阅读说明：本技术 卡格列净在制备治疗胰腺癌药物中的应用 (Application of canagliflozin in preparation of medicine for treating pancreatic cancer ) 是由 周长林 何良愿 许世霖 庞树洋 徐兑悦 于 2020-07-23 设计创作，主要内容包括：本发明公开了卡格列净在治疗胰腺癌中的应用。卡格列净化学名为(1S)-1,5-脱氢-1-C-[3-[[5-(4-氟苯基)-2-噻吩基]甲基]-4-甲基苯基]-D-葡萄糖醇。本发明利用胰腺癌肿瘤细胞模型和小鼠胰腺癌移植瘤模型,发现卡格列净能显著抑制胰腺癌细胞Capan-1和PANC-1的生长增殖；同时卡格列净能抑制肿瘤细胞的迁移；此外,经研究发现,卡格列净能干扰胰腺癌细胞糖酵解相关代谢功能,诱导胰腺癌细胞的凋亡。经卡格列净治疗的荷瘤小鼠,其胰腺癌皮下移植瘤PANC-1的肿瘤体积明显减小。因此,卡格列净在临床胰腺癌的治疗中有良好的应用前景。(The invention discloses application of canagliflozin in treating pancreatic cancer. Canagliflozin is chemically known as (1S) -1, 5-dehydro-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol. According to the invention, a pancreatic cancer tumor cell model and a mouse pancreatic cancer transplantation tumor model are utilized, and the Kagelagliflozin can obviously inhibit the growth and proliferation of pancreatic cancer cells Capan-1 and PANC-1; meanwhile, the canagliflozin can inhibit the migration of tumor cells; in addition, the study shows that the canagliflozin can interfere the glycolytic related metabolic function of pancreatic cancer cells and induce the apoptosis of the pancreatic cancer cells. The tumor volume of the subcutaneous tumor-transplanted PANC-1 of the pancreatic cancer of the tumor-bearing mice treated by the canagliflozin is obviously reduced. Therefore, the canagliflozin has a good application prospect in the clinical treatment of pancreatic cancer.)

1. Application of canagliflozin or a pharmaceutically acceptable derivative thereof in preparing a medicament for treating pancreatic cancer.

2. Use of canagliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a synergistic medicament for use in combination with gemcitabine in the treatment of pancreatic cancer.

3. Use according to claim 1, characterized in that the canagliflozin or a pharmaceutically acceptable derivative thereof is canagliflozin or a pharmaceutically acceptable derivative thereof or a composition containing canagliflozin or a pharmaceutically acceptable derivative thereof.

4. The use according to claim 3, characterized in that the composition is formulated from canagliflozin or a pharmaceutically acceptable derivative thereof in combination with a pharmaceutically acceptable adjuvant.

5. The use according to claim 4, wherein the formulation comprises tablets, capsules, pills, granules, oral liquids, injections.

Technical Field

The invention relates to application of a medicament, in particular to application of Canagliflozin (chemical name of (1S) -1, 5-dehydrogenation-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol, British name of Canagliflozin, CANA) in preparation of a medicament for treating pancreatic cancer.

Background

Pancreatic cancer is the most common solid malignancy, characterized by occult clinical symptoms, rapid progression, poor prognosis, etc., which may be due to low angiogenesis, significant fibrotic stromal response, genomic complexity and metabolic alterations. The low survival rate of pancreatic cancer is largely due to the fact that routine examination is hampered by its anatomically specific location, and patients are therefore already in an advanced stage of cancer when diagnosed. To date, radical resection remains the treatment of choice for patients with pancreatic cancer, but since most patients are found to be already advanced, less than 15% of patients have an opportunity to undergo radical resection. Gemcitabine is the first therapeutic agent for pancreatic cancer, which extends the survival of patients for several months, but is associated with many adverse reactions, such as nephrotoxicity, anaphylaxis, edema, hematopoietic atrophy, immunosuppression, and the like. Therefore, the search for novel drugs for treating pancreatic cancer is of clinical significance.

The chemical name of canagliflozin is (1S) -1, 5-dehydrogenation-1-C- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol, and the chemical structural formula is as follows. It is an oral drug for treating diabetes, can act by inhibiting sodium-glucose cotransporter 2, and is the only one oral hypoglycemic drug which is approved at present and has the function of reducing myocardial infarction, stroke or cardiovascular mortality.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to disclose application of canagliflozin in preparation of a medicine for treating pancreatic cancer.

The technical scheme is as follows: the invention relates to application of canagliflozin or a medicinal derivative thereof in preparing a medicament for treating pancreatic cancer.

Use of canagliflozin or a pharmaceutically acceptable derivative thereof in the preparation of a synergistic medicament for use in combination with gemcitabine in the treatment of pancreatic cancer.

The canagliflozin or the pharmaceutically acceptable derivative thereof is canagliflozin or the pharmaceutically acceptable derivative thereof or a composition containing the canagliflozin or the pharmaceutically acceptable derivative thereof.

The composition is prepared from canagliflozin or a medicinal derivative thereof and pharmaceutically acceptable auxiliary materials.

The preparation comprises tablets, capsules, pills, granules, oral liquid and injection.

The canagliflozin can effectively inhibit the growth of pancreatic cancer by inhibiting the glycolysis of the pancreatic cancer; can inhibit the migration of pancreatic cancer cells and induce the apoptosis of the pancreatic cancer cells; it can be used in combination with gemcitabine to enhance the effect of gemcitabine in inhibiting pancreatic cancer cells.

(1) The canagliflozin obtained through an MTT cell viability experiment and a plate cloning experiment can inhibit the proliferation and cloning formation of pancreatic cancer cells Capan-1 and PANC-1; the effect of gemcitabine in inhibiting pancreatic cancer cells can be enhanced in combination with gemcitabine.

(2) By a scratching experiment, the canagliflozin can inhibit the migration of pancreatic cancer cells.

(3) The canagliflozin obtained by AV/PI double staining can effectively induce the apoptosis of pancreatic cancer cells, namely Capan-1 and PANC-1.

(4) By constructing a PANC-1 pancreatic cancer nude mouse transplantation tumor model, the Kagelaglet can obviously inhibit the growth of pancreatic cancer PANC-1 tumors.

(5) By detecting the glucose concentration of cell supernatant, the canagliflozin can inhibit the glucose uptake of pancreatic cancer cells, namely Capan-1 and PANC-1.

(6) By detecting the concentration of lactic acid in cell supernatant, the canagliflozin can inhibit the release of lactic acid in pancreatic cancer cells Capan-1 and PANC-1.

Has the advantages that: compared with the prior art, the method confirms that the canagliflozin has the activity of inhibiting the proliferation and the clone formation of pancreatic cancer cells through an MTT cell viability experiment and a flat plate clone experiment, and the effect of treating pancreatic cancer by the canagliflozin can be enhanced by combining with gemcitabine; and the effects of canagliflozin on resisting pancreatic cancer cell migration and inducing apoptosis are discovered through a scratch experiment and an AV/PI double-staining experiment. Meanwhile, the in-vivo anti-pancreatic cancer activity of canagliflozin is obtained by constructing a PANC-1 pancreatic cancer nude mouse transplantation tumor model; by detecting the glucose uptake and lactate release changes of pancreatic cancer cells in a treatment group, the canagliflozin can inhibit glycolysis of the pancreatic cancer cells. The invention discloses a canagliflozin with good clinical application prospect in a pancreatic cancer treatment drug.

Drawings

FIG. 1 is a graph of the inhibitory effect of canagliflozin on pancreatic cancer cells, Capan-1;

FIG. 2 is a graph showing the inhibitory effect of canagliflozin on pancreatic cancer cells PANC-1;

FIG. 3 is a graph of the inhibitory effect of canagliflozin in combination with gemcitabine on pancreatic cancer cells, Capan-1;

FIG. 4 is a graph of the inhibitory effect of canagliflozin in combination with gemcitabine on pancreatic cancer cells PANC-1;

FIG. 5 is a graph of the inhibitory effect of canagliflozin on the formation of pancreatic cancer cell Capan-1 clones;

FIG. 6 is a graph showing the inhibitory effect of canagliflozin on pancreatic cancer cell PANC-1 colony formation;

FIG. 7 is a graph showing the inhibitory effect of canagliflozin on migration of pancreatic cancer cells, Capan-1;

FIG. 8 is a graph showing the results of canagliflozin inducing apoptosis in pancreatic cancer cells, Capan-1 and PANC-1;

FIG. 9 is a photograph of the in vivo inhibition of pancreatic cancer PANC-1 tumor by canagliflozin;

FIG. 10 is a graph quantifying the inhibition rate of canagliflozin against pancreatic cancer PANC-1 tumors;

FIG. 11 is a graph of the effect of canagliflozin on body weight in nude mice;

FIG. 12 is a graph of the inhibitory effect of canagliflozin on glucose uptake by pancreatic cancer cells, Capan-1;

FIG. 13 is a graph of the inhibitory effect of canagliflozin on glucose uptake by pancreatic cancer cells PANC-1;

FIG. 14 is a graph of the inhibitory effect of canagliflozin on lactate release from pancreatic cancer cells, Capan-1;

FIG. 15 is a graph showing the inhibitory effect of canagliflozin on lactate release from pancreatic cancer cells PANC-1.

Detailed Description

The main drugs and reagents used in the experiment:

the other chemical reagents such as sodium chloride, potassium chloride, sodium bicarbonate and the like are all made in China and analyzed and purchased from Nanjing chemical reagent Co.