CN116173023A - New application of lenvatinib in preventing and treating type II diabetes - Google Patents

New application of lenvatinib in preventing and treating type II diabetes Download PDF

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CN116173023A
CN116173023A CN202211103479.2A CN202211103479A CN116173023A CN 116173023 A CN116173023 A CN 116173023A CN 202211103479 A CN202211103479 A CN 202211103479A CN 116173023 A CN116173023 A CN 116173023A
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diabetes
lenvatinib
glut4
cells
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赵平
姚艳红
杨新洲
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South Central Minzu University
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South Central University for Nationalities
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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
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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Abstract

The invention provides a new application of lenvatinib or pharmaceutically acceptable salt thereof in preventing and/or treating type II diabetes. Experiments of the invention find that lenvatinib promotes GLUT4 expression and translocation mainly through activating PKC channel, and promotes L6 cells to take up glucose, and the effect of taking up glucose is equivalent to that of insulin (insulin).

Description

New application of lenvatinib in preventing and treating type II diabetes
Technical Field
The invention belongs to the field of medical treatment, and particularly relates to a novel application of lenvatinib in preventing and treating type II diabetes.
Background
Diabetes is a chronic disease with high incidence, and often causes a series of metabolic disorders of substances such as sugar, protein, fat, water and electrolytes. Studies have shown that the intake of more adequate nutrition increases the probability of developing diabetes, with more than 90% of type two diabetes (T2 DM). T2DM, also known as non-insulin dependent diabetes mellitus, is a major feature of T2DM in vivo. During the onset of T2DM, the patient's islet beta cells also have the ability to secrete insulin, after which the patient's body develops insulin resistance, resulting in compensatory secretion of more insulin by the islet beta cells to maintain normal blood glucose levels. When the patient's islet beta cells lose compensatory ability, blood glucose levels rise, causing T2DM. The pathogenesis of T2DM is quite complex and has not yet been fully elucidated. Current studies indicate that T2DM is related to genetic and environmental factors. The etiology of T2DM is mostly related to insufficient endowment, diet loss, movement disorder and the like, and the main pathogenesis of the disease is Insulin Resistance (IR) and islet beta cell damage. There are a number of hypoglycemic agents currently in clinical use for improving blood glucose levels in patients with T2DM. At present, more drugs such as biguanides, sulfonylureas, alpha-glucosidase inhibitors and the like are mainly used. And the medicines have more side effects such as gastrointestinal discomfort, hypoglycemia and the like after long-term administration. T2DM is characterized by chronic hyperglycemia and varying degrees of insulin resistance. One of the causes of insulin resistance is deregulation of GLUT4 protein expression and function. Therefore, understanding the translocation and expression mechanism of GLUT4 is extremely important for the prevention and treatment of diabetes.
Diabetes is a systemic chronic metabolic disease associated with environmental factors, the main influencing factor of which is the genetic gene. Diabetes is mainly caused by two reasons, one is that the body cannot produce enough insulin, the other is that the target cells have low sensitivity to insulin or that the insulin itself has structural defects, so that carbohydrate, fat and protein metabolism is disturbed, and diabetes patients basically have diseases caused by one or both of the two reasons and are mainly characterized by hyperglycemia. Type II diabetes mellitus, also known as non-insulin dependent diabetes mellitus. Type II diabetes mellitus is a metabolic disorder caused by insulin secretion and is characterized by hyperglycemia, insulin resistance or reduced beta cell function of the islets and elevated blood glucose after the age of 35 to 40 years are caused by a variety of factors including immune deficiency, genetics and psychology. The patients with the second type diabetes account for 90-95% of the whole diabetic population. During the onset of type II diabetes, the patient's islet beta cells also have the ability to secrete insulin, after which the patient's body develops insulin resistance, resulting in compensatory secretion of more insulin by the islet beta cells to maintain normal blood glucose levels. Current research indicates that type two diabetes is related to genetic and environmental factors. Insulin secretion deficiency and insulin resistance are the 2 major symptoms of type two diabetes. If not controlled in time, type II diabetes can lead to a range of chronic complications such as cardiovascular disease, retinopathy, renal failure, and the like. A series of hypoglycemic agents are currently clinically available for improving blood glucose levels in patients with type II diabetes. Glucose transporter 4 (GLUT 4) is mainly responsible for basal glucose uptake and glucose basal metabolism maintenance in cells, GLUT4 protein is widely distributed in tissues such as skeletal muscle, cardiac muscle and fat, under the action of insulin, insulin receptors on the cell surface transmit intracellular signals to GLUT4 storage vesicles, perinuclear GLUT4 vesicle displacement is promoted, and glucose is transported from outside to inside by fusion to cell membranes through three steps of tethering, anchoring and fusion, so that glucose transport is assisted, and blood glucose can be reduced to improve diabetes. Therefore, a new drug for treating type II diabetes can be searched and screened aiming at GLUT4 as a target spot.
The prior treatments of the type II diabetes have more application and mainly comprise biguanides, sulfonylureas, alpha-glycosidase inhibitors and the like. And the medicines have more side effects such as gastrointestinal discomfort, hypoglycemia and the like after long-term administration. Lenvatinib is used as a multi-receptor Tyrosine Kinase Inhibitor (TKI) for treating various cancers, and has target effects on vascular endothelial growth factor receptor (VascularEndothelialGrowthFactorReceptor, VEGFR), fibroblast growth factor receptor (FibroblastGrowthFactorReceptors, FGFR) 1-3, stem cell growth factor receptor and beta-type Platelet-derived growth factor receptor (PDGFR). However, the research of treating type II diabetes by promoting GLUT4 expression and transportation by lenvatinib has not been reported at home and abroad.
Disclosure of Invention
The invention provides a new application of lenvatinib or pharmaceutically acceptable salt thereof in preventing and/or treating type II diabetes.
The invention also provides application of the lenvatinib or the pharmaceutically acceptable salt thereof in preparing a GLUT4 activity promoter, and the GLUT4 activity promoter is used for treating and/or preventing type II diabetes.
The invention also provides an application of the lenvatinib or the pharmaceutically acceptable salt thereof in preparing a PKC activator, and the PKC activator is used for treating and/or preventing type II diabetes.
The invention also provides a medicament for treating type II diabetes, which comprises lenvatinib or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable medicament carriers.
Further, the preparation is in the form of tablet, powder, decoction, pill, or capsule.
Further, the drug carrier comprises: surfactants, lubricants, absorption promoters, diluents.
Further, the GLUT4 activity promoter is in the form of tablets, powder, decoction, pills and capsules.
Further, the preparation forms of the activator are tablets, powder, decoction, pills and capsules.
The invention has the beneficial effects that: the invention discovers a new application of lenvatinib in preventing and treating type II diabetes. Experiments find that lenvatinib promotes GLUT4 expression and translocation mainly through activating PKC (protein kinase) channels, promotes L6 cells to take up glucose, and the effect of taking up glucose is equivalent to that of insulin (insulin).
Drawings
FIG. 1 is a bar graph of Lenvatinib promoting glucose uptake by L6 cells and cell viability in the Lenvatinib environment;
FIG. 2 is a diagram of Lenvantinib promoting GLUT4 transport in L6 cells;
FIG. 3 is a diagram of the Lenvatinib promoting expression of GLUT4 in L6 cells;
fig. 4 shows that Lenvatinib promotes GLUT4 expression in dependence on PKC signaling pathway.
Detailed Description
In order to make the objects, technical solutions and advantageous effects of the present invention more apparent, preferred embodiments of the present invention will be described in detail below to facilitate understanding by the skilled person.
The lenretinib provided in this embodiment is derived from a selegk corporation. Lenretinib was used in 3% DMSO and was used for bioactivity assay detection as follows:
1. cell glucose uptake assay:
(1) When L6 cells grew to about 80% of the culture dish, L6 cells were inoculated into a 96-well plate, and 100. Mu.L/well of a complete culture medium for culturing L6 cells was added. After 48 hours, the complete culture solution for differentiating the L6 cells is added for 5 to 7 days.
(2) Serum-free alpha-MEM cell culture medium was added to 96-well plates, starved cells for 2h, experiments requiring a blank control and insulin (100 nM) positive control, 100. Mu.LLenvatinib (added at 5. Mu.M, 10. Mu.M, 30. Mu.M, respectively) was added, and the mixture was placed at 37℃with 5% CO 2 Is allowed to act for 30min and more than three replicates are performed for each group.
(3) Measuring the absorbance value by an enzyme-labeled instrument: 2. Mu.L of each well plate was removed to a new 96 well plate, and 200. Mu.L of glucose oxidase reagent was added to each well, and absorbance of each well was immediately measured with a microplate reader: shake for 10s, wavelength 505 nm.
(4) Toxicity was measured with a microplate reader: the remaining medium of the old 96-well plate was removed, 100. Mu.L (0.5 mg/mL) of MTT was added thereto for 4 hours, and then the waste liquid was removed, 150. Mu.L of LDMSO was added thereto, the absorbance of each well was measured at 492nm by an ELISA reader, and data were processed by GraphPadPrsm.
FIG. 1 is a graph of Lenvatinib promoting glucose uptake by L6 cells and toxicity detection of MTT on cells, as shown in FIG. 1, the left panel of FIG. 1 shows: lenretinib significantly promotes glucose uptake by L6 cells, and the effect of Lenretinib on promoting glucose uptake by L6 cells is equivalent to insulin (insulin); the right hand diagram in fig. 1 shows: lenretinib has little toxicity to cells, and the cell survival rate is above 90%.
2. Immunofluorescence experiments:
in this experiment, we used the structural characteristics of GLUT4 protein in the stably expressed myc-GLUT4-mOrangel6 cell line to carry out immunofluorescence experiment, since myc is the extracellular domain of GLUT4 protein, myc domain was marked by using myc specific primary antibody and FITC labeled secondary antibody in immunofluorescence experiment, GLUT4 showed two kinds of fluorescence under laser confocal microscope, one is mOrange red fluorescence, indicating total GLUT4, one is green fluorescence FITC indicating GLUT4 on cell membrane, and co-localization merge of both indicates GLUT4 transported to cell membrane. In this result, we can clearly see both fluorescence, indicating that GLUT4 is transported from the cell to the cell membrane under stimulation of 5 μmlenvantinib and 30 μmlenvantinib. Monitoring myc-GLUT4-mOrange can therefore be used to monitor GLUT4 transport within L6 cells. First, myc-GLUT4-mOrangel6 was starved for 2 hours in serum-free culture solution, 5. Mu. MLenvantinib and 30. Mu. MLenvantinib were added to act for half an hour, fluorescence of myc-GLUT4-mOrangel6 cells was observed under a confocal laser microscope, and fluorescence intensity on cell membranes was detected, thereby detecting the transport condition of GLUT4 in the cells.
FIG. 2 is a graph of the L6 cell GLUT4 transport promotion by Lenvantinib, and as shown in FIG. 2, after 5 mu MLvantinib and 30 mu MLvantinib are added, the fluorescence intensity (namely FITC) of myc-GLUT4-mOrangel6 cell membranes is obviously enhanced. It was demonstrated that Lenvatinib can promote L6 cell GLUT4 expression and fusion with cytoplasmic membranes.
3. Extraction of total protein and WesternBlotting:
(1) L6 skeletal muscle cells were cultured with L6 cell minimal medium until the cells accounted for 90% of the dish, then starved with 2mL of serum-free alpha-MEM minimal medium for 2h, and 100. Mu.L of blank, positive drug group (Insulin and PMA), 5. Mu.M envantinib, 30. Mu.M envantinib and 100. Mu.M envantinib were added for 30min.
(2) The dishes were placed on ice box, the drug in the L6 cell dishes was poured off, and then gently rinsed 3 times with ice-bath PBS. Finally, the PBS remained in the culture medium is completely sucked out as much as possible by using a small-range pipette.
(3) mu.L of lysate (PMSF: A: B: RIPA lysate=1:1:1:100) was added and the dishes were filled to digest the L6 cells, which were then scraped off as completely as possible using a 1mL gun head.
(4) The lysate containing L6 cells is sucked into an EP tube by a pipette, the EP tube is placed into ice water and then evenly mixed by ultrasonic waves, and the whole process is carried out on the ice in order to prevent protein degradation caused by failure of protease inhibitors.
(5) Pre-cooling the centrifuge in advance, centrifuging the L6 cells at the temperature of 4 ℃ and under the condition of 12000rpm for 15min, and sucking the supernatant by a pipetting gun to obtain the required protein.
(6) Protein concentration was determined:
(1) and (5) preparing a standard yeast solution according to the steps in the specification of the Biyundian BCA kit, and taking out the standard yeast solution for centrifugation.
(2) BSA solution was prepared (solution a: solution b=50:1).
(3) 8. Mu.L of PBS was added to the 96-well plate, 2. Mu.L of standard yeast and total protein of the sample were added, respectively, and finally 100. Mu.L of BSA solution was added.
(4) The mixture is placed in a 55 ℃ oven for 40min, the maximum absorption peak at 562nm excitation wavelength is measured by adopting an enzyme-labeled instrument, and a corresponding standard curve is drawn, so that the protein concentration is calculated.
(7) Storing protein:
(1) the extracted proteins were centrifuged briefly after adding a corresponding volume of 5 XSDS-PAGEloadingbuffer (protein solution volume: 5 XSDS-PAGEloadingbuffer volume=4:1).
(2) The extracted proteins were denatured in a metal heater at 95℃for 10min.
(3) Stored in a-20 ℃ refrigerator.
2.5.5WesternBlot
(1) SDS-PAGE electrophoresis:
(1) SDS-PAGE gels were prepared using a Yase PAGE gel rapid preparation kit (10%).
(2) After spotting, the sample was separated by electrophoresis at 80V for 30min and then at 100V for 90min.
(2) Transferring:
(1) the prepared 1 XTransbuffer is put in a refrigerator at 0 ℃ in advance for about 30min in ice bath.
(2) The sponge, filter paper, NC membrane, etc. are immersed in 1×transcuffer in advance.
(3) The glue of the desired strip was cut off and placed on the NC film, clamped.
(4) The film was transferred at 120V for about 90min.
(3) Placing the membrane in a small box with the front face upwards, adding appropriate amount of 5% skimmed milk powder, covering the membrane, and sealing with a shaker at room temperature for 2 hr.
(4) Washing with TBS-T shaker for 3 times and 10 min/time.
(5) Diluted primary antibody (TBS-T: primary antibody=1000:1) was added, followed by shaking overnight incubation in a refrigerator at 4 ℃.
(6) Washing with TBS-T shaker for 3 times and 10 min/time.
(7) Adding diluted secondary antibody (TBS-T: secondary antibody=10000:1), and incubating for 1h at room temperature;
(8) Washing 3 times with TBS-T shaker for 10 min/time.
(9) And (3) dropwise adding a developing solution (A solution: B solution=1:1), imaging in different exposure time, and collecting a chemiluminescent image under the optimal exposure time.
FIG. 3 is a graph of the Lenvatinib promoting GLUT4 expression in L6 cells, as shown in FIG. 3, with concentrations of 10. Mu. MLenvatinib, 30. Mu. MLenvatinib and 100. Mu. MLenvatinib promoting GLUT4 expression in L6 cells, wherein the concentration of 30. Mu. MLenvatinib promoting GLUT4 expression level is particularly apparent, demonstrating that Lenvatinib can promote GLUT4 protein expression in L6 cells.
Fig. 4 is a graph showing that Lenvatinib promotes GLUT4 expression in dependence on PKC signaling pathway. As shown in FIG. 4, in L6 cells, the phosphorylation of PKC was promoted by drug concentrations of 10. Mu. MLenvatinib, 30. Mu. MLenvatinib, and 100. Mu. MLenvatinib, wherein the phosphorylation of PKC was significantly increased by the concentration of 10. Mu. MLenvatinib, indicating that Lenvatinib promoted GLUT4 protein expression levels in L6 cells by PKC signaling pathways.
Finally, it is noted that the above-mentioned preferred embodiments illustrate rather than limit the invention, and that, although the invention has been described in detail with reference to the above-mentioned preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention as defined by the appended claims.

Claims (8)

1. New use of lenvatinib or a pharmaceutically acceptable salt thereof in the prevention and/or treatment of type II diabetes.
2. Use of lenvatinib or a pharmaceutically acceptable salt thereof for the preparation of a GLUT4 activity promoter, and the GLUT4 activity promoter is used for the treatment and/or prevention of type two diabetes.
3. Use of lenvatinib or a pharmaceutically acceptable salt thereof for the preparation of a PKC activator, and the PKC activator is used for the treatment and/or prevention of type two diabetes.
4. A medicament for treating type two diabetes mellitus, characterized in that: the pharmaceutical pack comprises lenvatinib or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable pharmaceutical carriers.
5. A medicament for the treatment of type ii diabetes as claimed in claim 4, wherein: the preparation is in the form of tablet, powder, decoction, pill, and capsule.
6. A medicament for the treatment of type ii diabetes as claimed in claim 4, wherein: the drug carrier comprises: surfactants, lubricants, absorption promoters, diluents.
7. The GLUT4 activity promoter according to claim 2, which is in the form of a tablet, powder, decoction, pill, capsule.
8. The activator of claim 3, wherein the preparation is a tablet, powder, decoction, pill, capsule.
CN202211103479.2A 2022-09-09 2022-09-09 New application of lenvatinib in preventing and treating type II diabetes Pending CN116173023A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124544A2 (en) * 2005-05-13 2006-11-23 Novartis Ag Use of tyrosine kinase inhibitors in the treatment of metabolic disorders
CN104876864A (en) * 2015-06-05 2015-09-02 北京康立生医药技术开发有限公司 Preparation method of lenvatinib
WO2020065682A1 (en) * 2018-09-29 2020-04-02 Translational Health Science And Technology Institute Ror antagonists, their use and method of treatment comprising the said modulators
WO2022182982A1 (en) * 2021-02-26 2022-09-01 Third Harmonic Bio, Inc. Methods for treating c-kit kinase mediated diseases and disorders using a selective c-kit kinase inhibitor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006124544A2 (en) * 2005-05-13 2006-11-23 Novartis Ag Use of tyrosine kinase inhibitors in the treatment of metabolic disorders
CN104876864A (en) * 2015-06-05 2015-09-02 北京康立生医药技术开发有限公司 Preparation method of lenvatinib
WO2020065682A1 (en) * 2018-09-29 2020-04-02 Translational Health Science And Technology Institute Ror antagonists, their use and method of treatment comprising the said modulators
WO2022182982A1 (en) * 2021-02-26 2022-09-01 Third Harmonic Bio, Inc. Methods for treating c-kit kinase mediated diseases and disorders using a selective c-kit kinase inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
吕青等: "伊马替尼―糖尿病患者的福音?", 《肿瘤代谢与营养电子杂志》, vol. 1, no. 03, pages 18 - 22 *

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