CN117159578A - Application of oleanolic acid and gemcitabine in preparation of pancreatic cancer drugs - Google Patents
Application of oleanolic acid and gemcitabine in preparation of pancreatic cancer drugs Download PDFInfo
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- CN117159578A CN117159578A CN202311315781.9A CN202311315781A CN117159578A CN 117159578 A CN117159578 A CN 117159578A CN 202311315781 A CN202311315781 A CN 202311315781A CN 117159578 A CN117159578 A CN 117159578A
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- Prior art keywords
- gemcitabine
- pancreatic cancer
- oleanolic acid
- cells
- gem
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- YBRJHZPWOMJYKQ-UHFFFAOYSA-N Oleanolic acid Natural products CC1(C)CC2C3=CCC4C5(C)CCC(O)C(C)(C)C5CCC4(C)C3(C)CCC2(C1)C(=O)O YBRJHZPWOMJYKQ-UHFFFAOYSA-N 0.000 title claims abstract description 51
- MIJYXULNPSFWEK-UHFFFAOYSA-N Oleanolinsaeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C)(C)CC5C4=CCC3C21C MIJYXULNPSFWEK-UHFFFAOYSA-N 0.000 title claims abstract description 51
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of oleanolic acid and gemcitabine in preparation of pancreatic cancer drugs, and relates to the technical field of biological medicines. The invention provides a pancreatic cancer therapeutic drug comprising oleanolic acid and gemcitabine, which are used together in pancreatic cancer drugs. The invention uses oleanolic acid and gemcitabine together in pancreatic cancer treatment, weakens adverse reaction caused by long-term administration of gemcitabine, avoids damage to viscera, enhances the sensitivity of gemcitabine, reduces side effects, and improves prognosis quality and physiological condition of patients with medium and late pancreatic cancer.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of oleanolic acid and gemcitabine in preparation of pancreatic cancer drugs.
Background
Pancreatic cancer is a malignant tumor mainly originating from pancreatic duct epithelium and acinar cells, is one of relatively common digestive tract malignant tumors in clinic, the incidence rate of the malignant tumor always shows a trend of rising year by year, the early stage of the malignant tumor is hidden, more than 80% of patients are middle and late stages in diagnosis, the optimal stage of surgical treatment is missed, the death rate of the malignant tumor is relatively high, and the survival rate of five years after diagnosis is only about 5%. Experts predict that pancreatic cancer is or will be the second leading cause of cancer-related death worldwide in 2030. The clinical first-line medicine recommended by the "guidelines for integrated diagnosis and treatment of pancreatic cancer of China anticancer Association" is mainly chemotherapy medicine, fluorouracil (5-FU, capecitabine, tegafur), gemcitabine, platinum (cisplatin, oxaliplatin), irinotecan (irinotecan, liposomal irinotecan), albumin-bonded taxol and the like. In addition, gemcitabine is the most widely used chemotherapeutic drug for the treatment of patients with middle and advanced pancreatic cancer. Gemcitabine (Gemcitabine, GEM) as an anticancer drug of a difluoro nucleoside antimetabolite that disrupts cell replication can inhibit pancreatic cancer cell proliferation by substituting cytidine and blocking the biosynthesis of deoxyribonucleotides during DNA replication. Although the GEM single drug has ideal effect of treating advanced pancreatic cancer, the clinical symptoms of patients caused by exocrine pancreatic insufficiency can be effectively improved, and the survival time of the patients can be prolonged. Ji Xita is a mainstream therapeutic drug for patients with advanced pancreatic cancer, but has strong toxicity as a chemotherapeutic drug, and many adverse reactions and even damage to viscera can occur when the patients take the drug for a long time. It has been reported previously that GEM treated rats have significantly elevated total bilirubin levels and significantly reduced total protein, albumin and globulin levels compared to normal rats, indicating hepatocyte or bile duct damage and significantly reduced liver synthesis, indicating drug-induced hepatotoxicity (Green and Flamm, 2002). In clinical application, GEM can generate drug resistance besides adverse reactions caused by toxic and side effects of drugs. The easy generation of drug resistance is one of the problems which are difficult to solve, so that the search for a new drug and GEM are used in combination to enhance the sensitivity of the GEM and reduce the side effects, and the drug has important significance for improving the prognosis quality and the physiological condition of patients with medium and advanced pancreatic cancer. Oleanolic Acid (OA) as a natural compound widely exists in various plants in nature, has the advantages of abundant storage, simple extraction and preparation, small adverse reaction, and various biological activities, and thus has wide application prospects. One of the most remarkable pharmacological actions of oleanolic acid and its derivatives is a broad liver protection action, and oleanolic acid and its derivatives are therefore also popular over-the-counter supplements and alternatives in Chinese pharmacies for the treatment of liver diseases, inflammatory diseases, diabetes and malignant diseases. In recent years, it has been found that OA has an antitumor effect. Along with the continuous and deep pharmacological research, it is found that OA can act on multiple stages of tumorigenesis, such as preventing tumor induction, inhibiting tumor formation and inducing tumor cell differentiation, and simultaneously can effectively inhibit tumor angiogenesis, migration and invasion of tumor cells. Aldehyde ketone reductase family 1B10 (Aldo-keto reductase family 1,member B10,AKR1B10) belongs to one of the members of the AKR1 family of Aldehyde Ketone Reductase Superfamilies (AKRs). AKR1B10 protein was originally isolated from hepatocellular carcinoma, and studies have now found that AKR1B10 is highly expressed in a variety of tumors, and may be involved in a variety of biological processes in different organisms, such as carbonyl detoxification, hormone metabolism, lipid synthesis, tumor development and treatment, etc. AKR1B10 has been reported to be highly expressed in pancreatic cancer and is associated with poor patient prognosis. Although studies have been made to clarify the effect of both GEM and OA alone in the treatment of pancreatic cancer, the killing effect and mechanism of action of the combination of the two drugs on pancreatic cancer cells have not been reported yet.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide an application of oleanolic acid and gemcitabine in preparing pancreatic cancer drugs, wherein the oleanolic acid and the gemcitabine are used in pancreatic cancer treatment together, so that adverse reactions caused by long-term administration of the gemcitabine are weakened, damage to organs is avoided, sensitivity of the gemcitabine is enhanced, side effects are reduced, and prognosis quality and physiological conditions of middle and late pancreatic cancer patients are improved.
The technical scheme for solving the technical problems is as follows: provides an application of oleanolic acid and gemcitabine in preparing pancreatic cancer drugs.
Further, the molar ratio of oleanolic acid to gemcitabine is 200-300:1.
Further, the molar ratio of oleanolic acid to gemcitabine is 250:1.
A pancreatic cancer therapeutic agent comprising oleanolic acid and gemcitabine as described above.
Further, oleanolic acid and gemcitabine concentrations are 15-25. Mu.M and 120-130nM, respectively.
Further, oleanolic acid and gemcitabine concentrations were 20. Mu.M and 128nM, respectively.
The invention has the following beneficial effects:
1. the invention uses oleanolic acid and gemcitabine together in pancreatic cancer treatment medicaments, weakens adverse reactions caused by long-term administration of gemcitabine, avoids damage to organs, enhances the sensitivity of GEM, reduces side effects, and improves the prognosis quality and physiological condition of patients suffering from medium and late pancreatic cancer.
2. In the invention, the OA combined GEM not only can obviously inhibit the growth of human metastatic pancreatic cancer cells AsPc-1, but also can obviously enhance the effect of the GEM on inducing tumor cell apoptosis. CCK-8 cell proliferation experiments prove that the value of the combined therapeutic index CI (Cooperativity Index) of the OA combined GEM is smaller than 1, and the OA combined GEM is suggested to have a synergistic effect in treating pancreatic cancer. Through flow cytometry experiments, the OA and GEM combined application is found, the apoptosis level of pancreatic cancer cells is enhanced, and the application potential of the combined administration mode in treating pancreatic cancer is suggested. In addition, when being used together with GEM, the OA is used as a natural medicine for protecting liver, and plays a role of resisting liver toxicity and liver injury under the condition of low concentration, so that toxic and side effects caused by using the GEM in the treatment process are reduced.
3. The invention finds that AKR1B10 is highly expressed in pancreatic cancer through biological database analysis and is related to poor prognosis of patients. The current research shows that AKR1B10 is over-expressed in malignant tumors such as lung cancer, breast cancer and the like, can promote proliferation and migration of the tumors, and is related to drug resistance of the tumors. It has been reported that oleanolic acid can inhibit the expression of AKR1B10, which is also confirmed by Western blot experiments in the present invention. Under the condition of the same curative effect proved by CCK-8 proliferation experiments, the IC50 of the gemcitabine of the combined administration group is obviously reduced, which suggests that the use of oleanolic acid enhances the sensitivity of pancreatic cancer cells to the gemcitabine. Flow cytometry experiments prove that the oleanolic acid and gemcitabine combined can promote apoptosis of AsPc-1 cells, and has synergistic pancreatic cancer resisting effect. The pharmaceutical composition reduces the drug resistance of pancreatic cancer cells, thereby achieving the purpose of treating pancreatic cancer; in addition, the toxic and side effects possibly caused by using the chemotherapeutic drugs are reduced, and the compliance and the medication safety of patients are improved.
Drawings
FIG. 1 is a graph showing the results of single administration of OA and GEM to AsPc-1 cells;
FIG. 2 shows the effect of OA in combination with GEM on AsPc-1 cell proliferation;
FIG. 3 is a schematic diagram of TCGA database analysis and Western blot experiment results;
FIG. 4 shows the effect of OA in combination with GEM on the apoptosis level of human metastatic pancreatic adenocarcinoma cells AsPc-1.
Detailed Description
The principles and features of the present invention are described below with examples given for the purpose of illustration only and are not intended to limit the scope of the invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1 CCK-8 experiment cell proliferation experiment
1. Reagent(s)
(1) Oleanolic Acid (C) 30 H 48 O 3 Molecular weight: 456.7 Purchased from seleck reagent company (cat No.: s2334), white powder, 99.88% purity, use pre-dimethyl sulfone (DMSO) to formulate the drug as a 10mM stock solutionPreserving at-80deg.C. Gemcitabine hydrochloride (Gemcitabine HCl) powder was purchased from Selleck reagent company (cat# S1149) and was prepared as a 5mM stock solution with dimethyl sulfoxide (DMSO) prior to use and stored at-80 ℃. All reagents were formulated at the desired concentrations in RPMI1640 medium containing 10% fetal bovine serum just prior to use.
(2) Cell culture reagent
(1) Culture solution: RPMI1640 medium, available from GIBCO company, was used as the culture medium, and 100U/ml penicillin streptomycin mixed solution was added
(2) Fetal bovine serum: exCell Co., ltd
(3) PBS buffer: punuocele company product
(3) Cell growth activity inhibition detection related reagent
CCK-8 kit: soy reagent company (goods number CA 1210)
(4) Cell strain
Human metastatic pancreatic adenocarcinoma cells AsPc-1: china Shanghai department of science cell platform
2. Experimental method
CCK-8kit is a detection kit containing a WST-8 (chemical name: 2- (2-methoxy-4-nitrophenyl) -3- (4-nitrophenyl) -5- (2, 4-disulfophenyl) -2H-tetrazolium monosodium salt) compound for detecting cell proliferation. The principle of action is that some dehydrogenase in cell mitochondria is reduced into orange yellow Formazan (Formazan) with high water solubility under the action of an electron coupling reagent. The faster the cell proliferates, the more Formazan is produced, the darker the color. The light absorption value is measured at the wavelength of 450nm by using an enzyme-labeled instrument, and the number of living cells can be indirectly reflected. Culturing cells in 96-well ELISA plates according to proper cell density, wherein the cell volume in each well is 200 mu L, sucking the culture medium when the cells are attached and the fusion degree reaches 50%, and adding 200 mu L of OA and GEM with specified concentrations; placing the cells subjected to the drug administration into a incubator for culturing for 48 hours, and adding a culture medium CCK8 mixed solution (the volume ratio of the two is 10:1) into each hole; after a further incubation time of 2h, 65. Mu.L of the supernatant was pipetted onto a new 96-well plate and its absorbance was measured using a wavelength of 450 nm.
3. Experimental results
The experimental results are shown in FIGS. 1-2. In fig. 2, p <0.05, p <0.01, and p <0.001.
As can be seen from FIG. 1, the CCK-8 assay detects IC 48h after OA treatment of AsPc-1 cells 50 A value of 36.21. Mu.M; IC after GEM treatment of AsPc-1 cells for 48h 50 The value was 127.38nM.
As can be seen from FIG. 2, GEM alone significantly inhibited the growth of AsPc-1 cells and was concentration dependent, and GEM alone acted for 48h 50 157.58nM; OA alone inhibited AsPc-1 cell growth, and also had concentration dependence, GEM alone acted for 48h 50 34.89. Mu.M; the molar ratio of OA to GEM was chosen to be 250:1 to treat AsPc-1 cells in combination with GEM IC in the group 50 87.0. Mu.M; the combination of the hints and the OA can obviously improve the growth inhibition effect of GEM on AsPc-1 cells.
Example 2 biological database analysis and Western blot experiments
1. Reagent(s)
(1) OA and cell culture reagents are the same as in example 1
(2) Western blot experiment reagent
(1) Western and IP cell lysate: biyundian company product (goods number: P0013J);
(2) 5x protein loading buffer (DTT containing): soy Corp (cat number: P1040);
(3) 30% acr-Bis gel formulation reagent: biosharp company product (cat# BL 513B);
(4) 1.5M Tris-HCl buffer (pH=8.8): soy Corp product (product number: T1010);
(5) 1M Tris-HCL buffer (ph=6.8): soy Corp product (goods number: T1020);
(6) TEMED: biyundian corporation product (goods number: ST 728);
(7) ammonium persulfate powder: biyundian company product (goods number: ST 005);
(8) hypersensitivity ECL chemiluminescent kit: biosharp company product (cat# BL 523A).
(3) Cell lines were as in example 1
2. Experimental method
(1) Biological database analysis
The correlation of pancreatic cancer patient survival curves, cancer stage, tissue transcriptome and AKR1B10 expression levels was analyzed by GEPIA (http:// GEPIA. Cancer-pku. Cn /).
(2) Western blot experiment
(1) Cell treatment and sample preparation: culturing cells in a 6-well plate according to proper density, sucking the culture medium after the cells are attached and the fusion degree reaches 90%, and adding 2mL of OA with the concentration of 0 mu M, 50 mu M and 100 mu M respectively; continuously placing the dosed cells in an incubator for culturing for 48 hours, adding 100-300 mu L of cell lysate, scraping the cells, collecting the cells into a 1.5mL centrifuge tube, performing ultrasonic crushing, and performing ice lysis for 30 minutes; the lysed cells were centrifuged at 12000rpm at 4℃for 15min, and the protein supernatant was collected and assayed for protein concentration to prepare samples.
(2) Preparation of SDS-PAGE gel
The separating gel is added into the glass plate, about 1/4 space is left, and absolute ethyl alcohol is used for carrying out liquid seal flattening. After 40min, the absolute ethyl alcohol is poured out, the prepared concentrated gel is added into the residual space of the glass plate, and the sample feeding comb is inserted into the concentrated gel to wait for solidification, thus obtaining the prepared SDS-PAGE gel.
(3) Protein loading and electrophoresis
And calculating the loading quantity before loading, and ensuring the consistent loading quality. The Marker and the protein sample are respectively added into the hole of SDS-PAGE gel, enough electrophoresis buffer solution is added, the voltage is firstly adjusted to 80mV, and the pressure is increased to 120mV until the end after the Marker runs to the separation gel.
(4) Transfer film
And after electrophoresis, placing the gel sample and the PVDF film into an electrotransfer solution together, wherein the PVDF film is firstly placed into methanol for soaking for 15s for activation, placing the gel sample and the PVDF film into a film transfer clamp in sequence, placing into an electrotransfer box for film transfer, and carrying out film transfer for 90min at a constant current of 200 mA.
(5) Antibody blocking
The membrane was washed with 1 XTBST, washed on a shaker for 2 minutes, and the PVDF membrane was placed in 5% nonfat milk powder and shaken on the shaker for 1 hour. The primary antibody was prepared in advance, and the membrane was cut into strips according to the size of the target protein, and the PVDF membrane was incubated with the primary antibody and placed on a shaker overnight. The next day, primary antibodies were recovered and the strips were washed 4 times with 1 XTBE for 6min each; then incubated with the corresponding secondary antibody for 1h. The secondary antibody was recovered and washed with 1 XTBE 4 times for 6min each.
(6) ECL chemical development
Preparing ECL luminous liquid and opening a gel imaging system; spreading a PVDF film in a gel imager, uniformly dripping ECL luminous liquid on the PVDF film, then performing image exposure by using a gel imaging system, and quantifying and analyzing the obtained picture result by using imageJ software.
3. Experimental results
The experimental results are shown in FIG. 3. In fig. 3, p <0.05, p <0.01, and p <0.001 are represented.
As can be seen from fig. 3, the high expression of AKR1B10 was associated with poor prognosis of human pancreatic cancer patients as analyzed by TCGA database, the expression level increased with the prolongation of cancer stage, and the expression level of AKR1B10 in normal pancreatic tissue was significantly lower than that in pancreatic cancer tissue; the WB results show that OA has an inhibitory effect on the expression of AKR1B10 in AsPc-1 cells and is concentration-dependent.
Example 3 apoptosis experiments
1. Reagent(s)
(1) Cell culture reagent as in example 1
(2) Apoptosis detection-related reagents
Annexin V-FITC/PI apoptosis detection kit: next san francisco (commodity number 40302ES 50).
2. Experimental method
Cells were cultured in 6-well plates at appropriate density, and after the cells had adhered to the walls and reached a confluence of 90%, the medium was aspirated off, and 2mL of OA at the indicated concentration of 20 μm and GEM at 80nM were added; placing the cells after administration in an incubator for culturing for 48 hours, digesting with pancreatin without EDTA, centrifuging at 1000rpm and 4 ℃ for 5min, and collecting the cells; the cells were washed 2 times with pre-chilled PBS, each time with 1000rpm, and centrifuged at 4℃for 5min. Collecting 1-5×10 5 cells; the PBS was pipetted off and 100. Mu.L of 1 Xbinding Buffer was added to resuspend the cells; add 5. Mu.L Annexin V-FITC and 10. Mu. LPI Staining Solution and mix gently; light-shielding and reacting at room temperature for 10-15min; 400 μL of 1 Xbinding Buffer was added, mixed well and placed on ice, and the sample was examined with a flow cytometer or fluorescence microscope over 1 hour.
3. Experimental results
The experimental results are shown in FIG. 4. In fig. 4, p <0.05, p <0.01, and p <0.001.
As can be seen from fig. 4, the apoptosis level of the combination group was significantly higher than that of the control group and the single group, suggesting that the combination OA can significantly increase the apoptosis level of GEM-induced AsPc-1 cells.
In conclusion, experiments prove that the oleanolic acid and difluoro nucleoside antimetabolite anticancer drug gemcitabine can not only enhance the inhibition effect of gemcitabine on pancreatic cancer cells, but also reduce the toxic and side effects of liver injury caused in the treatment process of gemcitabine, and can be applied to the preparation of medicaments for treating pancreatic cancer.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (6)
1. Application of oleanolic acid and gemcitabine in preparing pancreatic cancer drugs.
2. The use of claim 1, wherein the molar ratio of oleanolic acid to gemcitabine is 200-300:1.
3. The use according to claim 1 or 2, wherein the molar ratio of oleanolic acid to gemcitabine is 250:1.
4. A pancreatic cancer therapeutic agent comprising oleanolic acid and gemcitabine according to any one of claims 1-3.
5. The pancreatic cancer therapeutic agent of claim 4, wherein said oleanolic acid and gemcitabine concentrations are 15-25 μm and 120-130nM, respectively.
6. The pancreatic cancer therapeutic agent of claim 4 or 5, wherein said oleanolic acid and gemcitabine concentrations are 20 μm and 128nM, respectively.
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