CN117414410A - Application of Microcolin A - Google Patents

Application of Microcolin A Download PDF

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Publication number
CN117414410A
CN117414410A CN202311314488.0A CN202311314488A CN117414410A CN 117414410 A CN117414410 A CN 117414410A CN 202311314488 A CN202311314488 A CN 202311314488A CN 117414410 A CN117414410 A CN 117414410A
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microcolin
osteosarcoma
cells
cell
apoptosis
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CN202311314488.0A
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Inventor
刘玉杰
张丹
王达
刘繁荣
杨明磊
马小雨
于豪冰
肖建如
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Shanghai Changzheng Hospital
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Shanghai Changzheng Hospital
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/07—Tetrapeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention relates to the field of biological medicine, in particular to an application of Microcolin A; provides the application of Microcolin A in preparing a medicament for treating osteosarcoma; the invention shows that Microcolin A can effectively inhibit proliferation capability of osteosarcoma cells, remarkably promote apoptosis of osteosarcoma cells, promote expression of apoptosis-related protein p-H2AX in osteosarcoma cells, and discloses application of Microcolin A in preparation of medicines for treating osteosarcoma; meanwhile, microcolin A and cisplatin have good combined treatment effect.

Description

Application of Microcolin A
Technical Field
The invention relates to the field of biological medicine, in particular to an application of Microcolin A.
Background
Osteosarcoma is the most common primary malignant bone tumor, originating from primitive mesenchymal cells in bone and soft tissue. Osteosarcoma usually occurs in children and young children, accounting for about 5% -6% of all pediatric tumors. Osteosarcoma is most commonly found in metaphyseal parts of long bones of extremities, mainly in areas where bones grow rapidly, such as distal femur, proximal tibia, proximal femur and proximal humerus, and in small parts in axial bones. Osteosarcoma is typically manifested as localized pain in the limb, with localized swelling and limited joint movement, and in a few cases pathological fractures. At present, the treatment principle of osteosarcoma is combined with complete surgical excision and auxiliary chemotherapy, and the survival rate of chemotherapy drugs including doxorubicin, cisplatin, methotrexate and ifosfamide is increased to 60-70% in 5 years. However, osteosarcoma is a tumor that is particularly susceptible to developing resistance to chemotherapeutic agents. Cisplatin is still the first line drug of osteosarcoma chemotherapy, most cancer cells are initially sensitive to platinum, but over time sensitivity tends to decrease. Some patients develop resistance to chemotherapy, which can lead to tumor recurrence and tumor progression. Local and distant metastasis occurs in 40% of patients, and the overall survival rate of patients with metastasis or relapse is less than 20%. The problems of tumor recurrence, metastasis, drug resistance and the like lead to still unsatisfactory treatment effect and poor prognosis of osteosarcoma.
Ocean occupies about 71% of the earth's surface area, marine organism species occupy more than 80% of the earth's organisms, and is a huge pool of biological resources. The uniqueness and diversity of marine environments makes marine organisms produce active substances of special structure and function, which are very different from land-based products. The drugs developed based on the active ingredients in marine organisms and minerals are marine drugs. The ocean medicine has unique chemical structure, very strong specificity and unique biological activity. The marine drug has the characteristics of high activity, high pharmacodynamic property, good stability and the like. Compared with the traditional medicine research and development, the research and development success rate of the marine medicine is higher. It is reported that the success rate of drug development from marine sources is about 0.03%, while the success rate of drug development from non-marine sources is only 0.01% -0.02%. The research and development of antitumor drugs is the focus of research on marine drugs, and about 10% of marine products have antitumor activity. By the year 2020, there are 10 anti-tumor drugs developed on the market based on marine natural products or derivatives thereof; there are 23 marine drugs entering phase III, phase II, phase I clinical studies, of which 19 (83%) are being tested as anticancer drugs.
Microcolin A is a small molecule chain lipopeptide compound separated from marine blue algae Lyngbyamajuscula, and has molecular formula of C 39 H 65 O 9 N 5 The molecular weight is 747. Microcolin a has good biological activity due to unique free hydroxyl functional groups and pyrrolidone or hydroxyproline structures, and is easy to structurally perform various transformation and group modification, thereby having the potential of developing into medicines.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an application of Microcolin A.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the first aspect of the invention provides an application of Microcolin A in preparing a medicament for treating osteosarcoma.
Preferably, the medicament for treating osteosarcoma inhibits osteosarcoma cell proliferation.
Preferably, the medicament for treating osteosarcoma promotes osteosarcoma cell apoptosis.
In a second aspect, the invention provides the use of Microcolin A in combination with a chemotherapeutic agent for the manufacture of a medicament for the treatment of osteosarcoma.
Preferably, the chemotherapeutic agent is cisplatin.
Preferably, the Microcolin a has a drug combination index of less than 1 with the chemotherapeutic drug.
In a third aspect, the present invention provides the use of an agent that promotes expression of p-H2AX in the manufacture of a medicament for the treatment of osteosarcoma, said agent that promotes expression of p-H2AX comprising: microcolin a.
Compared with the prior art, the invention has the following technical effects:
the invention shows that Microcolin A can effectively inhibit proliferation capability of osteosarcoma cells, remarkably promote apoptosis of osteosarcoma cells, promote expression of apoptosis-related protein p-H2AX in osteosarcoma cells, and discloses application of Microcolin A in preparation of medicines for treating osteosarcoma; meanwhile, microcolin A and cisplatin have good combined treatment effect.
Drawings
FIG. 1 is a formula of Microcolin A in an embodiment of the present invention;
FIG. 2 is a graph showing IC50 of Microcolin A in various osteosarcoma cell lines according to an embodiment of the present invention; FIG. 2A is a graph of IC50 s for various osteosarcoma cell lines; FIG. 2B is IC50 data for a variety of osteosarcoma cell lines;
FIG. 3 shows the results of an osteosarcoma cell proliferation assay according to an embodiment of the invention; FIG. 3A shows proliferation of 143B cells; FIG. 3B shows proliferation of U2OS cells;
FIG. 4 shows the results of osteosarcoma cell colony formation in an embodiment of the invention; FIG. 4A is a view of the under-the-mirror observation; FIG. 4B is a graph of relative colony quantification of 143B cells; FIG. 4C is a plot of U2OS cell versus colony quantification;
FIG. 5 shows the migration ability test results of osteosarcoma cells according to an embodiment of the present invention; FIG. 5A is a view of the under-the-mirror observation; FIG. 5B is a graph of relative migration quantification of 143B cells; FIG. 5C is a graph showing relative migration quantification of U2OS cells;
FIG. 6 is a diagram showing Western blotting results according to an embodiment of the present invention;
FIG. 7 shows the ratio of apoptosis of osteosarcoma cells according to an embodiment of the present invention; FIG. 7A is a scattergram of osteosarcoma cells; FIG. 7B is a quantitative graph of apoptosis of 143B cells; FIG. 7C is a quantitative plot of apoptosis of U2OS cells;
FIG. 8 is a graph showing the co-drug index of Microcolin A and cisplatin for inhibiting osteosarcoma cells according to an embodiment of the present invention; FIG. 8A is a combination index of Microcolin A and cisplatin inhibiting 143B cells; FIG. 8B is a combination index of Microcolin A and cisplatin inhibiting U2OS cells; FIG. 8C is a combination index of Microcolin A and cisplatin inhibiting HOS cells; FIG. 8D is a combination index of Microcolin A and cisplatin inhibiting MG63 cells;
FIG. 9 shows the ratio of apoptosis of osteosarcoma cells according to an embodiment of the present invention; FIG. 9A is a scattergram of osteosarcoma cells; FIG. 9B is a quantitative graph of apoptosis of 143B cells; FIG. 9C is a quantitative plot of apoptosis of U2OS cells;
FIG. 10 is a graph showing the comparison of tumor growth and tumor weight in mice bearing osteosarcoma treated with Microcolin A in combination with cisplatin in accordance with one embodiment of the present invention; FIG. 10A is a schematic representation of tumor growth change; FIG. 10B is a comparison of tumor weights;
FIG. 11 is a graph showing the primary organ HE staining of a mouse with osteosarcoma after treatment with Microcolin A according to an embodiment of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
The invention is further described below with reference to the drawings and specific examples, which are not intended to be limiting.
Examples
1. Osteosarcoma cell IC50 assay
The IC50 values of the respective cells were calculated by treating MG63, HOS,143B and U2OS cells with microcollinA, respectively, and performing CCK8 test, and the results are shown in FIG. 2, wherein the IC50 of the MG63 cell is 3.07nM, the IC50 of the HOS cell is 3.80nM, the IC50 of the 143B cell is 2.84nM and the IC50 of the U2OS cell is 4.55, which indicate that microcollinA has remarkable inhibitory effect on four osteosarcoma cell lines.
2. Osteosarcoma cell proliferation assay
1. Inoculating cells: fully re-suspending the 143B cell and U2OS cell sediment into single cell state by using normal culture medium, and adding the single cell state into a 96-well plate every 500-2000 cell suspensions;
2. culturing the cells for 24 hours, 48 hours, 72 hours and 96 hours, and collecting plates for detection;
3. incubation and color development: adding CCK8 solution (100 mu L of Free culture medium and 10 mu L of CCK8 solution) into each hole, and placing into an incubator for incubation for 1h;
4. the absorption was measured at a wavelength of 450nm, and the results were analyzed and plotted.
As shown in fig. 3, microcorina significantly inhibited proliferation of 143B and U2OS cells, and the inhibition effect was more significant with increasing concentration.
3. Transwell experiment
1. Serum starving cells prior to cell collection;
2. taking out the cells from the incubator, placing the cells under a microscope to observe the density and state of the cells, then digesting the cells, and re-suspending the cells with a proper amount of serum-free culture medium;
3. gently adding appropriate amount of cell suspension into a Transwell chamber, and adding 1.5ml of normal culture medium into a 12-well plate lower chamber;
4. after the cells are added, the cells are uniformly distributed in a small chamber and are placed in an incubator to be cultured for 12-48 hours, and then the orifice plate is taken out;
5. transferring the Transwell cell into a new hole, adding an appropriate amount of PBS for washing twice, fixing the room temperature with 4% paraformaldehyde for 25min, obliquely hanging the cell in the hole for proper air drying, dyeing with 0.1% crystal violet for 15min-20min, visually observing invasion condition, wiping the cell with a cotton swab if the cell also contains more uninfected cells, and observing and recording under a microscope.
As shown in fig. 4-5, microcorina can significantly inhibit the scratch healing ability and the pore migration ability of 143B and U2OS cells, and the inhibition effect thereof is more significant with increasing concentration.
4. Western Blot experiment for detecting influence of Microcolin A on DNA damage repair path of osteosarcoma cells
1. Preparing a sample: microcoolin A at different concentrations was used to treat 143B and U2OS cell samples, which were lysed using 1 XSDS loading to collect the samples, and boiled in a metal bath at 100deg.C for 15min to denature the proteins;
2. preparing protein gel: washing protein gel plate with ddH 2 Washing O once, putting into a baking oven for drying after washing, aligning the glue plates, clamping the glue plates in parallel on a glue plate frame, preparing lower layer separation glue according to a formula of the protein glue, flattening the glue plates by using absolute ethyl alcohol, discarding the absolute ethyl alcohol after the lower layer is gelled and fixed, preparing upper layer concentrated glue according to the formula, inserting a comb, and putting into a refrigerator at 4 ℃ for preservation after the upper layer glue is solidified;
3. electrophoresis: loading the prepared protein samples sequentially from left to right according to the sequence of experimental design, reserving protein markers on the pore canals on the left and right sides, and supplementing by using a 1 x loading buffer; after the sample loading is finished, adding 1 Xrunning buffer into the glue Running groove, starting to perform constant voltage electrophoresis at 80V, and performing constant voltage electrophoresis at 120V until the lower layer of glue marker is separated;
4. transferring: 1 XTransferbuffer (700 ml ddH) 2 O,200ml of methanol, 100ml of 10 Xtransfer buffer), a Transfer membrane clip, NC membrane, filter paper, and a Transfer buffer were prepared, and immersed in the Transfer buffer; after the electrophoresis of the protein glue is finished, a thin plate is tilted lightly by using a scraper, the upper glue is cut, the lower glue is reserved, the lower glue is transferred into a film transferring liquid, and a film transferring clamp is clamped according to the sequence of one layer of sponge, three layers of filter paper, the lower glue, an NC film, three layers of filter paper and one layer of sponge; placing the film transfer clamp into a film transfer groove, introducing film transfer liquid, placing into an ice box, and transferring films under the conditions of 200mA constant current and ice bath;
5. closing: after the transfer, the protein on the protein gel was successfully transferred to the NC membrane, the NC membrane was washed once with PBS buffer, and the NC membrane was blocked with 7% skimmed milk powder (PBS preparation) for 60min;
6. incubation resistance: after the sealing is finished, the skimmed milk powder is discarded, PBS is used for cleaning for 5min, strips where p-H2AX and ACTIN proteins are located are cut according to the indication of a protein marker, the strips are placed into a cassette, a corresponding primary antibody is poured into the cassette, and the cassette is placed into a constant temperature shaking table at 4 ℃ for incubation overnight;
7. fluorescent secondary antibody binding: the next day, primary antibodies were recovered, the strips were washed three times with PBST (PBS buffer+0.05% Tween-20), 5min each time, and then the corresponding secondary fluorescent antibodies were poured and incubated in a constant temperature shaker at 4℃for 1h;
8. film sweeping: after the secondary antibody incubation was completed, the strips were washed three times with PBST for 5min each, the corresponding strips were scanned using an oddmeey membrane scanner, and the results were analyzed.
As a result, as shown in FIG. 6, the expression of the protein p-H2AX associated with DNA damage repair was elevated after Microcolin A treatment.
5. Effect of Microcolin a on osteosarcoma apoptosis
1. 143B cells and U2OS cells were inoculated into six-well plates, respectively, and after the cell density reached 50%, MCA (0 nM,2.5nM,5nM,10nM,20 nM) was added to treat for 24h;
2. culturing the collected cells in a 15ml centrifuge tube, performing pancreatin digestion on the collected cells in the centrifuge tube, centrifuging at 500rpm for 5min, discarding the supernatant, re-suspending the cell sediment by PBS, centrifuging, discarding the supernatant, repeating for two times, and leaving the cell sediment;
3. diluting 5 Xbinding Buffer in an Annexin V-APC/PI apoptosis kit to 1X by using PBS, re-suspending the cell sediment of the previous step, and gently blowing 300 mu L/tube; sequentially adding APC and PI dye, and performing light-shading treatment at room temperature for 15min;
4. analysis was performed with a flow analyzer.
The results are shown in fig. 7A-B, and flow cell results suggest that Microcolin a induces osteosarcoma cell apoptosis, and that this effect is concentration dependent, with a significant increase in apoptotic cell proportion following Microcolin a treatment of 143B and U2OS cells, and with an increase in proportion with increasing concentration.
6. Chou-talalay method for calculating drug Combination Index (CI)
1. Respectively carrying out digestion, centrifugation and resuspension on 143B cells, U2OS cells, HOS cells and MG63 cells, uniformly spreading in a 96-well plate, and ensuring 1500 cells per well;
2. after cell attachment, cells were treated with Microcolin A at 0nM, 0.25nM, 0.5nM, 1.0nM, 2.0nM, 4.0nM and Cisplatins at concentrations of 0. Mu.M, 0.625. Mu.M, 1.25. Mu.M, 2.5. Mu.M, 5.0. Mu.M, 10.0. Mu.M;
3. removing the supernatant after 48 hours, adding CCK-8 reagent for treatment for 1 hour, and detecting absorbance at a spectrum of 450 nm;
4. the drug combination index was calculated from the absorbance using the Compusyn software.
As shown in FIG. 8, microcolin A and cisplatin have synergistic effect in treating osteosarcoma, i.e. the drug combination index is less than 1.
7. Effect of Microcolin a and cisplatin on osteosarcoma apoptosis
Microcolin a and cisplatin were used singly or in combination to treat osteosarcoma cells and the proportion of apoptotic cells was measured by Chou-talalay.
As shown in fig. 9, microcolin a in combination with cisplatin increased the apoptosis rate of osteosarcoma cells and inhibited osteosarcoma cells more significantly.
8. Effect detection of Microcolin a and cisplatin combined treatment animal model
1. Digesting and centrifuging 143B cells in logarithmic phase, and re-suspending cells with PBS to ensure concentration of 5×10 5 /20μL；
2. After preparing cells, fixing a nude mouse by using a mouse fixer, drilling a hole through a clean insulin needle on the tibia of the nude mouse, and injecting the nude mouse into the tibia along the hole by using a needle with tumor cells;
3. after one week, the tumor grows to 100mm 3 About the size, mice were equally divided into four groups, namely PBS group (Vehicle group), microcolin a group (MCA group), cispratin group, and Microcolin a+cispratin group (ddp+mca group);
4. the mice were dissected, the tissues were removed, HE stained and placed under a microscope for microscopic examination.
As shown in FIGS. 10-11, microcolin A and cisplatin combined therapy can significantly inhibit osteosarcoma growth without causing damage to important organs such as heart, liver, spleen, lung, kidney, etc.
In conclusion, the Microcolin A is shown to be capable of effectively inhibiting proliferation capacity of osteosarcoma cells, remarkably promoting apoptosis of osteosarcoma cells and promoting expression of apoptosis-related protein p-H2AX in osteosarcoma cells, and application of Microcolin A in preparation of medicines for treating osteosarcoma is disclosed; meanwhile, microcolin A and cisplatin have good combined treatment effect.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, and it will be appreciated by those skilled in the art that equivalent substitutions and obvious variations may be made using the description and illustrations of the present invention, and are intended to be included within the scope of the present invention.

Claims (7)

  1. Application of microcolin A in preparing medicament for treating osteosarcoma.
  2. 2. The use according to claim 1, wherein the medicament for treating osteosarcoma inhibits osteosarcoma cell proliferation.
  3. 3. The use according to claim 1, wherein the medicament for treating osteosarcoma promotes osteosarcoma cell apoptosis.
  4. Use of microcolin a in combination with a chemotherapeutic agent for the preparation of a medicament for the treatment of osteosarcoma.
  5. 5. The use according to claim 4, wherein the chemotherapeutic agent is cisplatin.
  6. 6. The use according to claim 4, wherein the Microcolin a has a drug combination index of less than 1 with the chemotherapeutic agent.
  7. 7. Use of an agent that promotes expression of p-H2AX in the manufacture of a medicament for treating osteosarcoma, wherein the agent that promotes expression of p-H2AX comprises: microcolin a.
CN202311314488.0A 2023-10-11 2023-10-11 Application of Microcolin A Pending CN117414410A (en)

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CN117414410A true CN117414410A (en) 2024-01-19

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