CN115518067A - Medicine related to tumor treatment - Google Patents

Abstract

The invention provides a medicine related to tumor treatment, and the medicine is SB-705498. The invention proves that SB-705498 can effectively inhibit the migration of the tumor and has better treatment effect on the tumor through experiments. The invention also provides a pharmaceutical composition containing SB-705498 and application thereof. The SB-705498 provided by the invention provides a new method and thought, and has important significance for relevant research of tumor treatment.

Description

Medicine related to tumor treatment

Technical Field

The invention belongs to the field of biological medicines, and particularly relates to a medicine related to tumor treatment.

Background

Neoplastic diseases, especially malignant tumors, are a common and frequently encountered disease that seriously endangers human health. According to the report of the world health organization, 1000 more than ten thousand new cases of malignant tumors and 700 more than ten thousand death cases all year round account for 12 percent of total death, and the number can reach 25 percent in most developed countries.

Through the development of many years, the research and development of the anti-tumor drugs have made a lot of important progress. However, there is still a lack of effective drugs so far, which reflects the difficulty in developing antitumor drugs, and this means that new ideas, new technologies and new methods are also needed for the development of antitumor drugs.

The new use of old medicine or the reuse of medicine means that new adaptive diseases are found on the existing medicine, and new medical use is found, which is a powerful promotion to the medical industry and is a good news of patients. The reuse of the medicine has the advantages of low cost and short time. According to statistics, the development period of the traditional new medicine is about 12-16 years, while the development of the relocation medicine generally only needs 6 years. Drug discovery has a distinct speed advantage. Moreover, the recycling safety of the medicine is high, and the success rate is high. Since the drugs for redevelopment have passed preclinical testing and early clinical human trials, the safety of the selected targets has been verified, their molecular structures and chemical properties have been studied sufficiently, and reasonable modifications have been made on their original structures to reduce the risk of failure due to safety issues.

SB-705498 is reported to be a medicament for treating rhinitis-related diseases, and no research on the correlation between SB-705498 and tumors is found.

Disclosure of Invention

In order to make up the defects of the prior art, the invention researches the correlation between SB-705498 and the tumor, and the experiment proves that the SB-705498 can inhibit the migration of the tumor and has the treatment effect on the tumor.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect of the present invention there is provided a pharmaceutical composition for use in the treatment of tumours, said pharmaceutical composition comprising a therapeutically effective amount of SB-705498.

Further, the pharmaceutical composition also comprises a pharmaceutically acceptable carrier.

Further, the tumor includes breast cancer, lung cancer, stomach cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer.

Further, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

In a second aspect, the present invention provides the use of SB-705498 in the preparation of a pharmaceutical composition for the treatment of a tumour.

Further, the SB-705498 inhibits metastasis of tumors.

Further, the SB-705498 inhibits tumor metastasis by decreasing F-actin assembly.

Further, the concentration of the SB-705498 is 8nM to 5000nM.

Further, the concentration of SB-705498 is selected from: 8nM, 200nM, 5000nM and ranges between any two of the above.

Further, the medicine also comprises a pharmaceutically acceptable carrier.

Further, the pharmaceutical composition also comprises an alkylating agent, an antimetabolite, an antibiotic, a plant antineoplastic drug, platinum and/or a hormone drug with effective treatment amount.

Further, the pharmaceutical composition also comprises an auxiliary drug.

Further, the tumor includes breast cancer, lung cancer, stomach cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer.

Further, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

A third aspect of the present invention provides a method of inhibiting tumor cell metastasis in vitro comprising administering SB-705498.

Further, the SB-705498 inhibits metastasis of tumor cells by decreasing the assembly of F-actin.

Further, the method is a method for non-therapeutic purposes.

Further, the tumor includes breast cancer, lung cancer, stomach cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer.

Further, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

In a fourth aspect, the invention provides the use of SB-705498 for inhibiting tumor cell metastasis in vitro.

Further, the SB-705498 inhibits metastasis of tumor cells by decreasing the assembly of F-actin.

Further, the tumor includes breast cancer, lung cancer, stomach cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer.

Further, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

The invention has the advantages and beneficial effects that:

the invention discovers the correlation between SB-705498 and the tumor for the first time, and proves that SB-705498 can inhibit the migration of the tumor by inhibiting the assembly of F-actin to achieve the effect of treating the tumor through experiments.

Drawings

FIG. 1 is a drug screening graph, wherein 1A is a drug screening graph and 1B is a Wien graph;

FIG. 2 is a graph of cell migration, in which 2A is a graph of hepatoma cell activity, 2B is a graph of hepatoma cell migration line, 2C is a graph of hepatoma cell scoring experiment, 2D is a graph of pancreatic cancer cell activity, 2E is a graph of pancreatic cancer cell migration line, and 2F is a graph of pancreatic cancer cell scoring experiment;

FIG. 3 is a diagram showing F-actin assembly, wherein 3A is a diagram showing F-actin assembly of liver cancer cells, and 3B is a diagram showing F-actin assembly of pancreatic cancer cells.

Detailed Description

The following provides definitions of some terms used in this specification. 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 term "treatment" generally relates to the treatment and physical therapy of a human or animal (e.g., in veterinary applications) in which some desired therapeutic effect is achieved, such as inhibiting disease progression, including reducing the rate of progression, halting the rate of progression, alleviating symptoms of disease, ameliorating disease, and curing the disease. Treatment as a prophylactic means (i.e., prophylaxis) is also included. For example, the term "treatment" also includes the use of a patient who has not yet developed a disease but who is at risk of developing a disease.

The term "therapeutically effective amount" refers to an amount of a therapeutic agent that treats or prevents a disease or condition in a mammal. In the case of cancer, a therapeutically effective amount of a therapeutic agent can reduce the number of cancer cells; reducing the size of the primary tumor; inhibit (i.e., slow to some extent, preferably prevent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent, preferably prevent) tumor metastasis; inhibit tumor growth to some extent; and/or to some extent alleviate one or more symptoms associated with the condition. Depending on the extent to which the drug can prevent growth and/or kill existing cancer cells, it can be cytostatic and/or cytotoxic. For cancer therapy, in vivo efficacy can be measured by, for example, assessing survival duration, time to disease progression (TTP), response rate (e.g., CR and PR), response duration, and/or quality of life. The term "therapeutically effective amount" refers to the amount of a compound or material, pharmaceutical-containing composition or dosage form, that is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered according to a desired treatment regimen.

The term "inhibit" or "decrease" refers to the ability to cause an overall decrease of 20%,30%,40%,50%,60%,70%,75%,80%,85%,90%,95%, or greater. Inhibition or reduction may refer to, for example, symptoms of the condition being treated, the presence or size of metastases, or the size of the primary tumor. In the present invention, inhibition or reduction refers to inhibition of metastasis of a tumor.

In the present invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, which includes, but is not limited to, additives such as stabilizers, bactericides, buffers, isotonizing agents, chelating agents, pH control agents, and surfactants.

Wherein the stabilizer comprises human serum protein, L-amino acid, sugar and cellulose derivative. The L-amino acid may further include any one of glycine, cysteine and glutamic acid. Saccharides include monosaccharides such as glucose, mannose, galactose, fructose, and the like; sugar alcohols such as mannitol, cellosolve, xylitol, and the like; disaccharides such as sucrose, maltose, lactose, and the like; polysaccharides such as dextran, hydroxypropyl starch, chondroitin sulfate, hyaluronic acid, etc. and their derivatives. The cellulose derivatives include methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium hydroxymethylcellulose. Surfactants include ionic or non-ionic surfactants such as polyoxyethylene alkyl esters, sorbitan monoacyl esters, fatty acid glycerides. Additive buffers may include boric acid, phosphoric acid, acetic acid, citric acid, glutamic acid, and the corresponding salts (alkali metal or alkaline rare earth metal salts thereof, such as sodium, potassium, calcium, and magnesium salts). Isotonic agents include potassium chloride, sodium chloride, sugars and glycerol. The chelating agent comprises sodium ethylene diamine tetracetate and citric acid.

In the present invention, the pharmaceutical composition may be in a form suitable for administration by injection, in a form suitable for oral administration (e.g., solid form, liquid form, emulsion, suspension), in an ointment, cream or lotion form suitable for topical administration, in a delivery form suitable for use as eye drops, in an aerosol form suitable for administration by inhalation (e.g., by intranasal inhalation or oral inhalation), in a form suitable for parenteral administration, i.e., subcutaneous, intramuscular or intravenous injection.

Solid dosage forms for oral administration may contain binders, sweeteners, disintegrants, diluents, flavouring agents, coating agents, preservatives, lubricants and/or time delay agents (timedelayagent) acceptable in human and veterinary practice. Suitable binders include acacia, gelatin, cornstarch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrating agents include corn starch, methyl cellulose, polyvinylpyrrolidone, guar gum, xanthan gum, bentonite, alginic acid or agar. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, citrus or raspberry flavors. Suitable coating agents include polymers or copolymers of acrylic and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delays include glyceryl monostearate or glyceryl distearate.

Liquid dosage forms for oral administration may contain, in addition to the above-mentioned drugs, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil, sesame oil, sunflower oil, safflower oil, peanut oil, coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further include dispersing and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or acetyl ethanol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono-or di-oleate, -stearate or-laurate, polyoxyethylene sorbitan mono-or di-oleate, -stearate or-laurate and the like.

The pharmaceutical composition of the present invention further comprises other therapeutic drugs, and the other therapeutic drugs are not limited to the alkylating agents, antimetabolites, antibiotics, phyto-antineoplastic drugs, platins and/or hormones described in the present invention, so long as they have the effect of treating tumors within the scope of the present invention.

In the present invention, alkylating agents include, but are not limited to, cyclophosphamide, mechlorethamine, ifosfamide, formononetin, fosfamide bicine ethyl ester, melphalan, carmustine, lomustine, semustine, nimustine, chlorambucil, hexamethylmelamine, thiotepa, malilan, carmustine, mechlorethamine, antineotide, antitumor mustine, nitratecan, pyrimethamine, mechlorethamine, uracil mustard, mannitol mustard, phenylalanine mustard, dibromomannitol, fotemustine, orthoalanine nitramustine, 5-fluorouracil, 6-mercaptopurine, cytarabine.

Antimetabolites include, but are not limited to, antifolate, antipurine, antipyrimidine, fluorouracil, cytarabine, mercaptopurine, azathioprine, methotrexate, 5-fluorouracil.

Antibiotics include, but are not limited to, cephalosporins, tetracyclines, streptozotocin, mitomycins, adriamycins, daunorubicin.

The antineoplastic agent of plants includes, but is not limited to, vincristine, vinblastine, cephalotaxine, colchicine, camptothecin, paclitaxel, and gemcitabine.

Platinum drugs include, but are not limited to, cisplatin, carboplatin, nedaplatin, oxaliplatin, and lobaplatin.

Hormonal agents include, but are not limited to, prednisone, dexamethasone, goserelin, triptorelin, letrozole, exemestane, flutamide, bicalutamide.

In the present invention, the pharmaceutical composition further comprises auxiliary drugs including, but not limited to: blood-increasing agents (including but not limited to G-CSF, GM-CSF, interleukin-11, EPO), antiemetics (including but not limited to ondansetron, granisetron hydrochloride), analgesics (including but not limited to aspirin, paracetamol, codeine, tramadol, morphine, fentanyl).

The term "tumor" is a neoplasm formed by the proliferation and abnormal differentiation of cells of the body under the action of various initiation and promotion factors. The growth of the tumor is not regulated by the physiology of normal organisms, but rather destroys normal tissues and organs.

<xnotran> , , , , , , , ( , , , ), , , , , , , /, , , , , , , , , (EHE), , , , , , , (GIST), , , , , , , ( ), , (), , ( , ( ), ( ), ), , , ( , ), ( , , , , , T ), , /, </xnotran> Medulloblastoma, melanoma, merkel cell carcinoma, primary focal occult metastatic cervical squamous carcinoma, multiple endocrine tumor syndrome, bone marrow cancer, multiple myeloma/plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myxoma, cancer of the nasal cavity and paranasal sinuses, neuroblastoma, ovarian cancer, epithelial carcinoma (superficial epithelial interstitial tumor), ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer (hypopharynx cancer, nasopharyngeal cancer, oropharyngeal cancer), pheochromocytoma, pineal germ cell tumor, pineal blastoma, supratentorial primitive neuroectodermal tumor, pituitary adenoma, pleural pneumococcus, prostate cancer, rectal cancer, renal pelvis and ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland carcinoma, szary syndrome, merkel cell skin carcinoma, small intestine carcinoma, soft tissue sarcoma, squamous cell carcinoma, gastric cancer, testicular cancer, thymoma, thyroid carcinoma, urethral carcinoma, uterine sarcoma, vaginal sarcoma, vulval carcinoma.

In an embodiment of the invention, the tumor is selected from liver cancer, lung cancer, pancreatic cancer, breast cancer.

The term "administering" refers to a method of administering a dose of a drug or compound (e.g., an inhibitor or antagonist) or a pharmaceutical composition (e.g., a pharmaceutical composition comprising an inhibitor or antagonist) to a subject (e.g., a patient). Administration may be by any suitable means, including parenteral, intrapulmonary, and intranasal, and intralesional administration if desired for topical treatment. Parenteral infusion includes, for example, intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. Administration may be by any suitable route, for example by injection, such as intravenous or subcutaneous injection, depending in part on whether administration is transient or chronic. Various dosing schedules are contemplated in the present invention, including but not limited to a single administration or multiple administrations over multiple time points, bolus administration and pulse infusion. The subject refers to any animal, and also refers to human and non-human animals. Non-human animals include all vertebrates, e.g., mammals, such as non-human primates (particularly higher primates), sheep, dogs, rodents (e.g., mice or rats), guinea pigs, goats, pigs, cats, rabbits, cattle, and any domestic or companion animal; and non-mammals, such as chickens, amphibians, reptiles, and the like. In a preferred embodiment of the invention, the subject is preferably a human.

The invention is further illustrated below with reference to specific examples. It should be understood that the particular embodiments described herein are presented by way of example and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention.

Example SB-705498 inhibits migration of tumor cells

1. Experimental Material

Liver cancer cell line: SK-Hep-1, pancreatic cancer cell line: SW1990, non-small cell lung cancer cell: a549, breast cancer cells: MDA-MB-231.

Cell lines purchased from ATCC company, in DMEM medium, 5% CO ₂ And cultured at 37 ℃.

2. Experimental method

Drug screening

The method comprises the steps of screening drugs for inhibiting tumor cell migration by using a microfluidic-based restrictive migration drug screening platform, wherein tumor cells are selected from liver cancer cells (SK-Hep-1), pancreatic cancer cells (SW 1990), non-small cell lung cancer cells (A549) and breast cancer cells (MDA-MB-231), adding the cells into one channel of the restrictive migration drug screening platform, adding related drugs into the other channel for screening, and screening the channels layer by layer to obtain the target drug.

MTT method for detecting and screening influence of drug on cell activity

Hepatoma cells (SK-Hep-1), pancreatic cancer cell line (SW 1990) were seeded in 96-well plates at 2000 cells per well, 3 replicates per sample. After 24 hours of drug incubation, cell viability was checked with thiazole blue (MTT) (MedChemExpress, usa) and used every 24 hours for the next 5 days. The absorbance of each well was measured using a 560nm microplate reader (BioTek, agilent, USA).

Ibidi chamber scratch experiment for detecting influence of screened drugs on tumor cell migration

In Ibidi culture dish (

Munich, germany) composed of two cell culture chambers with a width of 500 μm. Each chamber was inoculated with 70. Mu.L of cell suspension at a concentration of 5X 10 ⁵ Cells/ml. After 8 hours, the cells were completely adhered to the cavity floor and the insert was removed. Different concentrations of drug and media were then added to the wells, left for 24 hours to observe wound healing rates, and mitochondrial distribution was observed using a confocal microscope (Nikon, A1HD25, japan).

Confocal microscope observation of F-actin distribution

Distribution images of F-actin were acquired using a confocal microscope (Nikon, A1HD25, japan).

3. Results of the experiment

SB-705498 (figure 1) which has an effect in four cell lines of liver cancer, pancreatic cancer, non-small cell lung cancer and breast cancer is screened by using a restrictive migration drug screening platform, MTT detection results and scratch test results show that SB-705498 does not influence cell activity, but can inhibit tumor cell migration speed (figure 2) in a scratch test, and SB-705498 can reduce F-actin assembly and inhibit tumor cell migration (figure 3).

The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.

Claims (10)

1. A pharmaceutical composition for treating a tumor, comprising a therapeutically effective amount of SB-705498.

2. The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier;

preferably, the tumor comprises breast cancer, lung cancer, gastric cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer;

preferably, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

Application of SB-705498 in preparing pharmaceutical composition for treating tumor is provided.

4. The use of claim 3, wherein SB-705498 inhibits metastasis of tumors.

5. The use of claim 4, wherein SB-705498 inhibits metastasis of tumors by reducing F-actin assembly.

6. The use according to claim 3, wherein the concentration of SB-705498 is 8nM-5000nM;

preferably, the concentration of SB-705498 is selected from: 8nM, 200nM, 5000nM and ranges between any two of the above.

7. The use of claim 3, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

8. The use according to claim 3, wherein the pharmaceutical composition further comprises an alkylating agent, an antimetabolite drug, an antibiotic, a phyto-antineoplastic drug, a platinum-based and/or hormone-based drug;

preferably, the pharmaceutical composition further comprises an auxiliary drug;

preferably, the tumor comprises breast cancer, lung cancer, gastric cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer;

preferably, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

9. A method of inhibiting tumor cell metastasis, comprising administering SB-705498;

preferably, the SB-705498 inhibits metastasis of tumor cells by reducing F-actin assembly;

preferably, the tumor comprises breast cancer, lung cancer, stomach cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer;

preferably, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

The application of SB-705498 in inhibiting tumor cell metastasis;

preferably, the SB-705498 inhibits metastasis of tumor cells by reducing F-actin assembly;

preferably, the tumor comprises breast cancer, lung cancer, gastric cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer;

preferably, the tumor is selected from liver cancer, lung cancer, pancreatic cancer and breast cancer.

Images