CN113332298A - New use of minocycline as a tyrosine kinase inhibitor - Google Patents

New use of minocycline as a tyrosine kinase inhibitor Download PDF

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CN113332298A
CN113332298A CN202110584948.6A CN202110584948A CN113332298A CN 113332298 A CN113332298 A CN 113332298A CN 202110584948 A CN202110584948 A CN 202110584948A CN 113332298 A CN113332298 A CN 113332298A
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minocycline
tyrosine kinase
cancer cell
cells
kinase inhibitor
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张涛
潘克俭
杨菁
兰景彬
杨铃
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Chengdu Medical College
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Chengdu Medical College
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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
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a new application of minocycline as a tyrosine kinase inhibitor. In order to provide a novel tyrosine kinase inhibitor which can effectively inhibit the invasion and metastasis of tumor cells and provide a new idea for treating tumors, the invention provides a new application of minocycline as a tyrosine kinase inhibitor. Minocycline serving as a novel tyrosine kinase inhibitor inhibits cancer cell metastasis by inhibiting the activity of tyrosine kinase, thereby providing a novel mode for preparing a medicament for inhibiting cancer cell metastasis.

Description

New use of minocycline as a tyrosine kinase inhibitor
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a new application of minocycline as a tyrosine kinase inhibitor.
Background
Src is the prototype member of the non-receptor membrane-associated tyrosine kinase family, including Fyn, Yes, Blk, Yrk, Fgr, Hck, Lck, and Lyn. Src is a 60kDa protein, consisting of multiple functional domains, and can exert its biological effects not only through its enzymatic activity, but also by virtue of its multiple structural domains, by interacting with other proteins in critical cellular compartments. The basic function of Src is to transmit external signals to the interior of the cell, and Src accomplishes this task by phosphorylating tyrosine residues on substrates located primarily downstream of RTKs and integrins. Notably, the role of Src non-receptor cytoplasmic tyrosine kinases in tumors is of increasing interest. Src is the first oncogene to be found and has been the focus of cancer research. The biological role of Src non-receptor cytoplasmic tyrosine kinases in cells is complex, Src is ubiquitously expressed in various tissues, with higher concentrations in neurons, platelets and osteoclasts. Under normal conditions, Src regulates essential cellular activities. Src is involved in the maintenance of normal cellular homeostasis and a wide range of physiological functions including cell proliferation and survival, regulation of cytoskeleton, cell shape control, maintenance of normal intercellular contact, cell matrix adhesion dynamics, motility and migration. There is increasing evidence that Src tyrosine kinases can promote the tumor EMT process. The proto-oncogene protein Src was first discovered in the Rous sarcoma retrovirus, and led to the field of non-receptor tyrosine kinases in subsequent studies. The Src tyrosine kinase family plays an important role in gene transcription, cell migration, apoptosis and differentiation, and signal transduction biological processes. In addition the Src tyrosine kinase family enhances the migration and invasion of tumor cells in different cancers.
The LYN tyrosine kinase belongs to the Src non-receptor tyrosine kinase category, is located on the cell surface and can interact with STAT3 to directly mediate the activation of STAT3 to accomplish specific signaling. Moreover, LYN promotes the proliferation, migration and invasion process of tumor cells. The research shows that LYN can start Vav-Rac1-PAK1 signal cascade reaction in breast cancer and bladder cancer to increase Snail transcription factor, thereby promoting EMT process. Yoon-La Choi et al have determined that LYN is an invasion-associated therapeutic target in breast cancer.
EMT is an essential physiological phenomenon in mammalian embryonic development. Studies have shown that tumor cells can form local spread by EMT, a process that is accompanied by alterations in a number of molecular markers, including upregulation of expression of cytokines such as Snali, Slug, Twist, etc., leading to downregulation of E-Cadherin and upregulation of expression of Vimentin and N-Cadherin, etc. The occurrence of EMT involves multiple signal transduction pathways, and the relationships between the pathways are complex and affect each other. Among them, signal transducer and activator of transcription 3(STAT3) is involved in many physiological and pathological processes of the body, and its mediated signal pathway is closely related to proliferation, anti-apoptosis, invasion, metastasis, angiogenesis and immune escape of tumor cells. Upstream signals can activate STAT3, and phosphorylated STAT3 can enter nucleus to bind specific EMT transcription factors (Slug, Snail, ZEB1 and the like), regulate the expression of EMT related genes in tumor cells, finally enable the tumor cells to generate the transformation from an epithelial phenotype to a mesenchymal phenotype, and enable the tumor cells to invade and metastasize.
There is increasing evidence that antibiotic drugs have the effect of inhibiting tumor metastasis. Minocycline, as a tetracycline antibiotic, has the strongest antibacterial action and higher lipid solubility, is absorbed from intestinal tracts after being orally taken, and is metabolized in vivo more quickly. In addition to antibacterial effects, minocycline is also widely used for inflammation control and neuroprotection in clinical treatments. Recent studies report that minocycline inhibits tumor cell growth by autophagy or apoptosis, demonstrating anticancer properties of minocycline and its derivatives. However, in the existing reports, there are no reports on whether minocycline can inhibit the invasion and metastasis of colorectal cancer cells, and no reports on the action target of minocycline, and further research on the mechanism of inhibiting the invasion and metastasis of tumor cells by minocycline is needed.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a novel tyrosine kinase inhibitor which can effectively inhibit the invasion and the metastasis of tumor cells and provides a new idea for the treatment of tumors.
The technical scheme for solving the technical problems comprises the following steps: provides a new application of minocycline as a tyrosine kinase inhibitor.
In the new application, the minocycline has the following structure:
Figure BDA0003086829470000021
the invention also provides a new application of minocycline in inhibiting cancer cell metastasis.
Wherein the cancer cell is at least one of colorectal cancer cell, liver cancer cell, breast cancer cell, lung cancer cell, ovarian cancer cell or prostate cancer cell.
Wherein, the cancer cell is a colorectal cancer cell.
Wherein said inhibition of cancer cell metastasis is effected by inhibiting tyrosine kinase activity.
Furthermore, the invention also provides a new application of minocycline in preparing a medicament for preventing or treating colorectal cancer, liver cancer, breast cancer, lung cancer, ovarian cancer or prostate cancer.
The invention has the beneficial effects that:
the minocycline is found for the first time to be a tyrosine kinase inhibitor, interact with LYN and effectively inhibit the activity of LYN enzyme, and can effectively inhibit the phosphorylation of tyrosine kinase and effectively treat diseases which are regulated and controlled by tyrosine kinase and are related to the abnormality of tyrosine kinase signal transduction pathways, such as colorectal cancer, liver cancer, breast cancer, lung cancer, ovarian cancer, prostate cancer and the like. The invention provides a new inhibition method for invasion and metastasis of tumor cells, develops new application of minocycline in tumor resistance, and provides a new mode for prevention and treatment of tumors.
Drawings
FIG. 1 is a immunoblot of affinity purification of minocycline to LYN of example 1;
FIG. 2 is a immunoblot of affinity purification of minocycline and human recombinant LYN protein of example 1;
FIG. 3 is a graph showing the plasmon resonance of minocycline and human recombinant LYN protein of example 1;
FIG. 4 is a graph showing the effect of minocycline on LYN enzyme activity in example 2;
figure 5 is a graph showing the effect of minocycline on cancer cell migration in vitro in example 3;
FIG. 6 is a graph showing the results of Transwell migration and matrigel invasion of minocycline on cancer cells in vitro in example 3;
figure 7 shows the results of the inhibition of lung metastasis of mouse colorectal cancer cells by minocycline in vivo in example 4.
Detailed Description
The following examples are intended to illustrate specific embodiments of the present invention without limiting the scope of the invention to the examples.
The reagents and starting materials used in the examples are all conventional commercial products.
Example 1 interaction study of minocycline with LYN
The experimental method comprises the following steps:
1. minocycline conjugated to Epoxy-activated μ Sphere was incubated with SW480 and SW620 cell lysates and immunoblotted with anti-LYN antibody.
2. Preparing human recombinant LYN protein by using genetic engineering technology, incubating minocycline coupled on Epoxy-activated mu Sphere with the human recombinant LYN protein, and detecting the binding condition of the minocycline and the human recombinant LYN protein by SDS-PAGE electrophoresis.
3. The affinity of minocycline to LYN protein was determined by plasma resonance analysis (Biacore, GE) of minocycline with prepared recombinant LYN protein of human origin.
The experimental results are as follows:
1. compared with the control group, the minocycline group can perform affinity purification on LYN at 55-57 kD. (as shown in FIG. 1)
2. Compared with the control group, the minocycline group can affinity purify the human recombinant LYN protein at 55-57 kD. (as shown in FIG. 2)
3. Warp beamPlasma resonance analysis (Biacore, GE) found that minocycline had KD-39.33X 10 affinity for human recombinant LYN protein-7Binding of minocycline to LYN was demonstrated to have high affinity. (as shown in FIG. 3)
It follows that minocycline has the ability to interact with LYN.
Example 2 Effect of minocycline on LYN enzymatic Activity
The experimental method comprises the following steps:
1. kinase immunoprecipitation
250 μ L of cell lysate/sample (200-500mg protein) was transferred to a microcentrifuge tube. The optimal cell lysate volume is 250. mu.L. An appropriate amount of anti-tyrosine kinase antibody (usually 2-4. mu.L) was added. Mix gently, place tube on ice while equilibrating EZview redprotein affinity Gel beads. The gel beads were carefully mixed until uniformly suspended. 30 μ L of 50% slurry was dispensed into clean 1.5ml microcentrifuge tubes. The tube was centrifuged at 8000rpm for 30s with 750. mu.L PBS. The supernatant was carefully removed or aspirated off with a micropipette. And repeating the steps once. The tube containing the sample and antibody was centrifuged at 8000rpm and 4 ℃ to collect all liquid to the bottom of the microfuge tube. All liquid was transferred to a tube containing washed gel beads. Briefly vortexed and incubated at 4 ℃ for 4h with gentle shaking to allow the antibody-antigen complex to bind to the EZview Red protein affinity Gel beads. Centrifuge at 8000rpm and 4 ℃ for 30 s. The tube was placed on ice, the supernatant carefully aspirated, and the tube with beads was placed on ice. The beads were washed by adding 400ml of ice cold 1 × Wash Buffer. Briefly vortexed and incubated with gentle thorough shaking at 4 ℃ for 1 min. The tubes were centrifuged in a microcentrifuge for 30s at 8000rpm and 4 ℃. The supernatant was carefully aspirated and the bead pellet was then placed on ice. The washing was repeated 2-3 times.
2. Substrate phosphorylation and radioactivity detection
To 100. mu.L of assay buffer was added 1. mu.L of γ 32P-ATP with a specific activity of 10 mCi/ml. Pipet gently into 15 μ L assay buffer containing radioactive ATP. Positive control assays were performed by adding 15. mu.L of assay buffer containing radioactive ATP to positive control tubes containing 15. mu.L of 10% glycerol solution and 2. mu.L of EGFR solution. Negative control assays were performed by adding 15 μ L of assay buffer containing radioactive ATP to a tube containing 15 μ L of 10% glycerol solution. The tubes were incubated at 30 ℃ for 30 min. The reaction was stopped by spotting 10. mu.L of the liquid phase of the assay mixture on a 2 cm. times.2 cm square of phosphocellulose P81. The cellulose phosphate dice were immersed in a 0.5% phosphoric acid solution. The phosphocellulose squares were washed 4 times with 0.5% phosphoric acid solution. For each wash, gently stir for 5-6 min. Washing with ethanol for 1 min. Wash with acetone for 1 min. The cellulose phosphate cake was dried at room temperature or under a heating lamp and the incorporated radioactivity was counted using the cerenkov model.
The experimental results are as follows:
the LYN enzyme activity was measured after SW480 and SW620 cells were treated with minocycline, and the results are shown in FIG. 4. The results show that: compared with the control group, the minocycline inhibits the activity of LYN enzyme in SW480 and SW620 cells. As can be seen, minocycline effectively inhibits the enzymatic activity of LYN.
Example 3 minocycline in vitro anti-cancer Effect study (colorectal cancer)
The experimental method comprises the following steps:
1. scratch experiment for detecting healing degree of scratches after minocycline treatment
When SW480 and SW620 cells are in logarithmic growth phase, the cells are passaged and counted according to the ratio of 8X 105Density of individual cells/well, the cell suspension was added to six well plates, 2mL per well and labeled with cell name and plating time, and placed in a cell incubator for 12 h. The principle of inoculation is that the fusion rate reaches 100% after overnight. A sterile ruler is prepared and is perpendicular to the cell plane, a 200-mu L tip is used for scratching the cell layer of the 6-well plate along the ruler, and each hole of the 6-well plate is scratched with a horizontal line and two vertical lines. After completion of the scratch, nonadherent cells were washed away using sterile PBS, and line-observed and photographed under a microscope. And (3) replacing and adding serum-free culture medium or low-serum culture medium containing minocycline with different concentrations (0, 4 and 8 mu mol/L) for culture and labeling, culturing at 37 ℃, and culturing for 48h strictly in a dark place. After 48h, the cells were removed, washed free of adherent cells using sterile PBS, observed under a microscope and photographed. Calculating the distance between cells and counting the data to detect the healing degree of the scratches after the minocycline treatment.
2. Transwell and matrigel experiments to detect the influence of minocycline on the migration and invasion capacity of colorectal cancer cells
The cells were serum deprived for 12h prior to preparation of the cell suspension to further remove the effects of serum. The matrigel was thawed on ice and diluted with 1640 medium without FBS. The upper face of the bottom membrane of the Transwell chamber was coated with 50. mu.L of Matrigel 1:8 dilution and placed in an incubator at 37 ℃ for 2-3 hours to solidify. The log-grown SW480, SW620 cells were collected. After the digestion of the cells is terminated, the culture solution is removed by centrifugation, the cells are washed 1-2 times with PBS, the cells are resuspended in serum-free medium and counted, and then the same number of cells are transferred to the control group and the experimental group. Cell density of 1X 105Cells/ml. 200 μ L of suspension was added to the upper compartment and 600 μ L of medium supplemented with 10% FBS was added to the lower compartment. At 5% CO2At 37 ℃ for 48 h. After the incubation was stopped, 1mL of 4% paraformaldehyde solution was added to each well and fixed for 15 min. The cotton swab wiped off the cells remaining on top of the transwell. Removing the fixing solution, adding 1mL of crystal violet dye solution, and dyeing for 15 min. The residual crystal violet stain on the lower chamber was rinsed with PBS solution. And (5) observing and photographing by using a microscope line, calculating the number of cells on the lower chamber membrane and counting the data.
The experimental results are as follows:
1. the scratching experiment shows that after SW480 and SW620 cells are treated by minocycline, the cell migration rate is slowed down, the scratching healing capacity is slowed down, and the concentration is dependent. (as shown in FIG. 5)
2. The Transwell migration and matrigel invasion assay showed that the number of cells migrating and invading SW480 and SW620 cells from the upper chamber to the lower chamber was effectively inhibited after treatment of SW480 and SW620 cells with minocycline, and that the number of cells in the minocycline group at 8. mu. mol/L was less than the number of cells in the minocycline group at 4. mu. mol/L, the data was statistically significant. (as shown in FIG. 6)
From the test results it can be seen that: in vitro, minocycline is effective in inhibiting the migration and invasion of colorectal cancer cells. Example 4 in vivo study of the anticancer Effect of minocycline (colorectal cancer)
The experimental method comprises the following steps:
the CT-26 cells (1X 10) treated by minocycline for 48h5Cell/mouse) was injected into mice via tail vein, mice were killed after 2 weeks, and lungs were taken to observe lung metastasis of tumor cells.
The experimental results are as follows:
CT26 cells treated with minocycline (2. mu. mol/L, 4. mu. mol/L) for 48 hours were injected via tail vein into mice and then fed for 2 weeks, and the results were statistically analyzed using ImageJ software. The experimental results represent the mean ± SD of three independent experiments. P <0.01, p <0.001 compared to control. The test results show that: the number of tumors on the lungs of mice was significantly reduced after minocycline treatment compared to the control group (shown in figure 7).
It can be seen from this that: minocycline was effective in inhibiting lung metastasis of colorectal cancer cells in mice.
The embodiment shows that minocycline can inhibit the metastasis of colorectal cancer cells in vivo and in vitro, can be used for preparing a medicament for preventing or treating tumor cell invasion or metastasis, and has important significance.

Claims (7)

1. A new use of minocycline as a tyrosine kinase inhibitor.
2. The new use of minocycline as a tyrosine kinase inhibitor according to claim 1 characterized in that: the structure of minocycline is shown as follows:
Figure FDA0003086829460000011
3. a new use of minocycline in inhibiting cancer cell metastasis is provided.
4. The new use of minocycline to inhibit cancer cell metastasis according to claim 3, characterized in that: the cancer cell is at least one of colorectal cancer cell, liver cancer cell, breast cancer cell, lung cancer cell, ovarian cancer cell or prostate cancer cell.
5. The novel use of minocycline to inhibit cancer cell metastasis according to claim 4, characterized in that: the cancer cell is a colorectal cancer cell.
6. The novel use of minocycline to inhibit cancer cell metastasis according to any one of claims 3 to 5, characterized in that: the inhibition of cancer cell metastasis is achieved by inhibiting the activity of tyrosine kinase.
7. New use of minocycline in the preparation of a medicament for the prevention or treatment of colorectal cancer, liver cancer, breast cancer, lung cancer, ovarian cancer or prostate cancer.
CN202110584948.6A 2021-05-27 2021-05-27 New use of minocycline as a tyrosine kinase inhibitor Pending CN113332298A (en)

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CN102118968A (en) * 2008-06-10 2011-07-06 雅培制药有限公司 Novel tricyclic compounds
CN106551944A (en) * 2015-09-25 2017-04-05 南开大学 Purposes of the Tetracyclines derivative as PAR-1 inhibitor
CN111870607A (en) * 2020-07-09 2020-11-03 温州医科大学 Application of minocycline hydrochloride in preparation of medicine for treating autoimmune uveitis and treatment method of minocycline hydrochloride

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010552A2 (en) * 1998-08-24 2000-03-02 Global Vascular Concepts, Inc. Use of anti-angiogenic agents for inhibiting vessel wall injury
CN101307017A (en) * 2002-03-08 2008-11-19 帕拉特克药品公司 Amino-methyl substituted tetracycline compounds
CN102118968A (en) * 2008-06-10 2011-07-06 雅培制药有限公司 Novel tricyclic compounds
CN106551944A (en) * 2015-09-25 2017-04-05 南开大学 Purposes of the Tetracyclines derivative as PAR-1 inhibitor
CN111870607A (en) * 2020-07-09 2020-11-03 温州医科大学 Application of minocycline hydrochloride in preparation of medicine for treating autoimmune uveitis and treatment method of minocycline hydrochloride

Non-Patent Citations (5)

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Title
LING YANG，等: "Minocycline binds and inhibits LYN activity to prevent STAT3-meditated metastasis of colorectal cancer", 《INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES》 *
PARVIN ATAIE-KACHOIE，等: "Minocycline Suppresses Interleukine-6, Its Receptor System and Signaling Pathways and Impairs Migration, Invasion and Adhesion Capacity of Ovarian Cancer Cells:In Vitro and In Vivo Studies", 《PLOS ONE》 *
李灵玲，等: "米诺环素通过自噬抑制结肠癌细胞增殖的作用研究", 《成都医学院学报》 *
苏宁: "Lyn在CD24调控结直肠癌侵袭过程中的作用及机制", 《南方医科大学硕士学位论文》 *
黄礼年，等: "米诺环素抑制小鼠肺癌生长、转移及抗血管生成的研究", 《蚌埠医学院学报》 *

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Application publication date: 20210903