CN116392521A - Application of acteoside combined anticancer therapeutic agent in medicine and pharmaceutical composition - Google Patents
Application of acteoside combined anticancer therapeutic agent in medicine and pharmaceutical composition Download PDFInfo
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- CN116392521A CN116392521A CN202310504061.0A CN202310504061A CN116392521A CN 116392521 A CN116392521 A CN 116392521A CN 202310504061 A CN202310504061 A CN 202310504061A CN 116392521 A CN116392521 A CN 116392521A
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- acteoside
- oxaliplatin
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Abstract
The invention belongs to the technical field of biological medicines, and relates to application of a acteoside combined anticancer therapeutic agent in medicines and a pharmaceutical composition. The invention aims to solve the problems, and by adopting an HCC cell strain and a tumor-bearing nude mouse model, the synergistic and attenuation bidirectional regulation effects of the acteoside on the HCC are comprehensively evaluated by technical means such as pharmacodynamics, pharmacology, molecular biology and the like, and the acteoside is definitely the main pharmacodynamic substance basis of cistanche deserticola for preventing and treating the HCC.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to application of a acteoside combined anticancer therapeutic agent in medicines and a pharmaceutical composition.
Background
Hepatocellular carcinoma (hepatocellular carcinoma, HCC) is a common malignancy of the digestive tract, with global mortality being the third leading point. The PLC mainly comprises three different pathological types of hepatocellular carcinoma (HCC), intrahepatic bile duct carcinoma (ICC) and HCC-ICC mixture, wherein HCC accounts for more than 85% -90%. HCC onset is a multi-factor, multi-step, complex process, mainly associated with hepatitis b and/or c virus infection, alcoholic and non-alcoholic cirrhosis, food contamination with aflatoxin, type ii diabetes, obesity and smoking, among which hepatitis b and c are the two most common important risk factors leading to HCC onset in our country. Currently, in many developing countries, the incidence of liver cancer is still on a continuous rise, resulting in huge psychological and economic burden on vast numbers of liver cancer patients.
The treatment of patients with advanced stage HCC is mainly systemic antitumor, wherein the chemotherapy regimen containing platinum drugs is the first choice, aiming at controlling tumor progression and improving patient prognosis. The national and foreign authoritative clinical guidelines such as the national primary liver cancer diagnosis and treatment guideline (2022 edition) indicate that the FOLFOX4 regimen based on Oxaliplatin (OXA) is a first-line chemotherapy regimen for patients with intermediate and late stage HCC. Oxaliplatin is used as a 3 rd generation platinum anti-tumor drug, compared with cisplatin and carboplatin, the drug effect and the safety are greatly improved, and the drug has no cross drug resistance. With the widespread use of oxaliplatin, it has been found that oxaliplatin has low sensitivity to HCC and high incidence of toxic and side effects, compared with other tumors, limiting the effective implementation of chemotherapy regimens, and has become a bottleneck problem to be solved in the field of HCC treatment.
In clinical applications, adverse reactions common to oxaliplatin are gastrointestinal reactions (diarrhea, nausea, vomiting, etc.), blood system toxicity (neutrophil, thrombocytopenia, etc.), peripheral nervous system toxicity, liver and kidney dysfunction, etc. The main purpose of the synergistic attenuation strategy is to improve the treatment effect of tumors, prolong the long-term survival time of patients and reduce the toxic and side effects of chemotherapy. Compared with the 'synergy' type study, the 'attenuation' focusing type study is less, and the method is worthy of deep exploration and analysis. In recent years, research shows that the combination of the traditional Chinese medicine compound preparation (ginseng and astragalus strengthening body resistance, pagodatree ear particles, cinobufagin, elemene and the like), single traditional Chinese medicines (astragalus, bighead atractylodes rhizome, curcuma zedoary, medlar and the like) and the traditional Chinese medicine monomer components (ginsenoside Rg3, sinomenine, ligustrazine and the like) with the chemotherapeutic drugs has the effects of improving the anti-tumor curative effect or relieving the adverse reaction of the chemotherapeutic drugs. Therefore, by means of the synergistic attenuation strategy, chemotherapeutic drug synergists such as oxaliplatin and the like are inherited and discovered from traditional Chinese medicines, and are highly matched with the integral view and the dialectical treatment of the traditional Chinese medicine theory, so that the synergistic attenuation strategy becomes the necessary trend of constructing an HCC control system.
Cistanche is a dry fleshy stem of cistanche deserticola Cistanches deserticola Y.C.Ma or cistanche tubulosa Cistanche tubulosa (Schenk) Wight of Orobanchaceae, and is listed as an upper-grade product by Shennong herbal Jing as a well-known tonic traditional Chinese medicine, and has the effects of tonifying kidney yang, replenishing essence and blood, relaxing bowel and the like. Modern pharmacological researches show that cistanche deserticola has various biological activities of protecting liver, resisting oxidation and aging, relieving physical fatigue and the like. The traditional Chinese medicine basic theory holds that HCC belongs to liver accumulation, clinically HCC patients mostly show deficiency of healthy qi and deficiency of qi and blood, and the main treatment principle is strengthening body resistance and consolidating constitution, dredging and hiding blood. Oxaliplatin is cold and cool, and can damage spleen and stomach after long-term application, so that qi and blood are biochemically used as a source of deficiency, thereby causing kidney deficiency and blood stasis, and the induced peripheral neurotoxicity belongs to the category of 'blood arthralgia' and 'arthromyodynia' in traditional Chinese medicine, and the pathogenesis is deficiency of vital qi, cold congealed pulse, and the clinically adopted treatment method aims at the toxicity mainly for activating blood circulation to remove blood stasis and warming channels and dredging collaterals. Thus, cistanche deserticola is taken as a classical tonic traditional Chinese medicine, and has the effects of tonifying liver and qi, warming kidney and tonifying yang, nourishing yin and enriching blood by combining both principal and subordinate symptoms and medicinal food homology, and is combined with the basic treatment principle of traditional Chinese medicine for preventing and treating HCC and the treatment method of oxaliplatin peripheral neurotoxicity.
Acteoside (ACT) is used as main active ingredient of cistanche phenylethanoid glycosides, is an effective protein kinase C inhibitor, and has various pharmacological activities such as anti-tumor, liver and kidney protecting, antioxidant and antiinflammatory effects. In recent years, researches on prevention and treatment of HCC by using cistanche phenylethanol total glycosides and acteoside have been as follows: (1) Clinical experiments show that the traditional prescription taking cistanche deserticola as a monarch drug has the advantages of reducing the neurotoxicity of oxaliplatin and improving the survival quality in the process of assisting oxaliplatin to treat digestive tract tumors. (2) Animal experiments show that the tumor growth of the nude mice of each administration group of cistanche phenylethanol total glycosides is inhibited, the alpha fetoprotein content is reduced, and the immunity is improved; (3) In vitro research shows that the cistanche phenylethanol total glycosides can inhibit the growth of H22 cells; the acteoside regulates and controls proliferation, apoptosis, oxidative stress or autophagy of tumor cells through STAT-3 or JNK signal channels, and plays a role in preventing and treating HCC; in addition, acteoside can play a role in protecting liver by antagonizing hepatitis B virus, which is a high risk factor for HCC. In conclusion, the potential of the acteoside for treating the HCC is huge, but no research on the prevention and treatment of the HCC by combining the acteoside and oxaliplatin from the aspect of 'synergism and attenuation' is seen so far.
Aiming at HCC, a drug which can generate a synergistic effect with oxaliplatin is sought, the clinical application range of oxaliplatin is expanded, the clinical application of platinum drugs in HCC treatment is improved, and the drug has important value.
Disclosure of Invention
In view of the above-mentioned drawbacks of the prior art, the present invention aims to provide an application of cistanche deserticola combined oxaliplatin in preparing a medicament for treating liver cancer and an application of acteoside or a pharmaceutically acceptable salt thereof in preparing a medicament for treating cancer, which are used for solving the problems of low sensitivity and high toxic and side effects of platinum drugs in the aspect of HCC treatment in the prior art. Meanwhile, the invention also provides a pharmaceutical composition or a combination pharmaceutical composition.
To achieve the above-mentioned objects and other related objects,
the invention provides an application of cistanche deserticola combined oxaliplatin in preparing a medicine for treating liver cancer.
In an embodiment of the invention, the cistanche extract and oxaliplatin are combined for preparing a medicament for treating liver cancer.
In a second aspect, the invention provides the use of a acteoside or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cancer.
In one embodiment of the present invention, the use of the acteoside or a pharmaceutically acceptable salt thereof in combination with an anticancer therapeutic agent for the preparation of a medicament for the treatment of cancer.
In an embodiment of the invention, the cancer is at least one selected from liver cancer, lung cancer, pancreatic cancer, breast cancer, colorectal cancer or lymphoma;
the anticancer therapeutic agent is at least one selected from platinum drugs, alkylating agents, topoisomerase inhibitors, taxol, antitumor antibiotics, plant alkaloids, nucleoside analogues, DNA damage repair inhibitors and immune checkpoint inhibitors;
preferably, the platinum-based drug is selected from cisplatin, carboplatin, oxaliplatin and satraplatin.
In one embodiment of the present invention, the use of the acteoside or a pharmaceutically acceptable salt thereof in combination with oxaliplatin for the preparation of a medicament for the treatment of cancer.
In an embodiment of the invention, the acteoside or the pharmaceutically acceptable salt thereof is combined with oxaliplatin for preparing the medicine for treating liver cancer.
In one embodiment of the present invention, the daily dose of the herba cistanches acteoside or the pharmaceutically acceptable salt thereof is 2-10 mg/kg.
In a third aspect of the invention, there is provided a pharmaceutical composition or combination comprising:
cistanche deserticola;
oxaliplatin.
In a fourth aspect of the invention, there is provided a pharmaceutical composition or combination comprising:
acteoside;
the anticancer therapeutic agent.
As the optimization of the technical scheme, the herba cistanches and the acteoside are combined for preparing the drugs for treating the hepatocellular carcinoma to achieve synergistic and attenuated effects.
As a preferable mode of the technical scheme, the treatment mechanism is based on the synergistic inhibition effect of the combination of the herba cistanches and the acteoside on HepG2 cells.
As the preferable choice of the technical scheme, the treatment mechanism is based on the synergistic induction of apoptosis effect of cistanche salsa and oxaliplatin on HepG2 cells.
As a preferable mode of the technical scheme, the medicine concentration of the herba cistanches acteoside is 5-100 mu M.
As the preferable choice of the technical scheme, the treatment mechanism is based on the synergistic inhibition effect of the combination of the herba cistanches and the acteoside on HepG2 tumor-bearing nude mice.
As the optimization of the technical scheme, the treatment mechanism is based on the inhibition effect of the combination of the herba cistanches and the acteoside on the adverse reaction of HepG2 tumor-bearing nude mice.
As described above, the application of the cistanche salsa or verbascoside combined anticancer therapeutic agent in preparing the anticancer therapeutic agent has the following beneficial effects:
the liver cancer in the prior art, particularly the late liver cancer, has high anti-tumor drug tolerance, and based on the high anti-tumor drug tolerance, the invention researches the effect and mechanism research of drugs on tumors by in vitro culturing of a liver cell carcinoma HepG2cell strain and a tumor-bearing nude mouse model. The study shows that the combination of the herba cistanches and the acteoside can obviously inhibit proliferation, migration and invasion of HepG2cells, induce apoptosis of hepatocellular carcinoma cells, and have obvious treatment effect on tumor growth of tumor-bearing nude mice, so that the herba cistanches and acteoside can be used for treating hepatocellular carcinoma. In addition, the adverse reaction induced by oxaliplatin can be improved by combining the cistanche verbascoside with the oxaliplatin. The invention not only provides a new application of the herba cistanches acteoside, expands the clinical application field of the herba cistanches acteoside, but also provides a new scheme for treating hepatocellular carcinoma by combining the herba cistanches acteoside and oxaliplatin, increases the selection of a chemotherapy scheme of the hepatocellular carcinoma, and has good clinical application prospect.
The invention aims to solve the problems, and by adopting an HCC cell strain and a tumor-bearing nude mouse model, the synergistic and attenuation bidirectional regulation effects of the acteoside on the HCC are comprehensively evaluated by technical means such as pharmacodynamics, pharmacology, molecular biology and the like, and the acteoside is definitely the main pharmacodynamic substance basis of cistanche deserticola for preventing and treating the HCC.
Drawings
FIG. 1A is the inhibitory activity of oxaliplatin on HepG2, PLC/PRF/5 and Hepa 1-6.
FIG. 1B shows the inhibitory activity of acteoside on HepG2, PLC/PRF/5 and Hepa 1-6.
FIG. 2 shows the dose-response curve and the Combination Index (CI) curve of acteoside in combination with oxaliplatin for inhibiting proliferation of HepG2 cells.
FIG. 3 is a graph showing the evaluation of the effect of acteoside in combination with oxaliplatin on the invasiveness and migration ability of HepG2 cells.
FIG. 4 is a graph showing the evaluation of the effect of acteoside in combination with oxaliplatin on apoptosis of HepG2 cells.
FIG. 5 is a graph showing the effect of acteoside in combination with oxaliplatin on tumor volume in HepG2 tumor-bearing nude mice.
FIG. 6 is a schematic representation of the effect of acteoside in combination with oxaliplatin on tumor weight in HepG2 tumor-bearing nude mice.
FIG. 7 is a graph of HepG2 tumor-bearing nude mice and tumor tissue after treatment with acteoside in combination with oxaliplatin.
FIG. 8 is a graph showing the evaluation of the effect of acteoside and oxaliplatin on the pathological morphology of tumor tissue in HepG2 tumor-bearing nude mice.
FIG. 9 is an ultrastructural view (8000X and 25000X) of the tumor tissue of HepG2 tumor-bearing nude mice with acteoside and oxaliplatin.
FIG. 10 is a graph showing the effect of acteoside and oxaliplatin on body weight of HepG2 tumor-bearing nude mice.
FIG. 11 is a graph showing the evaluation of the effect of acteoside in combination with oxaliplatin on the mechanical foot-reduction threshold of HepG2 tumor-bearing nude mice.
FIG. 12 is a graph showing the evaluation of toxicity of acteoside in combination with oxaliplatin on the blood system of HepG2 tumor-bearing nude mice.
FIG. 13 is a graph showing the evaluation of the effect of acteoside in combination with oxaliplatin on liver function in HepG2 tumor-bearing nude mice.
FIG. 14 evaluation of the effect of acteoside and oxaliplatin on renal function in HepG2 tumor-bearing nude mice.
Detailed Description
Further advantages and effects of the present invention will become apparent to those skilled in the art from the disclosure of the present invention, which is described by the following specific examples.
Experiment-research on synergistic Activity of acteoside and oxaliplatin in inhibiting liver cancer cells
A. The experimental part comprises the following steps:
1. cell culture and passage
HepG2, PLC/PRF/5, hepa1-6 cell lines were each prepared using a DMEM medium containing 10% serum, a MEM medium and a DMEM medium, and the cell culture was carried out at 37℃under 5% CO 2 And saturated humidity. Observing the state of the cells under a microscope, after the cell fusion degree reaches 80-90%, digesting for 1-2 min by using 0.25% pancreatin (containing EDTA), adding a complete culture medium to stop digestion, blowing the cells, and taking a proper amount of cells for passage.
2. CCK-8 cell viability assay
Counting proper cell resuspension, inoculating proper cells (3000-5000) into 96-well plate, inoculating cells for 24 hr, adding medicine with corresponding concentration, and dividing into oxaliplatin (1.5625, 3.125, 6.25, 12.5, 25, 50, 75, 100 μm) group and acteoside (3.125, 6.25, 12.5, 25, 50, 100, 200, 400 μm) group, and arranging 6 parallel multiple holes in each group. CCK-8 experiments were performed 48h after drug intervention, 3 replicates, survival was averaged, and half-inhibitory concentrations (half maximalinhibitoryconcentration, IC 50) of drug-treated HepG2, PLC/PRF/5, hepa1-6 cells were calculated using GraphPadPrism5 software.
Evaluation of synergistic action of 3-acteoside and oxaliplatin on inhibition of liver cancer cell proliferation
A proper amount of HepG2cells were inoculated in 96-well plates and divided into blank control groups, oxaliplatin (1.5625, 3.125, 6.25, 12.5, 25 μm) groups, acteoside (6.25, 12.5, 25, 50, 100 μm) groups, oxaliplatin+acteoside were co-administered (oxaliplatin: acteoside at a fixed concentration ratio=4:1, i.e. 1.5625+6.25, 3.125+12.5, 6.25+25, 12.5+50, 25 μm+100 μm) groups, and after 24 hours of cell inoculation, 6 parallel multiplex wells were set for each group, each group was added with the corresponding concentration of drug. The inhibition rate of HepG2cells after 48h of drug treatment was examined by CCK8 method. The combination index of oxaliplatin in combination with acteoside was calculated using CompuSyn (Biosoft, oxford, UK) software (CombinationIndex, CI) and CI curves were plotted.
4 cell proliferation assay
The groups were set as a Control group (Control), oxaliplatin (12.5. Mu.M) group (OXA), acteoside (50. Mu.M) group (ACT), oxaliplatin+acteoside (12.5. Mu.M+50. Mu.M) group (OXA+ACT), each group was provided with 6 parallel auxiliary wells, and the respective drug treatments were added for 48 hours, and the cell proliferation capacity of each group was evaluated by the CCK-8 method.
5 Transwell experiment
Matrigel gel was thawed in liquid form in a refrigerator at 4 ℃ and incubated with serum-free DMEM medium at 1:8 volume ratio dilution, coating Transwell cell. HepG2cells were resuspended to a density of 5X 10 with serum-free DMEM medium 4 Per mL, 100. Mu.L of the cell suspension was inoculated and incubated for 12h. After the cells had adhered, 600. Mu.L of DMEM complete medium containing 10% FBS was added to each well lower chamber. The same 1.2.4 groups of 3 cells are arranged, after the corresponding medicines are added into each group for 48 hours, the Transwell cells are taken out, the cells at the inner layer of the microporous membrane are wiped off by using precooled PBS for 2 times, the cells at the outer layer are fixed for 30 minutes by using 95% ethanol, then the cells are dyed for 15 minutes by using crystal violet, and the cell films are placed under an inverted microscope for image shooting.
6 scratch test
HepG2cells are inoculated in a 6-hole plate, when the monolayer of the cell growth surface grows to be about 70% -80%, the culture solution is discarded, the culture solution is replaced by a serum-free culture medium for 2h, a 200 mu L sterilization gun head is perpendicular to the hole plate, cell scratches are manufactured at the bottom, and the scratches are ensured to be in a straight line as much as possible and have consistent width. The cell culture broth was aspirated and the well plate was gently washed 3 times with PBS. The grouping setting is same as 1.2.4, after each group is added with corresponding medicine for 48 hours, the inverted optical microscope is adopted to shoot the medicine for 0, 12, 24 and 48 hours respectively, the change condition of scratch healing is observed, and the scratch distance is counted through imageJ software.
7 cell apoptosis assay
HepG2cells were seeded in 6-well plates until the cell growth surface monolayer was about 70% -80%. The grouping set was the same as 1.2.4, and each group was added with the corresponding drug treatment for 48 hours. Cells were collected, resuspended and washed 3 times with PBS, and centrifuged again to obtain cells. The prepared 10 XBuffer was diluted to 1X, fluorescein isothiocyanate (Fluorescein Isothiocyanate, FITC) and Propidium Iodide (PI) were mixed in equal proportions, and the mixture (10. Mu.L) was added to a centrifuge tube containing cells. Transferring the cell suspension into a flow tube, incubating for 20min at normal temperature and in a dark place, and detecting apoptotic cells by using a cell flow analyzer.
8 statistical analysis
IC50 and CI indices were calculated using GraphPadPrism5.0 and CompuSyn software, respectively. SPSS22.0 software is used for data analysis and data metering
The comparison between the two groups is shown by t test; the counting data are expressed in percentage, and the comparison between the two groups is adopted 2 And (5) checking. P (P)<The 0.05 difference is statistically significant, P<The 0.01 difference has a significant difference.
B. The experimental results are specifically analyzed as follows:
1. effects of Acteoside (ACT) and Oxaliplatin (OXA) on proliferation of liver cancer cells
Oxaliplatin (1.5625, 3.125, 6.25, 12.5, 25, 50, 75, 100. Mu.M) and acteoside (3.125, 6.25, 12.5, 25, 50, 100, 200, 400. Mu.M) ACT on 3 liver cancer cell lines (HepG 2, PLC/PRF/5, hepa 1-6), respectively, and after 48h of intervention, the effects of Oxaliplatin (OXA), acteoside (ACT) on liver cancer cell viability were detected by CCK-8 experiments, wherein FIG. 1A is the inhibitory activity of oxaliplatin on HepG2, PLC/PRF/5 and Hepa1-6, and FIG. 1B is the inhibitory activity of acteoside on HepG2, PLC/PRF/5 and Hepa 1-6.
The results show that both Acteoside (ACT) and Oxaliplatin (OXA) can inhibit the viability of liver cancer cells, respectively, and that the inhibition ability is in a dose-dependent manner. After 48h of oxaliplatin action on 3 liver cancer cell lines, hepG2 had an IC50 value of 15.81 μm, which was lower than that of PLC/PRF/5 cells (ic50=22.56 μm) and Hepa1-6 cells (ic50=16.79 μm). After 48h of acteoside action on 3 liver cancer cell lines, the IC50 value of acteoside action on HepG2 was 71.72. Mu.M, which is lower than that of PLC/PRF/5 cells (IC50= 74.74. Mu.M) and Hepa1-6 cells (IC50=241.4. Mu.M). Therefore, hepG2 was considered more sensitive to the effects of oxaliplatin and acteoside than PLC/PRF/5 and Hepa1-6, and HepG2 was selected as the sensitive cell line screened in this study for subsequent experimental study.
2 acteoside cooperated with oxaliplatin to inhibit proliferation of HepG2cells
Since it was necessary to examine whether or not the potentiation was achieved after the combination of acteoside with acteoside, hepG2cells with higher sensitivity were selected. The CompuSyn software was used to make a dose-response curve and a joint index (CI) curve for acteoside and/or oxaliplatin, fig. 2A is a dose-response curve, wherein the red curve is the dose-response curve for Acteoside (ACT), the blue curve is the dose-response curve for Oxaliplatin (OXA), and the green curve is the dose-response curve for acteoside in combination with oxaliplatin. FIG. 2B is a graph of the Combination Index (CI), with specific values shown in Table1 (indicating synergy when CI is less than 0.9, antagonism when CI is greater than 1.1, and additive when CI is between 0.9 and 1.1).
TABLE1inhibition of HepG2cells by Calycosin in combination with oxaliplatin Table1inhibition of the enzyme digestion of HepG2cells
The results show that the combination of acteoside and oxaliplatin at different concentrations intervenes in HepG2cells, the CI values are smaller than 0.9, the acteoside and the oxaliplatin have a synergistic effect, and the CI value is as low as 0.25+/-0.41 after 50 mu M acteoside and 12.5 mu M oxaliplatin are combined (see table 1), and 50 mu M acteoside and 12.5 mu M oxaliplatin are selected as the drug intervention concentration of the subsequent experiment in consideration of the economy and safety of the drug.
3. Acteoside in combination with oxaliplatin inhibits proliferation, invasion and migration of HepG2cells
Fig. 3 is a graph showing the effect of acteoside and oxaliplatin on the invasiveness and migration ability of HepG2cells, fig. 3A shows the effect of acteoside and oxaliplatin on proliferation of HepG2cells, fig. 3B shows the Transwell experimental result (200×) of acteoside and oxaliplatin, fig. 3C shows the scratch experimental result (40×) of acteoside and oxaliplatin, and fig. 3D shows the statistical result of the scratch experimental result of acteoside and oxaliplatin, wherein P <0.05 and P <0.01.
The results of the HepG2cell viability detection of each group by CCK-8 show that the cell viability of the OXA group (oxaliplatin alone group), the ACT group (acteoside alone group) and the OXA+ACT group (acteoside synergized oxaliplatin inhibition combination group) is remarkably reduced (P < 0.01) compared with that of a blank group; the oxa+act group was significantly reduced (P < 0.01) compared to the OXA group (see fig. 3A). The migration capacity and invasion capacity of the acteoside combined with oxaliplatin to interfere with HepG2cells are evaluated by a Transwell experiment and a scratch experiment respectively. The Transwell experimental result shows that the cell number of the liver cancer cells transferred to the lower layer of the cell of the OXA group is reduced compared with that of the control group; the number of liver cancer cells transferred to the lower layer of the cell in the oxa+act group was significantly increased compared to that in the OXA group (see fig. 3B). The results of the scratch experiments showed that the cell scratches of the blank, OXA combination, and ACT groups all tended to heal with prolonged treatment time, while the oxa+act group cell scratch distance tended to widen (see fig. 3C-D). After 48h of drug intervention, the scratch distances of the OXA, ACT and oxa+act group cells were widened compared to the blank group, with a significant difference (P < 0.01); compared to the OXA group, the scratch distance of the oxa+act group cells was significantly widened (P < 0.01). The above demonstrates that the combination of acteoside and oxaliplatin synergistically inhibits HepG2cell migration and invasion.
4. Acteoside and oxaliplatin cooperate to promote apoptosis of HepG2cells
FIG. 4 shows the effect of acteoside and oxaliplatin on apoptosis of HepG2cells, FIG. 4A shows the apoptosis after acteoside and oxaliplatin are combined to treat HepG2cells, and FIG. 4B shows the early apoptosis rate result of acteoside and oxaliplatin combined to treat HepG2 cells.
The results showed that the early apoptosis rate was significantly increased (P < 0.01) in OXA, ACT and oxa+act groups compared to the blank group; the early apoptosis rate was significantly increased in the oxa+act group compared to the OXA group (approximately 4 times that of the OXA group). It is shown that acteoside synergistically promotes apoptosis of HepG2cells after oxaliplatin treatment, thereby achieving the effect of antagonizing HCC.
Experimental study on synergistic effect of combination of coleus forskohlii glycoside and oxaliplatin on HepG2 tumor-bearing nude mice
A. The experimental part comprises the following steps:
1. animal model building
Taking human liver cancer cell HepG2 in logarithmic growth phase, regulating cell density to 1×10 with physiological saline 7 Individual cells/150 μl, ice bath. The armpit skin of nude mice was sterilized with iodophor, and the cell suspension was thoroughly shaken and inoculated to the armpit at 150. Mu.L/min. After two weeks, the armpit of the nude mice appears white hard lumps subcutaneously, and the die is successful when the tumor volume is 100mm 3 The tumor-bearing nude mice were then randomly grouped.
2. Grouping and administration
Tumor-bearing nude mice which were successfully molded were randomly divided into a Model (Model) group, oxaliplatin (OXA) group, acteoside (ACT) group, oxaliplatin combined with acteoside (oxa+act) group, and blank groups were nude mice which were not molded, and were 5 groups of nude mice each of which was 12. The corresponding medicines are respectively injected into the abdominal cavity except for a blank group and a model group, and the blank control group and the model group are respectively injected with 5% glucose injection with equal volume according to clinical medication experience and reference documents; oxaliplatin group administration of 5 mg.kg -1 2 times per week; 25 mg/kg of acteoside group administration -1 Is administered 1 time per day; oxaliplatin in combination with a verbascoside group at 5 mg.kg -1 Oxaliplatin and 25 mg.kg -1 Is administered frequently with the single administration group, and is interfered for 4 weeks.
3. Tumor volume, weight measurement and survival curve mapping
The efficacy was evaluated by measuring the volume and weight of nude mice tumor.
a) Tumor volume:
the length and diameter of the tumor were measured with a vernier caliper 1 time every 3 days.
The calculation formula is as follows: v=0.5 axb 2 (a, long diameter; b, short diameter).
b) Tumor weight:
after the administration is finished, 6 nude mice are randomly selected for each group, eyeballs are picked for blood taking, neck removal and sacrifice are carried out, dissection is carried out after the nude mice take a picture, tumor tissues are completely stripped and picked, and the wet weight of the tumor is measured.
(1) Tumor weight inhibition = (1-average tumor weight of dosing group/average tumor weight of model group) ×100%.
(2) Determining the interaction between the co-administered drugs based on the Weeb coefficient, the formula:
the predicted effect is c=a×b
Wherein A, B refers to the tumor growth rates of the acteoside group and oxaliplatin group, respectively. When the actual growth rate of the combined administration group is less than C, the synergistic effect is obtained; when the actual growth rate of the combined administration group is less than or equal to C and is less than or equal to A and B, the addition effect is obtained; antagonism is indicated when the actual survival rate of the combination administration group > a and B.
4. Preparation of sections of tumor tissue
The dissected tumor tissue was immersed in 4% paraformaldehyde solution and fixed for 24h. After finishing the fixed tissue, placing the tissue into a tissue embedding box, marking the tissue with a pencil, and placing the tissue into an automatic dehydrator for dehydration treatment. Taking out the embedding box, pouring the embedding box into an embedding machine for pre-melting wax, cooling the embedding box in a refrigerating area, thoroughly solidifying the embedding box into wax blocks, and stripping the wax blocks. Cutting the embedded wax block into slices with the thickness of about 4 mu m by using a paraffin slicer, spreading on the water surface in the slice spreading machine, taking out the slices smoothly by using a glass slide, and marking on the glass slide. Baking at 70deg.C on a sheet baking machine, and preserving at normal temperature. Tumor tissue sections were H & E stained to evaluate the effect of acteoside in combination with oxaliplatin on tumor histopathology in HepG2 tumor-bearing nude mice.
5. Ultrastructural observation of tumor tissue
Swelling of anatomical extractionPlacing tumor tissue in a glass dish, and trimming the tumor tissue to a cross section of 1-2 mm by using a scalpel 2 The left and right long strips were collected in a 1.5mLEP tube, and 2.5% glutaraldehyde was added thereto and stored at 4 ℃. Tumor tissue slices were fixed for 24h and sent to a Xinjiang university electron microscope (TEM) and samples were observed and mapped with a transmission electron microscope (JEM-100 CXII).
6. Statistical analysis
SPSS22.0 statistical software is adopted for data analysis and data metering
The comparison between the two groups is shown by t test; the counting data are expressed in percentage, and the comparison between the two groups is adopted 2 And (5) checking. P (P)<The 0.05 difference is statistically significant, P<The 0.01 difference has a significant difference.
B. The experimental results are specifically analyzed as follows:
synergistic inhibition of tumor growth by combination of 1 acteoside and oxaliplatin
Based on a HepG2 tumor-bearing nude mouse model, the influence of the combination of the acteoside and oxaliplatin on the tumor volume, the tumor wet weight and the survival period of the HepG2 tumor-bearing nude mouse is examined.
(1) The combination of the acteoside and the oxaliplatin synergistically inhibits the tumor volume increase of HepG2 tumor-bearing nude mice
FIG. 5 is a graph showing the effect of acteoside in combination with oxaliplatin on tumor volume in HepG2 tumor-bearing nude mice, with the tumor volume of model nude mice increasing rapidly, while the tumor volume of acteoside in combination with acteoside in nude mice increases slowly, and remains substantially at a relatively stable level throughout the treatment. At 12d, tumor volumes were reduced (P > 0.05) for both OXA and oxa+act groups compared to the model group. The tumor volume was reduced (P > 0.05) in the oxa+act group compared to the OXA group (see fig. 5).
(2) The combination of the acteoside and the oxaliplatin synergistically reduces the tumor weight increase of HepG2 tumor-bearing nude mice
FIG. 6 is a graph showing the effect of acteoside in combination with oxaliplatin on tumor weight in HepG2 tumor-bearing nude mice, and is annotated: * P <0.05, < P <0.01, ns. Table 2 shows tumor growth data of mice bearing HepG2 tumor inhibition in vivo by combination of acteoside and oxaliplatin. FIG. 7 is a graph of HepG2 tumor-bearing nude mice and tumor tissue after treatment with acteoside in combination with oxaliplatin.
The results showed that the tumor inhibition rates of the OXA group and the oxa+act group on HepG2 tumor-bearing nude mice were 45.63% and 64.39%, respectively. Tumor weights were significantly reduced (P < 0.01) in OXA and oxa+act groups compared to model groups; tumor weight was decreased in the oxa+act group compared to the OXA group (P < 0.05). Furthermore, the synergy between the co-administered drugs was judged based on the actual growth rate (35.67%) of the Weeb coefficient C of 38.17% > in the co-administered group (see table 2 and fig. 6).
TABLE 2 inhibition of tumor growth in HepG2 tumor-bearing mice in combination with acteoside in vivo
Table2InhibitingeffectofacteosidecombinedwithoxaliplatinonHepG2
tumorbearingnudemice
Note that: in comparison with the Model group, # P<0.05， ## P<0.01; in contrast to the OXA group, * P<0.05， ** P<0.01。
2. influence of Calycosin in combination with oxaliplatin on the histopathological morphology of tumors
FIG. 8 is an effect of acteoside and oxaliplatin on pathological morphology of tumor tissue in HepG2 tumor-bearing nude mice, wherein FIG. 8A is an H & E stained image (200X) of each group of HepG2 tumors, V-tumor survival; n-tumor necrosis zone; fig. 8B is the area percentage of tumor necrosis area, annotated: * P <0.05, P <0.01.
The histopathological changes of tumors after the interference of the acteoside and oxaliplatin on HepG2 tumor-bearing nude mice are observed through H & E staining, and tumor necrosis areas (Necroicarea, N) can be seen to crack, shrink and disappear; the nuclei of the tumor survival region (V) are intact and well defined. H & E staining results showed a significant increase in intratumoral necrosis area (P < 0.01) for OXA, ACT and oxa+act groups compared to the model group. The oxa+act group showed a significant increase in intratumoral necrosis area (P < 0.01) compared to the OXA group (see fig. 8).
3. Influence of Calycosin in combination with oxaliplatin on tumor tissue ultrastructure
FIG. 9 is an ultrastructural view (8000X and 25000X) of the tumor tissue of HepG2 tumor-bearing nude mice with acteoside and oxaliplatin.
The result shows that the cell nucleus of the model group is abnormal, the nuclear membrane is partially sunken to form nuclear notch, double nuclei are formed, and the cell organelle of the liver tumor is not abundant; mitochondrial ridges in OXA group tumor cells dissolve, swell, vacuolation; dissolving ACT group nuclear membrane, changing flocculent sample, and dissolving mitochondrial ridge; the oxa+act group cell membrane disintegrated, the perinuclear gap significantly widened, mitochondrial cavitation, complete dissolution of the outer mitochondrial membrane, coarse endoplasmic reticulum degranulation, and significant dilation (see fig. 9).
Experiment study on toxicity reduction effect of combination of three-acteoside and oxaliplatin on HepG2 tumor-bearing nude mice
A. The experimental part comprises the following steps:
1. animal models were constructed as in example 2.
2. Grouping and administration were as in example 2.
3. Drawing of body weight-time curve
During the administration, the weight of the nude mice is weighed every 3 days, the change condition of the weight of the nude mice is recorded, and the average weight of each group of nude mice is taken to draw a weight-time curve.
4. Diarrhea status observation
The diarrhea of the nude mice was observed, and the diarrhea of the nude mice was recorded in grades according to the following standard: 0. normal (no diarrhea); 1. slight diarrhea (staining around anus); 2. moderate diarrhea (staining of the upper part of the lower abdomen and hind legs); 3 severe diarrhea (staining of hind legs and lower abdomen).
5. Mechanical stimulus foot-reduction response threshold (PWMT)
The pain sense is induced by stimulating the middle part of the sole of a nude mouse through von Frey fiber filaments, and the mechanical stimulus foot contraction response threshold is detected to evaluate the influence of acteoside on peripheral neurotoxicity caused by oxaliplatin, and the specific steps are strictly operated according to the literature report.
6. Blood routine testing
After the last administration, the patients are fasted (not forbidden) for 8 hours, and blood is collected (whole blood) after the eyeballs are taken for routine blood detection. The whole blood sample is subjected to blood routine detection by using a Coulter blood cell analyzer, and the white blood cell (WBC, red Blood Cell (RBC) and Platelet (PLT) numbers in the blood routine detection result are subjected to statistical analysis.
7. Serum biochemical index detection
a) Liver function index detection
Blood was collected by taking the eyeball, placing the whole blood in a heparin sodium coated 1.5mLEP tube, centrifuging 12000 Xg at 4℃for 15min, and collecting the supernatant. The levels of glutamic pyruvic transaminase (ALT), glutamic oxaloacetic transaminase (AST), alkaline phosphatase (AKP) and Lactate Dehydrogenase (LDH) in nude mice serum are detected by the kit, and are determined strictly according to the operation of the kit.
b) Renal function testing
Serum Creatinine (CRE) and urea nitrogen (BUN) levels were measured by the kit, and determined strictly according to the kit instructions.
8. Statistical analysis
SPSS22.0 statistical software is adopted for data analysis and data metering
The comparison between the two groups is shown by t test; the counting data are expressed in percentage, and the comparison between the two groups is adopted 2 And (5) checking. P (P)<The 0.05 difference is statistically significant, P<The 0.01 difference has a significant difference.
B. The experimental results are specifically analyzed as follows:
1. weight change in nude mice
Fig. 10 is a graph showing the effect of acteoside and oxaliplatin on body weight of HepG2 tumor-bearing nude mice, annotated: * P <0.05, < P <0.01, ns. The results show that the weight of the nude mice in the normal group is gradually increased; the weight of the nude mice in the model group is in a descending trend; the weight of the nude mice in the OXA group is obviously reduced; whereas the weight of nude mice in the ACT+OXA group tended to decrease before 9d, and after 9d, the weight began to rise. The body weight results at 12d administration showed a significant decrease in body weight of the nude mice in the model group compared to the blank group (P < 0.01). Weight loss in OXA group compared to model group, not statistically significant (P > 0.05); the body weights of the ACT group and oxa+act group increased significantly, with statistical significance (P < 0.05). The body weight gain of the oxa+act group was statistically significant (P < 0.01) compared to the OXA group (see fig. 10).
2 diarrhea status
Table 3 shows the effect of acteoside in combination with oxaliplatin on diarrhea in HepG2 tumor-bearing nude mice. The results showed that none of the blank, model, and ACT groups had diarrhea. Diarrhea in the mice of the OXA group is most severe, and the diarrhea degree of the mice is relieved after the acteoside is combined with oxaliplatin. Diarrhea scoring results showed a significant increase in diarrhea score (P < 0.01) in nude mice in OXA group compared to model group; the diarrhea score was reduced (P < 0.05) in the oxa+act group compared to the OXA group (see table 3).
TABLE 3 Effect of acteoside in combination with oxaliplatin on diarrhea in HepG2 tumor-bearing nude mice
Table3EffectofacteosidecombinedwithoxaliplatinondiarrheaofHepG2tumor
bearingmice
Note that: in comparison with the Model group, ## P<0.01， # P<0.05; in contrast to the OXA group, ** P<0.01， * P<0.05。
3. evaluation of oxaliplatin neurotoxicity
FIG. 11 is a graph showing the effect of acteoside in combination with oxaliplatin on the mechanical foot-reduction threshold of HepG2 tumor-bearing nude mice, annotated: * P <0.05, < P <0.01, ns. The mechanical stimulus foot-constriction response threshold (PWMT) was determined by von frey fiber filaments to evaluate the effect of acteoside on oxaliplatin peripheral neurotoxicity. The results showed no statistical change in PWMT values (P > 0.05) for the model group compared to the blank group. PWMT values were elevated for the OXA group and the OXA+ACT group compared to the model group, with statistical significance (P < 0.05). The PWMT value was significantly reduced (P < 0.01) for the oxa+act group compared to the OXA group (see fig. 11).
4. Evaluation of toxicity in the blood System
FIG. 12 is a graph showing the evaluation of toxicity of acteoside in combination with oxaliplatin on the blood system of HepG2 tumor-bearing nude mice, wherein FIG. 12A shows the effect of white blood cell count, FIG. 12B shows the effect of red blood cell count, and FIG. 12C shows the effect of platelet count; and (3) injection: * P <0.05, < P <0.01, ns.
Blood routine test results show that three lines (white blood cells, red blood cells and platelets) are reduced in the plasma of nude mice of the model group (P < 0.05) compared with the blank group; three lines were all reduced in OXA group compared to model group (P < 0.05); however, the white blood cell (P < 0.01), red blood cell (P < 0.05) and platelet (P > 0.05) numbers were all elevated in the oxa+act group compared to the OXA group (see fig. 12).
5. Evaluation of liver toxicity
FIG. 13 is a graph showing the effect of acteoside in combination with oxaliplatin on liver function in HepG2 tumor-bearing nude mice, wherein A is glutamic pyruvic transaminase activity, B is glutamic oxaloacetic transaminase activity, C is alkaline phosphatase content, and D is lactic acid dehydrogenation activity; note P <0.05, P <0.01, ns.
The results showed that the AST, AKP, LDH levels were elevated in the serum of mice in the model group compared to the normal group (P < 0.05); ALT and LDH levels were elevated in the OXA group (P > 0.05) and AST levels were significantly elevated (P < 0.01) and AKP levels were decreased (P < 0.05) as compared to the model group; both ALT, AST, AKP and LDH levels were reduced in the oxa+act group compared to the OXA group, with significantly reduced AST and AKP levels (P < 0.05) (see fig. 13).
6. Evaluation of renal toxicity
FIG. 14 is a graph showing the effect of acteoside and oxaliplatin on kidney function in HepG2 tumor-bearing nude mice, wherein A is the creatinine content and B is the urea nitrogen content; note P <0.05, P <0.01, ns.
The results showed that the serum CRE content was significantly increased in the mice of the model group compared to the normal control group (P < 0.01); compared with the model group, the BUN content of the OXA group is significantly increased (P < 0.01); compared to the OXA group, CRE was decreased (P > 0.05) and BUN was significantly decreased (P < 0.01) in the oxa+act group (see fig. 14).
In summary, the invention not only provides a new application of the herba cistanches acteoside, expands the clinical application field of the herba cistanches acteoside, but also provides a new scheme for treating hepatocellular carcinoma by combining the herba cistanches acteoside and oxaliplatin, increases the selection of chemotherapy scheme of the hepatocellular carcinoma, and has good clinical application prospect. Therefore, the invention effectively overcomes various defects in the prior art and has high industrial utilization value.
The above embodiments are merely illustrative of the principles of the present invention and its effectiveness, and are not intended to limit the invention. Modifications and variations may be made to the above-described embodiments by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is intended that all equivalent modifications and variations of the invention be covered by the claims, which are within the ordinary skill of the art, be within the spirit and scope of the present disclosure.
Claims (10)
1. Application of cistanche deserticola combined oxaliplatin in preparing medicine for treating liver cancer is provided.
2. The use according to claim 1, wherein the cistanche extract is combined with oxaliplatin for the preparation of a medicament for the treatment of liver cancer.
3. The application of acteoside or pharmaceutically acceptable salt thereof in preparing medicine for treating cancer is provided.
4. The use according to claim 3, wherein said acteoside or pharmaceutically acceptable salt thereof is combined with an anticancer therapeutic agent for the preparation of a medicament for the treatment of cancer.
5. The use according to claim 4, wherein the cancer is selected from at least one of liver cancer, lung cancer, pancreatic cancer, breast cancer, colorectal cancer or lymphoma;
the anticancer therapeutic agent is at least one selected from platinum drugs, alkylating agents, topoisomerase inhibitors, taxol, antitumor antibiotics, plant alkaloids, nucleoside analogues, DNA damage repair inhibitors and immune checkpoint inhibitors;
preferably, the platinum-based drug is selected from cisplatin, carboplatin, oxaliplatin and satraplatin.
6. The use according to claim 5, wherein said acteoside or pharmaceutically acceptable salt thereof is combined with oxaliplatin for the preparation of a medicament for the treatment of cancer.
7. The use according to claim 6, wherein said acteoside or pharmaceutically acceptable salt thereof is combined with oxaliplatin for the preparation of a medicament for the treatment of liver cancer.
8. The use according to any one of claims 3 to 7, wherein the daily dose of the cistanche acteoside or a pharmaceutically acceptable salt thereof is 2 to 10mg/kg.
9. A pharmaceutical composition or combination comprising:
cistanche deserticola;
oxaliplatin.
10. A pharmaceutical composition or combination comprising:
acteoside;
the anticancer therapeutic of any one of claims 4 to 9.
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| CN113440534A (en) * | 2020-03-26 | 2021-09-28 | 上海医药工业研究院 | Application of verbascoside in preparation of medicines |
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| CN113304169A (en) * | 2021-07-19 | 2021-08-27 | 湖南省中医药研究院 | Application of pharmaceutical composition of phenylethanoid glycosides compounds and cisplatin in medicines for treating lung cancer |
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| PENGFEI YUAN 等: "Cistanche tubulosa Phenylethanoid Glycosides Induce Apoptosis of Hepatocellular Carcinoma Cells by Mitochondria-Dependent and MAPK Pathways and Enhance Antitumor Effect through Combination with Cisplatin", INTEGRATIVE CANCER THERAPIES, vol. 20, 31 December 2021 (2021-12-31), pages 1 - 19 * |
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