4 and binds to all bromodomains of the BET family, but not to the bromodomains outside the BET family.
  • the BET protein is usually overexpressed in various types of human cancers and is clinically associated with these cancers.
  • the present invention provides the use of JQ-1 to significantly inhibit the secretion of pancreatic cancer cells exosomes after inhibiting the BET protein. In view of the key role of exosomes secretion in tumors, this feature makes JQ-1 possible in clinical tumor treatment The important value provides a new theoretical basis for clinical patients to find potential drug targets.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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  • Hematology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Food Science & Technology (AREA)
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  • Tropical Medicine & Parasitology (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une utilisation de JQ-1 dans la préparation d'un médicament pour le traitement du cancer du pancréas. L'invention concerne en outre une composition pharmaceutique contre le cancer du pancréas, qui contient du JQ-1. L'invention concerne en outre une méthode de vérification de l'effet d'inhibition du JQ-1 sur la sécrétion d'exosomes de cellules du cancer du pancréas. La méthode comprend les procédés suivants : extraction d'un exosome surnageant de cellule à l'aide d'une méthode d'ultracentrifugation à basse température ; utilisation d'un microscope électronique à transmission pour vérifier une structure en forme de coupelle enveloppée par une membrane lipidique bicouche de l'exosome ; réalisation d'une NTA (analyse de suivi de particules) pour mesurer la concentration en exosomes ; lyse de l'exosome collecté, puis quantification de la protéine à l'aide d'un kit BCA, reflétant la quantité de l'exosome à l'aide de la quantité mesurée de la protéine ; et collecte de tissus du cancer du pancréas d'un modèle tumorigène sous-cutané de souris Nude construit par une lignée cellulaire CFPAC-1 et test des niveaux d'ARNm de CD63 et de Rab27a par PCR.
PCT/CN2020/142371 2020-03-02 2020-12-31 Utilisation de jq-1 dans la préparation d'un médicament pour le traitement du cancer du pancréas et méthode de vérification de l'inhibition de jq-1 sur la sécrétion d'exosomes du cancer du pancréas Ceased WO2021174995A1 (fr)

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CN202010134774.9 2020-03-02
CN202010134774.9A CN111012774A (zh) 2020-03-02 2020-03-02 一种jq-1在制备胰腺癌治疗药物中的应用及其抑制胰腺癌外泌体分泌的验证方法

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CN114081959A (zh) * 2021-11-05 2022-02-25 姜海涛 一种胰腺靶向载药外泌体及其制备方法、应用和运载体

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