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WO2023035201A1 - Application de penfluridol combiné à de l'acétate de médroxyprogestérone dans la préparation d'un médicament pour le traitement du cancer de l'endomètre - Google Patents

Application de penfluridol combiné à de l'acétate de médroxyprogestérone dans la préparation d'un médicament pour le traitement du cancer de l'endomètre Download PDF

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Publication number
WO2023035201A1
WO2023035201A1 PCT/CN2021/117536 CN2021117536W WO2023035201A1 WO 2023035201 A1 WO2023035201 A1 WO 2023035201A1 CN 2021117536 W CN2021117536 W CN 2021117536W WO 2023035201 A1 WO2023035201 A1 WO 2023035201A1
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Prior art keywords
endometrial cancer
penfluridol
cells
medroxyprogesterone acetate
pharmaceutical composition
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Chinese (zh)
Inventor
王玉东
孙笑
毛斐
伍慧雯
刘小虎
李丽娟
李剑
李晓康
朱进
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International Peace Maternity And Child Health Hospital
East China University of Science and Technology
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International Peace Maternity And Child Health Hospital
East China University of Science and Technology
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Priority to PCT/CN2021/117536 priority Critical patent/WO2023035201A1/fr
Publication of WO2023035201A1 publication Critical patent/WO2023035201A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the technical field of medicine, in particular to the application of penfluridol combined with medroxyprogesterone acetate in the preparation of medicines for treating endometrial cancer.
  • Endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium. It is one of the most common gynecological malignancies in the world, and its morbidity and mortality are increasing (Karen, Endometrial Cancer , The New England Journal of Medicine 2020, 383, 2053-2064).
  • EC Endometrial Cancer
  • the incidence of EC in young women has increased dramatically over the past decade, with younger and younger women being diagnosed with endometrial cancer, and the underlying cause of the increase is obesity
  • the prevalence and resulting hyperinsulinemia, and endometrial cancer rates are rising as obesity rates rise (Moore, Endometrial Cancer: Is This a New Disease? Am. Soc. Clin. Oncol. 2017, 37, 435-442).
  • 2020 there will be 420,000 new cases of endometrial cancer worldwide, including 80,000 new cases in China.
  • EC is usually divided into type I and type II.
  • type I EC is positive for progesterone receptor expression
  • type II EC is negative for progesterone receptor expression
  • progesterone receptor expression Bookhman, Gynecologic oncology, 1983, 15, 10-17 .
  • surgical treatment is a common method for the treatment of EC, but conservative treatment with progesterone therapy is required for patients who need to protect their reproductive function.
  • the main method of conservative treatment is hormone therapy with progesterone drugs (mainly medroxyprogesterone acetate (MPA)).
  • MPA medroxyprogesterone acetate
  • hormone therapy has limitations. It is only effective for patients with positive progesterone receptor expression and has a high recurrence rate, which is prone to drug resistance.
  • the purpose of the present invention is to provide a drug capable of treating EC, especially progesterone receptor-negative and progesterone-resistant EC.
  • composition comprising:
  • the pharmaceutical composition is used for treating and/or preventing endometrial cancer.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the endometrial cancer includes progesterone-sensitive endometrial cancer or progesterone-resistant endometrial cancer.
  • the endometrial cancer is progesterone receptor-negative and progesterone-resistant endometrial cancer.
  • the progestin is selected from the group consisting of medroxyprogesterone acid, megestrol acetate, progesterone caproate, or combinations thereof.
  • the progestin is medroxyprogesterone acetate.
  • the weight ratio of the first active ingredient to the second active ingredient is from 1:20 to 10:1, preferably from 1:15 to 1:1, more preferably from 1:10 to 1:5.
  • the content of the first active ingredient in the pharmaceutical composition is 0.01-90wt%, preferably 0.1-30wt%, more preferably 0.5-10wt%.
  • the content of the second active ingredient in the pharmaceutical composition is 0.01-90wt%, preferably 0.1-30wt%, more preferably 0.5-10wt%.
  • the first active ingredient and the second active ingredient account for 0.01-90wt% of the total mass of the pharmaceutical composition, preferably 0.1-50wt%, more preferably 0.5-30wt%.
  • the pharmaceutical composition further includes a pharmaceutically acceptable carrier.
  • the dosage form of the pharmaceutical composition includes injection dosage form and oral dosage form.
  • the dosage forms of the pharmaceutical composition include injections, tablets, capsules, pills, suspensions and emulsions.
  • the pharmaceutical composition further includes other anti-endometrial cancer drugs.
  • a kit which includes:
  • the progestin is selected from the group consisting of medroxyprogesterone acid, megestrol acetate, progesterone caproate, or combinations thereof.
  • the kit further includes instructions, which indicate that the first preparation and the second preparation are used in combination to treat and/or alleviate endometrial cancer.
  • the first preparation and the second preparation are administered simultaneously, separately or sequentially in the treatment of endometrial cancer.
  • the first preparation and the second preparation in the kit are independent of each other, or combined.
  • the first preparation and the second preparation in the kit are independent of each other.
  • the first preparation is an oral preparation or an injection preparation.
  • the dosage forms of the first preparation include injections, tablets, capsules, pills, suspensions and emulsions.
  • the second preparation is an oral preparation or an injection preparation.
  • the dosage forms of the second preparation include injections, tablets, capsules, pills, suspensions and emulsions.
  • a combination of active ingredients which includes:
  • the progestin is selected from the group consisting of medroxyprogesterone acid, megestrol acetate, progesterone caproate, or combinations thereof.
  • the fourth aspect of the present invention there is provided a use of the pharmaceutical composition described in the first aspect of the present invention, the kit described in the second aspect and/or the combination of active ingredients described in the third aspect, for the preparation of Medicines to treat and/or relieve endometrial cancer.
  • the present invention also provides the use of the pharmaceutical composition, the kit and/or the combination of active ingredients described in the present invention for treating and/or alleviating endometrial cancer.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the drug is also used for one or more of the following purposes:
  • the endometrial cancer cells are selected from the group consisting of ISK, KLE, or a combination thereof.
  • the endometrial cancer cells are ISK and/or KLE cells.
  • a method for inhibiting endometrial cancer cells in vitro comprising the steps of:
  • the method is non-therapeutic and non-diagnostic.
  • the inhibition is selected from the group consisting of:
  • the endometrial cancer cells are ISK and/or KLE cells.
  • a method for treating endometrial cancer comprising the step of: administering the pharmaceutical composition described in the first aspect of the present invention, the kit described in the second aspect or The combination of active ingredients described in the third aspect.
  • the subject is a patient with endometrial cancer.
  • the endometrial cancer includes type I and type II endometrial cancer.
  • the treatment method further includes administering other anti-endometrial cancer drugs to the subject in need.
  • Figure 1 is a schematic diagram of the inhibitory activity of penfluridol and medroxyprogesterone acetate on the proliferation of ISK and KLE cells.
  • A ISK cell proliferation inhibitory activity
  • B KLE cell proliferation inhibitory activity.
  • Figure 2 is a schematic diagram of the synergistic inhibitory effect of penfluridol and medroxyprogesterone acetate on ISK and KLE cells.
  • A Synergistic inhibitory effect of combined drugs on ISK cells;
  • B Synergistic inhibitory effect of combined drugs on KLE cells.
  • Fig. 3 is a schematic diagram of the effect of penfluridol combined with medroxyprogesterone acetate on the migration ability of ISK and KLE cells.
  • A ISK cell scratch;
  • B KLE cell scratch;
  • C ISK cell wound healing distance percentage;
  • D KLE cell wound healing distance percentage.
  • Fig. 4 is a schematic diagram of the effect of penfluridol and medroxyprogesterone acetate on the migration ability of ISK and KLE cells.
  • A ISK cell crystal violet staining
  • B ISK cell crystal violet staining quantification
  • C KLE cell crystal violet staining
  • D KLE cell crystal violet staining quantification.
  • Fig. 5 is a schematic diagram showing the effects of penfluridol and medroxyprogesterone acetate on the apoptosis of ISK and KLE cells.
  • A Effect of combined drug on ISK cell apoptosis;
  • B Effect of combined drug on KLE cell apoptosis;
  • C Quantification of ISK cell apoptosis ratio;
  • D KLE cell apoptosis ratio quantification.
  • the present inventor unexpectedly found that the combination of antipsychotic drug penfluridol and medroxyprogesterone acetate (MPA) can significantly improve the therapeutic effect on endometrial cancer, and can significantly improve the therapeutic effect on endometrial cancer ISK and
  • the proliferation and migration abilities of KLE cells have a synergistic inhibitory effect, and can synergistically induce the apoptosis of endometrial cancer ISK and KLE cells.
  • the synergistic therapeutic effect of penfluridol and medroxyprogesterone acetate is obviously better than that of penfluridol or medroxyprogesterone acetate alone. On this basis, the present invention has been accomplished.
  • the terms “comprising”, “including”, and “containing” are used interchangeably to include not only closed definitions, but also semi-closed, and open definitions. In other words, the terms include “consisting of”, “consisting essentially of”.
  • pharmaceutically acceptable carrier refers to ingredients suitable for humans and/or animals without undue adverse side effects (such as toxicity, irritation and allergic reactions), that is, with a reasonable benefit/risk ratio substance.
  • the term "therapeutically effective amount” refers to an amount that produces functions or activities on humans and/or animals and is acceptable to humans and/or animals. Those of ordinary skill in the art should understand that the “therapeutically effective amount” may vary depending on the form of the pharmaceutical composition, the route of administration, the adjuvant of the drug used, the severity of the disease, and the combination with other drugs. different.
  • Penfluridol Penfluridol
  • PFL the first active ingredient of the present invention
  • the penfluridol has the following structural formula:
  • Penfluridol is an oral long-acting antipsychotic drug approved by the U.S. Food and Drug Administration (FDA). For the treatment of various types of schizophrenia. Penfluridol is a potent inhibitor of dopamine D2 receptors and calcium channels.
  • penfluridol has a proliferation inhibitory effect on both endometrial cancer cells ISK (type I, progesterone-sensitive) and type II endometrial cancer cells KLE (progesterone-resistant). Further studies have found that its combined application with medroxyprogesterone acetate has a significant synergistic inhibitory effect on the two types of cells, can inhibit the proliferation and migration of the two types of EC cells, and induce EC cell apoptosis. Therefore, the present invention provides the use of penfluridol and medroxyprogesterone acetate in combination to prepare a medicine for treating endometrial cancer.
  • second active ingredient of the invention refers to a progestin.
  • the progestin is selected from the group consisting of medroxyprogesterone acid, megestrol acetate, progesterone caproate, or combinations thereof.
  • the progestogen is medroxyprogesterone acetate and pharmaceutically acceptable salts thereof.
  • endometrial cancer is a group of epithelial malignant tumors that occur in the endometrium, also known as uterine body cancer, and is one of the three most common malignant tumors of the female reproductive system. . Endometrial cancer is more likely to occur in perimenopausal and postmenopausal women. According to its pathogenesis and biological behavior characteristics, it can be divided into type I endometrial cancer (estrogen-dependent type) and type II endometrial cancer (non-estrogen-dependent type). hormone-dependent).
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the pharmaceutical composition is used for treating and/or preventing endometrial cancer.
  • the present invention also provides a kit, which includes:
  • the first preparation and the second preparation are different preparations or the same preparation.
  • the order of administration is not particularly limited, and they can be administered sequentially, together, or sequentially.
  • the progestin is selected from the group consisting of medroxyprogesterone acid, megestrol acetate, progesterone caproate, or combinations thereof.
  • the progestin is medroxyprogesterone acetate.
  • the weight ratio of the first active ingredient to the second active ingredient is preferably 1:20 to 10:1, more preferably 1:15 to 1:1, further preferably 1:10 to 1:1: 5.
  • the content of the first active ingredient in the pharmaceutical composition is preferably 0.01-90wt%, more preferably 0.1-30wt%, even more preferably 0.5-10wt%.
  • the content of the second active ingredient in the pharmaceutical composition is preferably 0.01-90wt%, more preferably 0.1-30wt%, even more preferably 0.5-10wt%.
  • the first active ingredient and the second active ingredient account for the total mass of the pharmaceutical composition, preferably 0.01-90 wt%, more preferably 0.1-50 wt%, further preferably 0.5-30 wt%.
  • the carrier includes conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, lubricants and the like in the pharmaceutical field.
  • the compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, injections, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can be present in suitable solid or liquid carriers or Diluent and appropriate sterile equipment for injection or infusion.
  • compositions of the present invention can be prepared according to conventional preparation methods in the field of pharmacy.
  • the pharmaceutical composition of the present invention can be clinically used in mammals, including humans and animals, and can be administered through oral, nasal, skin, lung or gastrointestinal tract and other routes. Oral administration is most preferred.
  • the most preferred daily dose is 0.01-400 mg/kg body weight, taken once, or 0.01-200 mg/kg body weight in divided doses. Regardless of the method of administration, the optimal dosage for an individual should depend on the specific treatment. Usually, start with a small dose and gradually increase the dose until you find the most suitable dose.
  • the drug or inhibitor of the present invention can be administered in various ways, for example, it can be introduced into the body by injection, spray, nasal drop, eye drop, penetration, absorption, physical or chemically mediated methods such as muscle, intradermal, subcutaneous, intravenous , mucosal tissue; or mixed or wrapped by other substances into the body.
  • the active ingredient of the present invention or the pharmaceutical composition containing it can be administered in unit dose form, and the route of administration can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, Eyes, lungs and respiratory tract, skin, vagina, rectum, etc.
  • the dosage form for administration may be a liquid dosage form, a solid dosage form or a semi-solid dosage form.
  • Liquid dosage form can be solution (including true solution and colloid solution), emulsion (including O/W type, W/O type and double emulsion), suspension, injection (including water injection, powder injection and infusion), eye drops Agents, nasal drops, lotions and liniments, etc.
  • solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules ( Including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, gas (powder) aerosols, sprays, etc.
  • semi-solid dosage forms can be ointments, Gels, pastes, etc.
  • the active ingredients of the present invention can be made into common preparations, sustained-release preparations, controlled-release preparations, targeted preparations and various microparticle drug delivery systems.
  • diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch slurry, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, arabic mucilage, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hypromellose Base cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.
  • disintegrants can be dry starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.
  • the wetting agent can be water, ethanol, Isopropanol, etc.
  • the binder can be starch
  • Tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.
  • the active ingredient of the present invention can be mixed with a diluent and a glidant, and the mixture is directly placed in a hard capsule or a soft capsule.
  • the active ingredients can also be made into granules or pellets with diluents, binders, and disintegrants, and then placed in hard or soft capsules.
  • Various diluents, binders, wetting agents, disintegrants, and glidants used to prepare the tablets of the present invention can also be used to prepare the capsules of the present invention.
  • water, ethanol, isopropanol, propylene glycol or their mixture can be used as a solvent and an appropriate amount of commonly used solubilizers, cosolvents, pH regulators, and osmotic pressure regulators in the field can be added.
  • the solubilizer or co-solvent can be poloxamer, lecithin, hydroxypropyl- ⁇ -cyclodextrin, etc.
  • the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.
  • the osmotic pressure regulator can be Sodium chloride, mannitol, glucose, phosphate, acetate, etc.
  • mannitol, glucose, etc. can also be added as proppants.
  • coloring agents can also be added to the pharmaceutical preparations, if necessary.
  • the two active ingredients or compositions of the present invention can be taken together or sequentially, or further combined with other therapeutic drugs or symptomatic drugs.
  • the active ingredient of the present invention has a synergistic effect with other therapeutic drugs, its dose should be adjusted according to the actual situation.
  • the present invention found through experiments that penfluridol combined with medroxyprogesterone acetate has a synergistic inhibitory effect on the proliferation and migration of endometrial cancer ISK and KLE cells, and can synergistically induce the apoptosis of endometrial cancer ISK and KLE cells .
  • the present invention also found that the synergistic therapeutic effect of penfluridol and medroxyprogesterone acetate is significantly better than that of penfluridol or medroxyprogesterone acetate alone.
  • Penfluridol is an oral long-acting antipsychotic drug, so it has high safety. Combined use with medroxyprogesterone acetate also has higher safety and lower side effects.
  • Example 1 Inhibitory effect of penfluridol and medroxyprogesterone acetate on the proliferation of endometrial cancer cells
  • medroxyprogesterone acetate can inhibit the proliferation of endometrial cancer cells ISK, while the same dose of medroxyprogesterone acetate has no obvious inhibitory effect on KLE cells, and the combination of penfluridol and medroxyprogesterone acetate can significantly Inhibits the proliferation of endometrial cancer cells ISK and KLE in a concentration-dependent manner.
  • Endometrial cancer cells ISK and KLE were purchased from the American Type Culture Collection (ATCC); phosphate buffered saline (PBS) was purchased from Bio-channel; DMEM/F12 medium was purchased from Biosharp; fetal calf Serum (FBS) and trypsin were purchased from Gibco; CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.; penfluridol was from the old drug store of the laboratory; medroxyprogesterone acetate was purchased from Selleck.
  • PBS phosphate buffered saline
  • FBS fetal calf Serum
  • trypsin were purchased from Gibco
  • CCK-8 was purchased from Biyuntian Biotechnology Co., Ltd.
  • penfluridol was from the old drug store of the laboratory
  • medroxyprogesterone acetate was purchased from Selleck.
  • ISK and KLE cells were cultured in DMEM/F12 (containing 10% fetal bovine serum, 1% penicillin/streptomycin) medium and placed in an incubator at 37°C and 5% CO 2 .
  • the endometrial cancer cells basically covered the cell culture dish (10 cm)
  • the cells were digested with trypsin, and seeded in a 96-well plate at a cell density of 5000 cells/well, 100 ⁇ L per well.
  • DMEM/F12 medium containing different concentrations of PFL was added, 200 ⁇ L per well, and 3 replicate wells were set up for each group. Incubate them for 72 hours in a cell culture incubator.
  • Inhibition rate calculation formula: cell inhibition rate% [1-(administration group A value-blank group A value)/(control group A value-blank group A value)] ⁇ 100%, IC50 value through Graphpad Prism 8.0 software fit.
  • Table 1 and Figure 1 show the anti-proliferation data of the combination of penfluridol and medroxyprogesterone acetate on two kinds of EC cells.
  • the proliferative activity of endometrial cancer cells decreased with the increase of penfluridol concentration, indicating that the combination of penfluridol and medroxyprogesterone acetate can inhibit the proliferation of endometrial cancer cells ISK and KLE in a concentration-dependent manner.
  • the IC 50 of penfluridol and medroxyprogesterone acetate on the proliferation of ISK cells were 2.74 ⁇ M and 23.72 ⁇ M respectively;
  • the inhibitory activity IC 50 were 2.89 ⁇ M and 41.43 ⁇ M, respectively.
  • MPA medroxyprogesterone acetate
  • PFL penfluridol
  • Example 1 For the cultivation of ISK and KLE cells and the detection of CCK-8, see the experimental materials and methods in Example 1.
  • the concentration gradient of medroxyprogesterone acetate was set to 0, 5, 10, 15 and 20 ⁇ M, and the concentration gradient of penfluridol was 0, 0.5, 1, 2, 4, 8, 10, 20 and 50 ⁇ M.
  • the absorbance value A at 450nm was detected using a Bio-Tek multifunctional microplate reader, and the inhibition rate and IC50 value were calculated.
  • Inhibition rate calculation formula: cell inhibition rate% [1-(administration group A value-blank group A value)/(control group A value-blank group A value)] ⁇ 100%.
  • the obtained inhibition rate was analyzed by using SynergyFinder 2.0 to obtain the synergy scores of penfluridol and medroxyprogesterone acetate in ISK and KLE cells, respectively.
  • MPA medroxyprogesterone acetate
  • PFL penfluridol
  • the source of experimental materials is the same as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin, prepared into a single cell suspension using serum-free DMEM/F12 medium, and seeded into a 6-well plate at a density of about 500,000 cells per well. After the cells adhered to the wall, they were divided into 6 groups, namely the control group, the MPA 5 ⁇ M group, the MPA 10 ⁇ M group, the PFL 1 ⁇ M group, the MPA 5 ⁇ M+PFL 1 ⁇ M group, and the MPA 10 ⁇ M+PFL 1 ⁇ M group, with 3 replicate wells in each group.
  • the percentage of wound healing distance between cell scratches was significantly lower than that in the single drug treatment group.
  • the vertical axis of the histogram indicates the percentage of wound healing distance of cells in each group, and the significant difference of the data was analyzed by One-way ANOVA method (Graphpad Prism8.0 software). Data are mean ⁇ SD: ***P ⁇ 0.001 vs Ctrl, ###P ⁇ 0.001 vs MPA 5 ⁇ M, $$$P ⁇ 0.001 vs MPA 10 ⁇ M.
  • the Transwell chamber was purchased from Costar Company; paraformaldehyde is a common reagent in the laboratory, commercially purchased without any treatment, and the sources of other experimental materials are the same as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin, prepared into a single cell suspension using serum-free DMEM/F12 medium, and seeded on the top of the Transwell chamber at a density of about 100,000 cells per well. Add 600 ⁇ L of DMEM/F12 medium containing 20% FBS to the bottom of the small chamber, taking care to avoid the generation of air bubbles.
  • each group set 3 replicate wells.
  • 150 ⁇ L of serum-free DMEM/F12 medium containing different drugs was added to the upper chamber of the treatment group, and 150 ⁇ L of serum-free DMEM/F12 medium without drug was added to the upper chamber of the control group. Place in an incubator at 37°C with 5% CO 2 for 24 hours.
  • the vertical axis of the histogram indicates the number of cells passing through the small chamber in each group, and the significant difference of the data was analyzed by One-way ANOVA method (Graphpad Prism8.0 software). Data are mean ⁇ SD: **P ⁇ 0.01, ***P ⁇ 0.001 vs Ctrl, ###P ⁇ 0.001 vs MPA 5 ⁇ M, $$$P ⁇ 0.001 vs MPA 10 ⁇ M.
  • Annexin V-FITC/PI cell apoptosis detection kit was used to test the effects of penfluridol and medroxyprogesterone acetate on the apoptosis of endometrial cancer cells ISK and KLE at the cellular level.
  • penfluridol can inhibit the apoptosis of endometrial cancer cells ISK and KLE, and its combination with medroxyprogesterone acetate can synergistically inhibit the apoptosis of endometrial cancer cells.
  • the Annexin V-FITC/PI Cell Apoptosis Detection Kit was purchased from Beyotime Biotechnology Co., Ltd., in which Annexin V-FITC Conjugate Solution, Annexin V-FITC, and Propidium Iodide (PI) are all reagents in the kit. All the other experimental materials are from the same sources as in Example 1.
  • the EC cells in the logarithmic growth phase were digested with trypsin to prepare a single cell suspension, seeded into a 6-well plate at a density of about 120,000 cells per well, and cultured overnight.
  • the cells adhered to the wall they were divided into 6 groups, namely the control group, the MPA 5 ⁇ M group, the MPA 10 ⁇ M group, the PFL 1 ⁇ M group, the MPA 5 ⁇ M+PFL 1 ⁇ M group, and the MPA 10 ⁇ M+PFL 1 ⁇ M group, with 3 replicate wells in each group. Incubate for 48 h at 37 °C in an incubator with 5% CO 2 .
  • the apoptosis ratios of ISK and KLE were 23.92% and 12.52%, respectively.
  • the apoptotic ratios of ISK and KLE were 22.97% and 35.16% when Lido combined with medroxyprogesterone acetate (10 ⁇ M).
  • the vertical axis of the histogram indicates the proportion of apoptosis in each group, and the significant difference of the data is analyzed by One-way ANOVA method (Graphpad Prism8.0 software).

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Abstract

Application de penfluridol combiné à de l'acétate de médroxyprogestérone dans la préparation d'un médicament pour le traitement du cancer de l'endomètre. Le penfluridol et l'acétate de médroxyprogestérone peuvent inhiber de manière synergique la prolifération et la migration de cellules cancéreuses endométriales, et favoriser l'apoptose des cellules cancéreuses endométriales.
PCT/CN2021/117536 2021-09-09 2021-09-09 Application de penfluridol combiné à de l'acétate de médroxyprogestérone dans la préparation d'un médicament pour le traitement du cancer de l'endomètre Ceased WO2023035201A1 (fr)

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