CN111281870B - Medicine for inhibiting invasion and metastasis of oral cancer cells - Google Patents

Medicine for inhibiting invasion and metastasis of oral cancer cells Download PDF

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CN111281870B
CN111281870B CN202010198395.6A CN202010198395A CN111281870B CN 111281870 B CN111281870 B CN 111281870B CN 202010198395 A CN202010198395 A CN 202010198395A CN 111281870 B CN111281870 B CN 111281870B
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oral cancer
cells
beta
metastasis
carbomethoxy
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CN111281870A (en
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孙强
郑宏雨
李紫璇
陈怡恒
赵军方
薛文华
李光辉
孙明磊
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First Affiliated Hospital of Zhengzhou University
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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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

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Abstract

The invention discloses a medicine for inhibiting invasion and metastasis of oral cancer cells. The invention discovers that the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline can inhibit the growth of oral cancer by inhibiting the proliferation of oral cancer cells on one hand, and can inhibit the metastasis of the oral cancer by inhibiting the migration activity of the oral cancer cells on the other hand. Therefore, the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline has the prospect of being developed into a medicament for resisting the growth of oral cancer and the metastasis of the oral cancer.

Description

Medicine for inhibiting invasion and metastasis of oral cancer cells
Technical Field
The invention belongs to the field of medicines, relates to screening discovery of oral cancer medicines, and particularly relates to a medicine for inhibiting invasion and metastasis of oral cancer cells.
Background
Oral cancer is a common head and neck tumor with a high incidence rate. In recent years, with the rapid development of global economy and the improvement of the living standard of people, the incidence rate of oral cancer is remarkably increased, and the incidence population tends to be younger.
At present, the surgical treatment is the most effective treatment method in clinic, but because the oral cancer is relatively hidden and is often found in an advanced stage, the best time for the surgical treatment is missed. In addition, chemotherapy is also an important treatment method for oral cancer, and therapeutic drugs include fluorouracil, cisplatin and the like, but the existing chemotherapy method not only has great toxic and side effects, but also is easy to generate drug resistance. Therefore, the search for high-efficiency and low-toxicity oral cancer prevention and treatment medicines is still a serious task for researchers.
The influence of tripterygium glycosides on the proliferation and apoptosis of human oral cancer KB cells and a PI3K/AKT signal pathway is discussed by Duveting and the like, and the result shows that the tripterygium glycosides have obvious inhibition effect on the proliferation of the human oral cancer KB cells and promote the apoptosis of the cells. Compared with a control group, the expression levels of p-PI3K and p-AKT proteins in human oral cancer KB cells in the tripterygium glycosides administration group are obviously reduced, and the tripterygium glycosides are proved to have the effects of inhibiting the proliferation and inducing the apoptosis of the human oral cancer KB cells, and the mechanism of the tripterygium glycosides is probably related to the inhibition of the activation of a PI3K/AKT signal channel (the literature: the influence of the tripterygium glycosides on the proliferation and the apoptosis of the human oral cancer KB cells and the PI3K/AKT signal channel, the university of Guangdong pharmacy, 2019).
The influence of kaempferol on the proliferation and the apoptosis of human oral cancer KB cells and a Wnt/beta-catenin signal path is discussed by prunus salicina and the like, and the result shows that the kaempferol has obvious inhibition effect on the proliferation of the human oral cancer KB cells; compared with a control group, the cell apoptosis rate, baxmRNA expression and Caspase-3 activity of each concentration group of kaempferol are obviously increased, the Bcl-2mRNA, beta-catenin, C-myc and cyclin D1 protein expression are obviously reduced (P is less than 0.05 or P is less than 0.01), and the kaempferol is proved to have the functions of inhibiting the proliferation and inducing the apoptosis of human oral cancer KB cells and is related to the inhibition of the activation of the Wnt/beta-catenin signal pathway (the document: the influence of the kaempferol on the proliferation and the apoptosis of the human oral cancer KB cells and the Wnt/beta-catenin signal pathway, a traditional Chinese medicine material, 2018).
The influence of genistein on the proliferation of human oral cancer TCA8113 cells is observed by Daihiang and the like, and the action mechanism of the genistein is discussed, so that the genistein can obviously inhibit the proliferation of the TCA8113 cells, and the antiproliferative activity of the genistein has concentration dependence; genistein also dose-dependently reduces the protein levels of VEGF, ERK and p-ERK; the expression of VEGF can be inhibited by ERK specific inhibitor U0126; the VEGF receptor antagonists, namely axitinib and U0126, remarkably inhibit the proliferation of TCA8113 cells, and prove that genistein can inhibit the proliferation of human oral cancer TCA8113 cells, and the mechanism of genistein is probably related to the inhibition of ERK expression and activation and further the inhibition of VEGF expression (the document is that genistein inhibits the proliferation of human oral cancer TCA8113 cells by inhibiting the VEGF expression, the Chinese pathophysiology journal, 2016).
The l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline is an alkaloid and has the following chemical structure:
Figure BDA0002418452720000021
at present, the application of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline in preparing the anti-oral cancer medicament is not reported.
Disclosure of Invention
The invention aims to provide a medicine for inhibiting invasion and metastasis of oral cancer cells, and provides a medical application of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline in preparing medicines for inhibiting growth and metastasis of oral cancer.
The above purpose of the invention is realized by the following technical scheme:
a medicine for inhibiting the invasion and metastasis of oral cancer cells contains l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline as active component.
The l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline is used for preparing the medicine for inhibiting the growth of oral cancer. In the specific embodiment of the invention, the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline can obviously inhibit the proliferation activity of human oral cancer KB cells, and the proliferation inhibition effect presents a relatively obvious dose-effect relationship.
The l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline is used for preparing the medicine for inhibiting the metastasis of oral cancer. In the specific embodiment of the invention, compared with the negative control group, the cell migration number of the drug treatment group is remarkably reduced, which indicates that the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline has the activity of inhibiting the migration of human oral cancer KB cells.
The l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline is used for preparing the medicine for treating the oral cancer.
A pharmaceutical preparation for treating oral cancer is prepared from l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline as effective component, and pharmaceutically acceptable adjuvants by making into pharmaceutically acceptable dosage forms.
Further, the auxiliary material is a liquid, solid or semisolid auxiliary material.
Further, the dosage forms comprise tablets, capsules and injections.
Has the beneficial effects that:
the invention discovers that the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline can inhibit the growth of oral cancer by inhibiting the proliferation of oral cancer cells on one hand, and can inhibit the metastasis of the oral cancer by inhibiting the migration activity of the oral cancer cells on the other hand. Therefore, the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline has the prospect of being developed into a medicament for resisting the growth of oral cancer and the metastasis of the oral cancer.
Drawings
FIG. 1 is an inhibition curve of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline on human oral cancer KB cells, the abscissa is the drug concentration, and the ordinate is the inhibition rate; the result shows that the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline has obvious inhibition effect on the proliferation activity of human oral cancer KB cells, and the proliferation inhibition effect presents a relatively obvious dose-effect relationship.
Detailed Description
The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.
1. Experimental Material
The human oral cancer KB cells are frozen in liquid nitrogen and recovered by a conventional method for use.
Fetal bovine serum, RPMI1640 medium, trypsin was branded Gibco.
The brands of penicillin and streptomycin are Sigma, and the PBS solution is prepared according to the formula.
The purity of the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline is not less than 98 percent.
Cell culture plates were purchased from ThermoScientific.
Transwell chambers (24 wells) were purchased from Corning.
CCK-8 kits were purchased from Tongren Japan.
2. Experimental methods
1. Cell recovery and subculturing
Taking human oral cancer KB cells out of a liquid nitrogen tank, placing the KB cells in a water bath kettle at 37 ℃ for gentle oscillation and melting, blowing and beating the KB cells by a pipette after melting, evenly mixing the KB cells by uniformly mixing the KB cells with the liquid, transferring the KB cells to a 15mL centrifuge tube, adding a proper amount of complete culture solution (RPMI 1640 culture medium containing 10% fetal calf serum, 100U/mL penicillin and 100 mu g/mL streptomycin), centrifuging the cells, discarding supernatant, adding a proper amount of complete culture solution for resuspending the cells, transferring the resuspension cells to a cell culture bottle, placing the cell culture bottle in a temperature of 37 ℃ and 5 percent CO 2 Culturing in incubator, removing culture medium when cell bottle is full of cells, washing with PBS, digesting cells with 0.25% trypsin, centrifuging when cell gap becomes large, removing supernatant, washing with PBS, adding complete culture medium, inoculating into new cell bottle, and placing at 37 deg.C and 5% CO 2 Culturing in an incubator and carrying out passage. Well-grown cells in logarithmic growth phase were collected for experiments.
2. Cell grouping and drug delivery culture
The experimental groups included:
(1) Negative control group: culturing with complete culture medium without medicine;
(2) Drug treatment group: culturing with complete culture medium containing 10, 20, 50, 100, 200 nML-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline respectively.
3. CCK-8 method for measuring cell proliferation activity
Digesting human oral cancer cells in logarithmic growth phase with 0.25% trypsin to obtain cell suspension, and adjusting cell density to 5 × 10 4 and/mL, transferring the cell suspension to a 96-well plate, wherein each well is 200 mu L, and pre-culturing for 24h until the cells adhere well. Grouping according to the '2, cell grouping and administration culture', each group comprises 6 multiple wells, after culturing for 48h, absorbing and discarding the original culture solution, adding 100 mu L of fresh culture medium and 10 mu L of CCK-8 reaction solution into each well, incubating for 4h, measuring the absorbance value (OD) of each group at 450nm by using an enzyme-labeling instrument, calculating the inhibition rate of the drug on human oral cancer cells according to the following formula, and drawing a concentration-inhibition rate curve.
Inhibition = (1-OD drug group/OD negative control group) × 100%
4. Determination of cell migration Activity by Transwell method
Collecting human oral cancer cells in logarithmic growth phase, digesting, centrifuging, culturing with complete culture medium containing or not containing drug for 48h (negative control group containing no drug, drug treated group containing 10nM drug), starving with serum-free culture medium for 12h, digesting, centrifuging, resuspending with serum-free culture medium, counting, adding 200 μ L cell suspension containing 2 × 10 per well in each upper chamber 5 And (4) cells. Putting the whole small chamber into a 24-pore plate containing complete culture medium for culturing for 24h, taking out the upper chamber, fixing with anhydrous methanol, staining with crystal violet, wiping off the upper surface without membrane cells, sealing, observing with an inverted microscope, randomly selecting 5 visual fields, counting under a high power microscope, and averaging.
5. Statistical treatment
Processing was performed using SPSS version 17.0 software. Data are presented as mean ± standard deviation, with t-test for inter-group comparisons and one-way anova for inter-group comparisons. The difference is statistically significant when P is less than 0.05.
3. Results of the experiment
1. Effect of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline on cell proliferative Activity
The results are shown in table 1 and fig. 1, l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline can obviously inhibit the proliferation activity of human oral cancer KB cells, and the proliferation inhibition effect presents a relatively obvious dose-effect relationship.
TABLE 1 proliferation inhibition rate of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline on human oral cancer KB cells
Figure BDA0002418452720000041
2. Effect of drugs on cell migration Activity
The results are shown in table 2, and it can be seen from the results that the number of cell migration in the drug-treated group is significantly reduced compared to the negative control group, indicating that l-acetyl-3-carbomethoxy-4-hydroxy- β -carboline has the activity of inhibiting the migration of human oral cancer KB cells.
TABLE 2 number of migrating cells in each group
Figure BDA0002418452720000042
In conclusion, the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline can inhibit the growth of oral cancer by inhibiting the proliferation of oral cancer cells on one hand, and can inhibit the metastasis of oral cancer by inhibiting the migration activity of the oral cancer cells on the other hand. Therefore, the l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline has the prospect of being developed into a medicament for resisting the growth of oral cancer and the metastasis of the oral cancer.
The above-described embodiments are intended to illustrate the material nature of the present invention, but those skilled in the art will recognize that the scope of the present invention should not be limited to such embodiments.

Claims (1)

  1. Use of l-acetyl-3-carbomethoxy-4-hydroxy-beta-carboline for the preparation of a medicament for the treatment of oral cancer.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN109453168A (en) * 2018-12-25 2019-03-12 南京盖斯夫医药科技有限公司 A kind of anti-carcinoma of mouth purposes of tetrahydro-beta-carboline derivative

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WO2010080756A2 (en) * 2009-01-06 2010-07-15 Osteogenex, Inc. Harmine derivatives for reducing body weight

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Publication number Priority date Publication date Assignee Title
CN109453168A (en) * 2018-12-25 2019-03-12 南京盖斯夫医药科技有限公司 A kind of anti-carcinoma of mouth purposes of tetrahydro-beta-carboline derivative

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金铁锁中 1 个新 β － 咔啉生物碱;王微等;《中国中药杂志》;20121101;3240-3242 *

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