CN110960523B - Application of anti-tumor compound aiming at Fyn-CD147 signal channel target and anti-tumor medicine - Google Patents
Application of anti-tumor compound aiming at Fyn-CD147 signal channel target and anti-tumor medicine Download PDFInfo
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Abstract
The invention relates to an application of an anti-tumor compound aiming at Fyn-CD147 signal channel targets and an anti-tumor medicament, wherein the anti-tumor compound has a structure represented by the following structural formula I. The anti-tumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the half inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 6.1 mu M, which shows that the anti-tumor compound has stronger capacity of inhibiting the growth and proliferation of tumors and inducing the apoptosis of tumor cells, and meanwhile, the anti-tumor compound can inhibit the migration of tumor cells only within 24 hours at the concentration of 5 mu M, can effectively inhibit the invasion of tumor cells at the concentration of 5 mu M, and can be applied to the preparation of anti-tumor drugs.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of an anti-tumor compound aiming at Fyn-CD147 signal channel targets and an anti-tumor medicine.
Background
A tumor is a cell proliferative disease, and the tumor cells have three significant basic characteristics: immobility, mobility and loss of contact inhibition. On a cellular level, carcinogenesis is a very rare event. Genetically, cancer develops from a cell and from a cell that has lost control of proliferation. Millions of cells in the human body divide by billions of cells every day, and theoretically almost any one cell may be cancerous by changes in genetic composition, but this is not true in practice. Malignant transformation of a cell requires multiple genetic changes, i.e., multiple genetic mutations in a cell. Tumorigenesis is thus a progressive process involving multiple stages of reaction and accumulation of mutations. In this process, cancerous cell lines become increasingly uncontrolled by regulatory mechanisms within the receptor and gradually invade normal tissues. After malignant transformation of the cells, the cancer cells continue to accumulate mutations, which confer new properties on the mutated cells and make the cancer cells more dangerous. At present, the antitumor drugs are still few and expensive, and other antitumor compounds need to be further searched.
Disclosure of Invention
Based on the above, there is a need for an anti-tumor compound targeted at Fyn-CD147 signaling pathway.
An application of an antitumor compound aiming at Fyn-CD147 signal channel targets in preparing antitumor drugs, wherein the antitumor compound has a structure represented by the following structural formula I:
in one embodiment, the tumor is malignant melanoma of the skin, colon cancer, liver cancer or lung cancer.
The invention also provides an anti-tumor drug aiming at the Fyn-CD147 signal channel target spot, which comprises the anti-tumor compound, wherein the mass percentage of the anti-tumor compound in the anti-tumor drug is not more than 99%.
In one embodiment, the dosage form of the antitumor drug is injection, tablet, paste or suppository.
In one embodiment, the antineoplastic drug further comprises a sclerosing agent and an analgesic.
In one embodiment, the hardening agent is one or more of ethanol, propylene glycol, glycerol, isopropyl alcohol, and polyethylene glycol.
In one embodiment, the analgesic agent is one or more of aspirin, ibuprofen, indomethacin, paracetamol, phenylbutazone, rofecoxib, and celecoxib.
In one embodiment, the anti-tumor drug further comprises a disintegrant and an absorbent.
In one embodiment, the disintegrant is one or more of sodium starch glycolate, an effervescent disintegrant, and crospovidone.
In one embodiment, the absorbent is one or more of calcium sulfate, calcium hydrogen phosphate, calcium carbonate, and light magnesium oxide.
The anti-tumor compound of the invention has a structure represented by the following structural formula I:
the anti-tumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the semi-inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 6.1 mu M, the semi-inhibition concentration of colon cancer cells is 6.12 mu M, the semi-inhibition concentration of liver cancer cells is 6.25 mu M, and the semi-inhibition concentration of lung cancer cells is 5.54 mu M, which shows that the anti-tumor compound has stronger capacities of inhibiting the growth and proliferation of tumors and inducing the apoptosis of tumor cells, and has better stability than chalcone. Meanwhile, the anti-tumor compound can inhibit the migration of tumor cells only in 24 hours at the concentration of 5 mu M, can effectively inhibit the invasion of the tumor cells at the concentration of 5 mu M, can weaken the phosphorylation of FYN kinase on CD147 tyrosine, is an anti-tumor compound aiming at a Fyn-CD147 signal channel target spot, can be applied to the preparation of anti-tumor medicaments, provides a new theoretical and experimental basis for the prevention and treatment of tumors, and can be widely used as a tool molecule in the research related to the tumors.
Drawings
FIG. 1 is a graph showing the results of CCK-8 experiments on human skin malignant melanoma cells SK-Mel-28 at different concentrations of the antitumor compound;
FIG. 2 is a diagram showing the results of CCK-8 experiments on colon cancer cells HT29 at different concentrations of the antitumor compound;
FIG. 3 is a diagram showing the results of CCK-8 experiments on hepatoma cell HepG2 with the anti-tumor compound at different concentrations;
FIG. 4 is a graph showing the results of CCK-8 experiments with the anti-tumor compound on lung cancer cell A549 at different concentrations;
FIG. 5 is a diagram of the result of CCK-8 experiment of human skin malignant melanoma cell SK-Mel-28 with chalcone at different concentrations;
FIG. 6 is a diagram showing the results of CCK-8 experiments on human malignant melanoma cells SK-Mel-28 at different concentrations for compounds of structural formula II;
FIG. 7 is a diagram showing the results of CCK-8 experiments on human malignant melanoma cells SK-Mel-28 at different concentrations for compounds of structural formula III;
FIG. 8 is a photograph showing the results of an experiment for inhibiting the migration of the antitumor compound at a concentration of 5. Mu.M to human malignant melanoma cells SK-Mel-5 in the skin;
FIG. 9 is a photograph showing the results of an experiment for inhibiting migration of the antitumor compound at a concentration of 5. Mu.M to human malignant melanoma cells SK-Mel-28;
FIG. 10 is a photograph showing the results of an experiment for inhibiting the invasion of human skin malignant melanoma cells SK-Mel-5 and SK-Mel-28 by the antitumor compound at a concentration of 5. Mu.M;
FIG. 11 is a diagram showing the results of an experiment in which FYN kinase and prokaryotic expression purified CD147 were subjected to in vitro phosphorylation reaction, and the inhibitory effect of an antitumor compound on CD147 phosphorylation was examined.
Detailed Description
In order that the invention may be more fully understood, a more particular description of the invention will now be rendered by reference to specific embodiments thereof that are illustrated in the appended drawings. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The application of the anti-tumor compound aiming at the Fyn-CD147 signal channel target in the preparation of the anti-tumor drug of one embodiment of the invention is that the anti-tumor compound has a structure represented by the following structural formula I:
in a specific example, the skin tumor is malignant melanoma of skin, colon cancer, liver cancer or lung cancer. It is understood that the tumor type is not limited thereto, and the test detects that the antitumor compound has an inhibitory effect on other tumors such as basal cell carcinoma, squamous cell carcinoma.
The anti-tumor drug aiming at the Fyn-CD147 signal channel target comprises the anti-tumor compound, and the mass percentage of the anti-tumor compound in the anti-tumor drug is not more than 99%. Optionally, the anti-tumor drug is in the form of injection, tablet, paste or suppository.
In a specific example, the anti-tumor drug further comprises a hardener and an analgesic. Optionally, the hardening agent is one or more of ethanol, propylene glycol, glycerol, isopropanol, and polyethylene glycol. Optionally, the analgesic agent is one or more of aspirin, ibuprofen, indomethacin, paracetamol, phenylbutazone, rofecoxib, and celecoxib.
In a specific example, the above antitumor drug further comprises a disintegrant and an absorbent. Optionally, the disintegrant is one or more of sodium hydroxymethyl starch, an effervescent disintegrant, and crospovidone. Optionally, the absorbent is one or more of calcium sulfate, calcium hydrogen phosphate, calcium carbonate, and light magnesium oxide.
The anti-tumor compound has a structure represented by the following structural formula I:
the anti-tumor compound can effectively inhibit the proliferation of skin tumor cells, colon cancer cells, liver cancer cells and lung cancer cells, wherein the semi-inhibition concentration of human skin malignant melanoma cells SK-Mel-28 is 6.1 mu M, the semi-inhibition concentration of colon cancer cells is 6.12 mu M, the semi-inhibition concentration of liver cancer cells is 6.25 mu M, and the semi-inhibition concentration of lung cancer cells is 5.54 mu M, which shows that the anti-tumor compound has strong capability of inhibiting the growth and proliferation of tumors and inducing the apoptosis of tumor cells, and the stability of the anti-tumor compound is superior to that of chalcone. Meanwhile, the anti-tumor compound can inhibit the migration of tumor cells only in 24 hours at the concentration of 5 mu M, can effectively inhibit the invasion of the tumor cells at the concentration of 5 mu M, can weaken the phosphorylation of FYN kinase on CD147 tyrosine, is an anti-tumor compound aiming at a Fyn-CD147 signal channel target spot, can be applied to the preparation of anti-tumor medicaments, provides a new theoretical and experimental basis for the prevention and treatment of tumors, and can be widely used as a tool molecule in the research related to the tumors.
CCK-8 experiments were performed using the above anti-tumor compounds: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well is 100ul, adding anti-tumor compounds (0 uM, 1 uM, 5 uM, 10 uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of drugs into DMSO group (0 uM), measuring at 0h, 24h, 48h and 72h, adding 10ul CCK-8 before measurement, incubating for 2 hours, measuring absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording result, and drawing cell growth curve with time as abscissa and absorption value as ordinate. The result is shown in figure 1, and the antitumor compound has a good inhibition effect on SK-Mel-28, and the half inhibition concentration is 6.1 mu M. Taking colon cancer cells HT29, liver cancer cells HepG2 and lung cancer cells A549 respectively, preparing single cell suspension by using a culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells in each hole to a 96-hole plate, adding 100ul of anti-tumor compounds (1 mu M, 5 mu M, 10 mu M and 20 mu M) with different concentrations after adherence, adding the maximum corresponding volume of the drugs into a DMSO group, measuring in 0h, 24h, 48h and 72h, adding 10ul of CCK-8 before measurement, measuring the absorption value of each hole at a wavelength of 450nm on a microplate reader after incubation for 2 hours, recording the result, and drawing a cell growth curve by taking time as a horizontal coordinate and the absorption value as a vertical coordinate. The results are shown in FIGS. 2 to 4, respectively, and it can be seen that the antitumor compound also has certain inhibitory effects on colon cancer, liver cancer and lung cancer, and the half inhibitory concentrations are 6.12. Mu.M, 6.25. Mu.M and 5.54. Mu.M, respectively.
CCK-8 testing was performed using the backbone compound chalcone: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume is 100ul, adding chalcone (1 uM, 5 uM, 10 uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of the drug into DMSO group, measuring at 0h, 24h, 48h and 72h, adding 10ul CCK-8 before measurement, incubating for 2 hours, measuring absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording result, and drawing cell growth curve with time as abscissa and light absorption value as ordinate. The results are shown in FIG. 5, where the half inhibitory concentration was 6.7. Mu.M, and the effect and stability were inferior to those of the antitumor compounds of the present invention.
CCK-8 testing was performed using a compound of formula II: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume being 100ul, adding the above compounds (1 uM, 5 uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of the drug into DMSO group, performing determination in 0h, 24h, 48h and 72h, adding 10ul CCK-8 before determination, incubating for 2h, determining absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording result, and drawing cell growth curve with time as abscissa and absorption value as ordinate. As shown in FIG. 6, the half inhibitory concentration was 20.1. Mu.M, and the effect was very poor, which was far from the antitumor compound of the present invention.
CCK-8 testing was performed using the compound of formula III below: taking human skin malignant melanoma cells SK-Mel-28, preparing single cell suspension with culture medium containing 10% fetal calf serum, counting, inoculating 1000 cells per well to 96-well plate, each well volume is 100ul, adding the above compounds (5 uM, 10 uM and 20 uM) with different concentrations after adherence, adding maximum corresponding volume of the drugs into DMSO group, measuring at 0h, 24h, 48h and 72h, adding 10ul CCK-8 before measurement, incubating for 2 hours, measuring the absorption value of each well at 450nm wavelength on enzyme labeling instrument, recording the result, and drawing cell growth curve with time as abscissa and the absorption value as ordinate. As shown in FIG. 7, the half inhibitory concentration was 20.7. Mu.M, which is far from the antitumor compound of the present invention.
The results of tumor cell migration inhibition experiments using the above-mentioned antitumor compounds are shown in fig. 8 and 9, which indicate that the antitumor compounds can inhibit the migration of tumor cells only in 24 hours at a concentration of 5 μ M. The results of tumor cell invasion inhibition experiments using the above antitumor compounds are shown in fig. 10, which indicates that the antitumor compounds can effectively inhibit invasion of tumor cells at a concentration of 5 μ M.
In vivo experiments: in order to further explore the in vivo effect of the anti-tumor compound, a xenograft model is established by using 5-6 weeks old nude mice, melanoma cells SK-Mel-28 with a high proliferation speed are selected as inoculated cells, cells with good growth state, no pollution and strong activity are selected for proliferation, and subcutaneous tumorigenesis is performed on 40 nude mice. Continuously observing 7-10 days after inoculation until the size of the tumor volume reaches 50mm 3 ～100mm 3 Selecting the nude mice meeting the above standard, and randomly dividing the nude mice into 3 groups: control group, 20mg/kg dose group and 40mg/kg dose group, each group containing 6 animals, dividing into groups, raising in cages, continuously injecting the anti-tumor compound of the present invention into abdominal cavity for treatment, measuring the tumor volume every other day until the tumor size of the control group reaches 1000mm 3 The experiment was terminated at this time, and the tumor bodies of the mice were removed for immunohistochemistry and Ki67 expression was detected.
The experimental results are as follows: after treatment, no mortality occurred in each group of nude mice, and the body weight average increased with the treatment time. The growth of tumors was significantly inhibited in the 20mg/kg dose group compared to the control group, whereas the growth was significantly inhibited in the 40mg/kg dose group compared to the 20mg/kg dose group. The above results can demonstrate that the anti-tumor compound of the present invention can effectively inhibit the growth of melanoma in vivo.
The invention further researches and screens the action mechanism of the anti-tumor compound, and finds that the anti-tumor compound mainly plays a role in the Fyn-CD147 signal channel target spot. By reacting Fyn kinase with purified CD147, the reaction system: fyn 1uL (100 ng), CD147 (5 uL), 10 XKinase Buffer (2 uL), ATP (1mM 1ul), an antitumor compound (5. Mu.M 2. Mu.L), reaction at 30 ℃ for 40 minutes, followed by Western Blot and Coomassie staining. The results are shown in fig. 11 (wherein anti-p is tyrosine phosphorylation antibody), which illustrates that the antitumor compound of the present invention can reduce phosphorylation of FYN kinase on CD147 tyrosine, thereby proving that the antitumor compound is an antitumor compound aiming at FYN-CD147 signal pathway target, providing new theory and experimental basis for prevention and treatment of tumor, and can be widely used as a tool molecule in tumor-related research.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is specific and detailed, but not to be understood as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (4)
1. The application of the anti-tumor compound aiming at Fyn-CD147 signal channel target spots in preparing anti-tumor drugs is characterized in that the anti-tumor compound has the following structural formula
The structure shown is:
2. the use of claim 1, wherein the tumor is malignant melanoma, colon cancer, liver cancer or lung cancer of the skin.
3. An anti-tumor drug against Fyn-CD147 signal pathway targets, which comprises the anti-tumor compound as claimed in claim 1, wherein the mass percentage of the anti-tumor compound in the anti-tumor drug is not more than 99%.
4. The antitumor drug as claimed in claim 3, wherein the dosage form of the antitumor drug is injection, tablet, paste or suppository.
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