CN111617075A - Application of canagliflozin in preparation of medicine for treating pancreatic cancer - Google Patents
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- CN111617075A CN111617075A CN202010715100.8A CN202010715100A CN111617075A CN 111617075 A CN111617075 A CN 111617075A CN 202010715100 A CN202010715100 A CN 202010715100A CN 111617075 A CN111617075 A CN 111617075A
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- canagliflozin
- pancreatic cancer
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
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- A—HUMAN NECESSITIES
- 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
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
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- 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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- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
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.
Description
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.
Example 1
Anti-tumor activity of canagliflozin on pancreatic cancer cells:
1. solution preparation
(1) Canagliflozin solution: weighing the canagliflozin bulk drug, dissolving the canagliflozin bulk drug in 1mL DMSO (dimethylsulfoxide) to prepare a mother solution of 80mmol/L, filtering and sterilizing the mother solution through a 0.22 mu m microporous filter membrane, then packaging the mother solution into a plurality of 200 mu L EP tubes, and storing the tubes in a refrigerator at the temperature of-20 ℃ for later use.
(2) DMEM medium: taking DMEM culture medium freeze-dried powder, dissolving in 1L double distilled water, magnetically stirring, adding about 1.6g of sodium bicarbonate, adjusting the pH of the solution to 7.2, filtering and sterilizing through a 0.22 mu m filter membrane in a sterile environment, and storing at 4 ℃ for later use. To the medium was added 10% Gibco fetal bovine serum and 100U/mL penicillin-streptomycin while culturing the cells.
(3) Pancreatin: separately weighing 4.0g NaCl, 0.1g KCl and Na2HPO4·12H2O 1.45g，KH2PO40.1g, dissolving in 400mL double distilled water, adding 0.125g EDTA and 1.25g pancreatin, stirring, fixing the volume to 500mL, filtering and sterilizing by a 0.22 mu m microporous membrane in a sterile environment, and storing at 4 ℃ for later use.
(4) Cell cryopreservation solution: mixing pure fetal calf serum and DMSO uniformly according to the volume ratio of 9:1, and storing in a refrigerator at 4 ℃.
(5) Phosphate Buffered Saline (PBS): KCl 0.2g, NaCl 8.0g and Na were weighed separately2HPO4·12H2O 1.44g，KH2PO40.24g, dissolved in 900mL double distilled water, pH adjusted to 7.4, made to 1L with ultrapure water, filtered to sterilize, and stored in a refrigerator at 4 ℃.
(6) Physiological saline (0.9% NaCl solution): weighing 4.5g of NaCl, dissolving in 500mL of double distilled water, sterilizing by high pressure steam, and storing in a refrigerator at 4 ℃.
(7) MTT solution: weighing 100mg of MTT in dark place, adding 20mL of PBS to prepare a solution of 5mg/mL, stirring for 30min by a magnetic stirrer until the solution is completely dissolved, filtering and sterilizing by a 0.22 mu m filter membrane, subpackaging in 1mL of EP tubes, and freezing in a low-temperature refrigerator at minus 20 ℃ in dark place.
2. Cell culture
(1) Cell resuscitation
Taking out the cell freezing tube frozen in the liquid nitrogen tank, rapidly placing in 37 deg.C water bath to rapidly shake cells, completely dissolving, sucking cell suspension into new culture medium or PBS, centrifuging at 1300rpm for 5min, discarding supernatant, suspending cells with complete cell culture medium, transferring to cell culture dish, and placing in 37 deg.C CO2Culturing in a cell culture box, and observing the growth condition of the cells the next day.
(2) Cell passage
When the adherent cell density is observed to be 80-90% under a microscope, carrying out cell passage: firstly, carefully absorbing cell culture solution in a biological safety cabinet by using a pipette, and adding 1mL of pancreatin to wash away residual culture medium; then 1.5mL of pancreatin is evenly covered on the cell surface, the mixture is kept stand and digested for about 1min, after the cells are observed to retract and become round under a microscope, the pancreatin is sucked off, a complete culture medium is added, and the cells are blown by a pipette and fall off, so that the cells are evenly dispersed. Subpackaging the cell suspension into two new cell culture dishes, adding culture medium respectively until the total volume of the cell suspension is 3mL, marking the date and the cell name, and placing at 37 ℃ with 5% CO2The incubator continues to culture, and the growth condition of the cells is observed the next day.
(3) Cell cryopreservation
When the cell density reaches 80-90%, selecting cells with good growth state for freezing: firstly, preparing a cell cryopreservation solution in a super clean bench; the cell culture medium was aspirated again, and 1mL of pancreatin was added to rinse the cells and discarded. Adding 1.5mL of pancreatin, standing and digesting for about 1min, sucking the pancreatin after the cell morphology is retracted and rounded, and adding a complete culture medium to stop digestion. Blowing cells to drop, uniformly dispersing the cells in a culture solution, transferring the cells into a 10mL EP tube, centrifuging the cells for 5min at 1300rpm, discarding supernatant, adding 1mL cell freezing solution for resuspension and sedimentation, transferring the cell freezing solution into a freezing tube, and marking the date and the cell name. The freezing tube is cooled in a gradient way (5 min at 4 ℃ and 30min at-20 ℃) and finally transferred to a low-temperature refrigerator or a liquid nitrogen tank at-80 ℃.
Detection of cell proliferation by MTT method
Will have a density of 5 × 104Cells per mL were plated evenly in 96-well plates in a super clean bench. CO at 37 deg.C2The cells are cultured in a cell incubator for 24h, and then the cells are grouped and treated with drugs.
Single dosing group: the drug treatment components are respectively added with canagliflozin with different concentrations, so that the final concentrations of the canagliflozin respectively reach 0, 20, 40, 60 and 80 mu M; gemcitabine was added to the positive control group at a final concentration of 0.5. mu.M.
Combination group: two groups of drug treatment groups are set, gemcitabine with different concentrations is added in the two groups, the final concentrations of gemcitabine and gemcitabine respectively reach 0, 0.12, 0.25 and 0.5 mu M, one group of gemcitabine and canagliflozin with the final concentration of 20 mu M are co-administered, and the effect of the two groups of drugs on treating pancreatic cancer cells is compared.
And after the medicine acts for 48 hours, adding 20 mu L of MTT solution into each hole in a dark state, putting the well in an incubator at 37 ℃ for incubation for 4 hours, completely absorbing the culture solution in the hole plate, finally adding 150 mu L of DMSO into each hole, placing the well on a micro-oscillator, slightly shaking the well for 5 minutes, and detecting the absorbance at the wavelength of 490nm by using an enzyme-labeling instrument.
From fig. 1 and 2, it can be seen that canagliflozin has the effect of inhibiting the proliferation and activity of both cells, and the inhibition effect is dose-dependent. The inhibition rate of 40 mu M canagliflozin on the cells of Capan-1 and PANC-1 reaches 33.8 percent and 38.9 percent respectively. Carpagliflozin is indicated to significantly inhibit the growth of pancreatic cancer cells.
It can be seen from FIGS. 3 and 4 that administration of canagliflozin in combination with gemcitabine enhanced the inhibitory effect of gemcitabine alone on pancreatic cancer cells. The inhibition of Capan-1 and PANC-1 cells after treatment with combination 20. mu.M canagliflozin increased from 21.5% and 26.6% to 29.8% and 36.4%, respectively, compared to 0.25. mu.M gemcitabine alone. It is described that the effect of gemcitabine in the inhibition of pancreatic cancer cells is enhanced by combretastatin in combination with gemcitabine.
4. Plate cloning to detect colony formation of cells
After digesting the cells in the logarithmic phase, transferring the cells into an EP tube, uniformly blowing the cells, and taking a small amount of the cells out to a sterilized and dried cell counting plate for observation and counting. After adjusting the cell concentration to 600/mL, the cells were spread evenly in 6-well plates and placed at 37 ℃ in 5% CO2Culturing in an incubator. After 72 hours of culture, canagliflozin was formulated at different concentrations (20 μ M, 40 μ M, 60 μ M) and incubated with the cells while setting a positive control group and a negative control group of 0.5 μ M gemcitabine. After 10 days of drug action, the cell culture plate was removed, the medium was aspirated and discarded, the monolayer of cells was rinsed with PBS, and the rinse was discarded. Adding 4% paraformaldehyde for fixation, standing for 15min, and removing the fixation solution. Adding 1mL of 0.5% crystal violet staining solution into each hole, standing for 15min, sucking out the staining solution, repeatedly washing for 3-5 times by using PBS (phosphate buffer solution) until no background color exists, and shooting a bright-field image.
Referring to fig. 5 and 6, cagelide dose-dependently inhibited colony formation of two pancreatic cancer cells, i.e., decreased cell colony numbers and lighter purple staining. Carpagliflozin is indicated to inhibit the colony formation of pancreatic cancer cells.
5. Scratch test for detecting cell migration
Firstly, uniformly marking transverse lines on the back of a 12-hole plate by using a marker pen with a ruler, crossing the transverse lines approximately every 0.5-1 cm, enabling each hole to pass through at least 2 lines, digesting the Capan-1 cells in a good growth state by using pancreatin, and adding 5 × 10 into each hole of the 12-hole plate5The cells were cultured overnight in a 37 ℃ cell culture chamber. After the cells are fully paved on the pore plate, the gun head is used for comparing with the ruler, the transverse line is scratched as far as possible and is vertical to the back, the cells are washed for 3 times by PBS, the scratched cells are washed off, and a serum-free culture medium is added. The cell culture plate was placed at 37 ℃ in 5% CO2An incubator is arranged in the culture box,and (5) culturing. The plates were photographed under a light microscope at 0, 24 and 48h after the administration of the treatment.
Referring to FIG. 7, 24h and 48h cell pictures were taken after the Capan-1 cells were treated with canagliflozin, and it can be seen that the migration capacity of tumor cells is continuously reduced with the increase of the administration concentration of canagliflozin. Over time, the effect of 60 μ M canagliflozin on inhibiting migration of cells was very significant compared to the control group. Carpagliflozin is indicated to inhibit the migration of pancreatic cancer cells.
6. Detection of apoptosis by flow cytometry
Pancreatic cancer cells in logarithmic growth phase at a density of 2 × 105Spreading in 12-well plate at 37 deg.C with 5% CO2Culturing in an incubator, after the cells adhere to the wall, adding canagliflozin to enable the final concentration of the medicine to be 20 muM, 40 muM and 60 muM, simultaneously setting a negative control group and a positive medicine group (0.5 muM GEM), culturing for 48 hours, digesting the cells by pancreatin without EDTA for about 5 minutes, stopping digestion, collecting the cells in a 10mL EP tube, centrifuging for 5 minutes at 1300rpm and 4 ℃, discarding the supernatant, adding precooled PBS, washing the cells twice, centrifuging for 5 minutes at 1300rpm and 4 ℃ each time, discarding the supernatant, adding 100 muL 1 × Bindingbuffer, lightly blowing the cells uniformly to a single cell suspension, transferring the single cell suspension to a flow tube, adding 5 muL Annexin V-FITC and 5 muL dyeing Solution, lightly blowing uniformly, incubating for 10 minutes at a dark room temperature (20-25 ℃), adding 400 muL 1 × Bindingbuffer, lightly mixing the cells uniformly, and detecting the dyed samples in a flow cytometer within 1 hour.
As shown in figure 8, after 60 μ M canagliflozin treatment, the apoptosis rates of the Capan-1 and PANC-1 cells (early apoptosis) are obviously improved compared with the Control group, and respectively reach 13.1% and 12.0%. However, the late apoptosis rate of PANC-1 cells was more pronounced than that of Capan-1 cells, indicating that PANC-1 cells may be more sensitive to canagliflozin than that of Capan-1 cells. From the aspect of the total apoptosis rate, the total apoptosis rate of the Capan-1 and PANC-1 cells is increased in a dose-dependent manner, and in the 40 mu M canagliflozin treatment group, the apoptosis rate of the Capan-1 cells reaches 18.4%, while the GEM treatment group is only 14.2%. The data are combined to show that canagliflozin can obviously induce the apoptosis of pancreatic cancer cells.
Thus, it can be seen from example 1 that canagliflozin in the present invention inhibits the growth, proliferation, migration and induction of apoptosis of pancreatic cancer cells; and the effect of gemcitabine on inhibiting pancreatic cancer cells can be enhanced when the gemcitabine is used together with gemcitabine.
Example 2
Antitumor activity of canagliflozin against pancreatic cancer bearing mice:
1. establishment of pancreatic cancer PANC-1 tumor-bearing mouse transplantation tumor model
Balb/c male mice are all raised in an animal experiment center of Chinese pharmaceutical university with the temperature of 22 +/-1 ℃ and the illumination of 12 hours per day, sufficient food and water are provided, the animal experiment operation follows the animal ethics committee of Chinese pharmaceutical university, the PANC-1 cells with good growth state and logarithmic growth phase are taken, the cells are digested, the cells are washed for 3 times by physiological saline, the culture medium remained on the surfaces of the cells is washed, the physiological saline is added, the suspension is uniform, the density of the PANC-1 cells is adjusted to 6 × 10 by counting6one/mL. Injecting 100 mu L of cell suspension into the armpit of each nude mouse, and after one week, growing the tumor to about 80-100 mm3At this time, Balb/c male nude mice were randomly divided into 6 groups of 5 mice each, which were set as model groups, low, medium, high (25mg/kg, 50mg/kg and 100mg/kg) and positive drug treatment groups, respectively, and treatment with drugs (canagliflozin and gemcitabine) was started.
2. Administration method for tumor-bearing mice
The model group injects normal saline into the abdominal cavity of each nude mouse every day; each nude mouse of the canagliflozin treatment group is subjected to intragastric administration to obtain canagliflozin suspension, and the drug concentration is respectively set to be 25mg/kg, 50mg/kg and 100 mg/kg; gemcitabine is injected into the abdominal cavity of each nude mouse of the positive drug group, and the drug is administered twice a week at the drug concentration of 10 mg/kg. The tumor volume and the weight of the nude mice were measured every two days using a vernier caliper, and the drug dose was calculated from the weight of the nude mice and administered with drug treatment. After 24h of the last administration, the mice were weighed and sacrificed by removing their necks, dissected and the tumors were removed, photographed, and placed in 10% formalin fixation or low temperature refrigerator at-80 ℃ for subsequent experiments. The calculation method of the tumor volume and the tumor inhibition rate is as follows:
The tumor inhibition rate was (1-a/B) × 100%, a represents the average tumor weight of the nude mice in the administration group, and B represents the average tumor weight of the nude mice in the model group.
Referring to fig. 9 and 10, the tumor volume of the canagliflozin group was significantly smaller than that of the control group, and the tumor inhibition rates were 20.7%, 29.4% and 45.1% at the doses of 25, 50 and 100mg/kg, respectively, while canagliflozin inhibited the tumor volume in a dose-dependent manner. Therefore, we can conclude that canagliflozin inhibits the growth of pancreatic cancer PANC-1 tumors in vivo.
Referring to fig. 11, body weights of nude mice were measured every other day during the administration period, and after four weeks of administration, the body weight of the canagliflozin-treated group was maintained at around 22g, while the body weight of mice in the gemcitabine-treated group was significantly reduced to 17g, indicating that the toxicity of canagliflozin was significantly lower than that of the positive drug gemcitabine. Indicating that the toxicity of the drug canagliflozin is very low.
Thus, as can be seen from example 2, canagliflozin was also able to inhibit the growth of pancreatic cancer PANC-1 tumors in mice, consistent with in vitro results and the drug canagliflozin was less toxic.
Example 3
A related study of canagliflozin inhibition of pancreatic cancer cell glycolysis:
1. glucose uptake assay
The glucose content was detected by a glucose kit. The experimental principle is as follows: glucose in a sample can be oxidized into gluconic acid and hydrogen peroxide by glucose oxidase, and the hydrogen peroxide can couple and condense the reducing 4-aminoantipyrine and phenol to form a quinone compound which can be measured by a spectrophotometer under the catalytic action of peroxidase. Placing the culture plate with the well-paved cells in an incubator for culture, adding canagliflozin for treatment after the cells adhere to the wall, respectively sucking cell supernatants at 6h, 12h and 24h after administration, adding a working solution for full mixing, placing the sample tubes in a spectrophotometer with the OD value adjusted to be 505nm wavelength, measuring the absorbance value of each sample tube, and finally recording data and processing the result.
As shown in FIGS. 12 and 13, the glucose uptake rates (60. mu.M canagliflozin) of the Capan-1 and PANC-1 cells after canagliflozin treatment were reduced by 4.8% and 4.9%, respectively, compared to the Control group. Carpagliflozin is indicated to inhibit glucose uptake by pancreatic cancer cells.
2. Lactic acid Release test
The content of lactic acid is detected by a lactic acid content kit. The experimental principle is as follows: the lactic acid generates pyruvic acid under the action of lactate dehydrogenase and makes NAD+Reduction to NADH and H+，H+The MTT is reduced by PMSH2 transferred to PMS to generate a purple substance, and a characteristic absorption peak is generated at 570 nm. After pancreatic cancer cells are subjected to adherent administration, cell supernatants are respectively sucked 6h, 12h and 24h after administration, after a working solution is added, the EP tubes are fully and uniformly mixed, the sample tubes are placed into a spectrophotometer with the OD value adjusted to be 530nm wavelength, the absorbance value of each sample tube is measured, and finally, data are recorded and the result is processed.
The results, as shown in FIGS. 14 and 15, indicate that the lactate release rates of Capan-1 and PANC-1 cells after the canagliflozin treatment were reduced by 25.5% and 43.4%, respectively. Carpagliflozin is indicated to inhibit lactate release from pancreatic cancer cells.
Thus, it can be seen from example 3 that canagliflozin inhibits the growth of pancreatic cancer cells by inhibiting their glycolysis.
Claims (5)
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.
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