CN104906578A - Application of proton pump inhibitor in preparation of medicine for treating hepatocellular carcinoma - Google Patents
Application of proton pump inhibitor in preparation of medicine for treating hepatocellular carcinoma Download PDFInfo
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- CN104906578A CN104906578A CN201510060273.XA CN201510060273A CN104906578A CN 104906578 A CN104906578 A CN 104906578A CN 201510060273 A CN201510060273 A CN 201510060273A CN 104906578 A CN104906578 A CN 104906578A
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- proton pump
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Abstract
The invention discloses an application of a proton pump inhibitor in preparation of medicine for treating hepatocellular carcinoma. The proton pump inhibitor can effectively inhibit propagation and growth of hepatocellular carcinoma, can inhibit generation of hepatocellular carcinoma, and can induce the apoptosis of hepatocellular carcinoma. The proton pump inhibitor can be used for preparing medicine for effectively treating hepatocellular carcinoma, the application of a proton pump inhibitor in preparation of medicine for treating hepatocellular carcinoma is firstly disclosed, and the proton pump inhibitor has unexpected effect on inhibition of propagation and growth of hepatocellular carcinoma.
Description
Technical field
The present invention relates to the novelty teabag of proton pump inhibitor, particularly relate to the application of proton pump inhibitor in the anti-hepatocarcinoma medicine of preparation.
Background technology
Hepatocarcinoma is common malignant tumor, occupies the 4th of China's generation rate of malignant tumour.Hepatocarcinoma grade malignancy is high, and PD is fast, and poor prognosis, the mean survival time (MST) 6-8 month, its mortality rate accounts for the second of China's malignant tumor, is only second to pulmonary carcinoma.Because hepatocarcinoma is all insensitive to the chemotherapeutics used clinically, current clinical treatment hepatocarcinoma effective method remains surgical operation therapy.But because the development of the hepatocarcinoma state of an illness is fast, due to poor liver function situation, the hepatic disease on basis or the appearance of metastasis when Most patients is gone to a doctor, be not suitable for carrying out surgical operation therapy.Even if minority can carry out the patient of surgical operation therapy, Post operation still has higher relapse rate.And, at present to the postoperative recurrence of hepatocarcinoma still without effective Therapeutic Method.In recent years, along with the progress of tumor cell molecular biology research, people are at the molecular targeted therapy of research for hepatocarcinoma.Develop with Sorafenib (Sorafenib) that to be representative a series of with tyrosine kinase receptor is the medicine of therapy target.At present, Sorafenib (being the multiple kinase whose inhibitor such as VEGF, platelet derived growth factor, epidermal growth factor and insulin-like growth factor) is by the treatment of U.S. FDA approval as hepatocarcinoma.But clinical experimental study finds widely, compared with placebo, Sorafenib extends only March life cycle of patient.And Sorafenib is expensive.Therefore, for the hepatocarcinoma with fearful prognosis, find its effective medicine remain in the urgent need to.
What research showed hepatocarcinoma is a complicated process, and involved a lot of change of cellular elements signal and the change of gene, several factors combined effect finally result in developing of hepatocarcinoma.No matter malignant tumor be by what reason caused and mechanism that its occurs how, a large amount of evidences shows that the acidic micro-environment of tumor cell plays an important role in the developing of tumor.Tumor cell is grown on hypoxia microenvironment usually, and it is active to have high glycolysis, can cause producing a large amount of acidic metabolite.But research shows that tumor cell is in extracellular meta-acid and the microenvironment of meta-alkali in cell.This acid just needing tumor cell can get rid of generation in cell is timely conducive to the Extra-cellular acidic microenvironment of growth of tumour cell, invasion and attack, transfer with maintenance to extracellular.Four kinds of main cellular pH regulatory mechanisms are had: Sodium-hydrogen exchanger, bicarbonate transport agents, proton-lactate be defeated body and proton pump altogether at tumor cell.And proton pump Vacuolar H
+-ATPase (V-ATPase) is considered to be in pH regulator mechanism important in tumor cell.
Proton pump inhibitor effectively can suppress the H+-K+-ATPase of gastric mucosa parietal cell.First proton pump inhibitor omeprazole (Omeprazole) is developed by Astrazeneca AB of Sweden and was first applied to clinical treatment peptic ulcer in 1988, and various countries develop lansoprazole (Lansoprazole), pantoprazole (Pantoprazole), rabeprazole (Rabeprazole), esomeprazole (Esomeprazole), ilaprazole (Iaprazole) etc. in succession subsequently.Because this kind of medicine can suppress the H+-K+-ATPase of gastric mucosa parietal cell, thus effective gastric acid secretion inhibiting, be widely used in the treatment of gastric acid related disease (as peptic ulcer, Gastroesophageal reflux disease etc.) at present clinically.Our research finds that proton pump inhibitor is except suppressing proton pump H+-K+-ATPase, also can effectively suppress proton pump V-ATPase.
But up to now, do not find the application of proton pump inhibitor in anti-hepatocarcinoma medicine.
Summary of the invention
Technical problem to be solved by this invention is to provide the application of proton pump inhibitor in preparation treatment hepatocellular carcinoma medicine.
The present invention proposes propagation and the growth that proton pump inhibitor effectively can suppress hepatocellular carcinoma cells, promotes the apoptosis of hepatocellular carcinoma cells, may be used for the new medicine preparing treatment hepatocarcinoma.
The present invention is achieved in that
1. the present invention inhibits propagation and the growth of human liver cell cancerous cell by the result display proton pump inhibitor pantoprazole of cell experiment;
2. inhibit the growth of human hepatocellular carcinoma cell in liver, the generation of the murine hepatocellular carcinoma that inhibit chemical substance to induce by the result display proton pump inhibitor pantoprazole of animal model experiment.
3. show proton pump inhibitor pantoprazole significantly induction of the apoptosis of human liver cell cancerous cell by the result of further cell experiment.
Therefore, the present invention proposes the technical scheme of the application of proton pump inhibitor in preparation treatment hepatocellular carcinoma medicine.
Technique effect of the present invention is: the present invention finds that proton pump inhibitor can suppress propagation and the growth of hepatocellular carcinoma cells effectively, suppresses the generation of hepatocarcinoma, the apoptosis of inducing hepatocyte cancerous cell.Proton pump inhibitor to be applied to the medicine that preparation effectively can treat hepatocarcinoma, and the purposes of proton pump inhibitor in the anti-hepatocarcinoma medicine of preparation belongs to first public, and it is having beyond thought effect for suppressing in propagation of human liver cell cancerous cell and growth, has therefore possessed outstanding substantive distinguishing features and significant progress.
Accompanying drawing explanation
Fig. 1 illustrates the impact of proton pump inhibitor pantoprazole on human liver cell cancerous cell HepG2, SMMC7721, Huh7, SK-HEP-1, PLC/PRF/5, MHCC-9H, MHHCC-97L and HCCLM3 cell proliferation.
Fig. 2 illustrates the impact of proton pump inhibitor pantoprazole on hepatocellular carcinoma cells clonality and growth curve.
Fig. 3 illustrates the hepatocellular carcinoma cells SMMC7721 cell of proton pump inhibitor pantoprazole on people in mice tumor growth and the impact on mouse liver cell carcinogenesis.
Fig. 4 illustrates the impact of proton pump inhibitor pantoprazole on hepatocellular carcinoma cells SMMC7721 and HepG2 apoptosis.
Detailed description of the invention
Below in conjunction with drawings and Examples, the present invention is described in further detail, but protection scope of the present invention is not by any restriction of specific embodiment, but be limited by claim.
Embodiment 1:
The preparation of proton pump inhibitor tablet involved in the present invention:
Get proton pump inhibitor pantoprazole or other proton pump inhibitor 400g, add customary adjuvant (food starch) 100g preparing tablet, mixing, and be prepared into 1000, tablet with conventional tablet presses.
Embodiment 2:
The preparation of proton pump inhibitor capsule involved in the present invention:
Get proton pump inhibitor pantoprazole or other proton pump inhibitor 400g, add customary adjuvant (food starch) 100g preparing capsule, mixing, and be encapsulatedly prepared into capsule 1000.
Embodiment 3: the preparation of proton pump inhibitor pill involved in the present invention:
Get proton pump inhibitor pantoprazole or other proton pump inhibitor 400g, add customary adjuvant (food starch) 100g preparing pill, mixing, is prepared into pill 1000 ball.
Embodiment: 4:
The preparation of proton pump inhibitor injection involved in the present invention:
Get proton pump inhibitor pantoprazole or other proton pump inhibitor 0.5g, add the aseptic solution of 2ml and be prepared into pantoprazole or other proton pump inhibitor injection.
The activity of proton pump inhibitor in anti-hepatocarcinoma medicine is further illustrated below by pharmacodynamic experiment.
Experimental example 1: the impact that proton pump inhibitor is bred the hepatocellular carcinoma cells of people:
We have selected the hepatocellular carcinoma cell lines of 8 strain people, 24,48 and 72 hours are cultivated in vitro respectively with the proton pump inhibitor pantoprazole (P) of various dose, pass through MTT[(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt] methods analyst various dose pantoprazole with these cytosis different times after impact that these hepatocellular carcinoma cells are bred.MTT method is a kind of method of conventional detection cell survival and propagation, has been widely used in large-scale screening anti-tumor medicine, cell toxicity test etc.To be dosage and time inhibit the propagation (see figure 1) of the hepatocellular carcinoma cells of people according to lazyness to result display pantoprazole.
Fig. 1: illustrate the impact of proton pump inhibitor pantoprazole on human liver cell cancerous cell HepG2, SMMC7721, Huh7, SK-HEP-1, PLC/PRF/5, MHCC-9H, MHHCC-97L and HCCLM3 cell proliferation.Pantoprazole (P) in dosage and time dependence inhibit the propagation of human liver cell cancerous cell.In every a series of middle n=8.
Experimental example 2: the growth curve of proton pump inhibitor on the hepatocellular carcinoma cells of people and the impact of clonality:
Cell growth curve is the important indicator judging cell viability.First we have studied the impact of proton pump inhibitor pantoprazole on the cell growth curve of hepatocellular carcinoma cells SMMC7721 and HepG2 by method for cell count.Result shows, and along with the rising of Determination of pantoprazole, the growth rate of hepatocellular carcinoma cells SMMC7721 and HepG2 obviously declines.(see part A in Fig. 2).
The growth of tumor, transfer, recurrence are all based on the propagation of clonogenic cell (stem cell).Colony forming experiment reflects the multiplication capacity of single clone's living cells, is measure the most reliable index of anticarcinogen activity.We select hepatocellular carcinoma cells SMMC7721 and HepG2 of people to form experimentation proton pump inhibitor to the impact of hepatocellular carcinoma cells clonality by plate clone further.In cell and the effect of proton pump inhibitor pantoprazole after 2 weeks, result display is along with the rising of Determination of pantoprazole, and the Colony forming ability of human liver cell cancerous cell SMMC7721 and HepG2 declines gradually.In pantoprazole 160 μMs of groups, there is no Colony forming (in see Fig. 2 part B) all completely at two cell strains.The clonogenic cell of prompting proton pump inhibitor to human liver cell hepatocyte HepG2 and SMMC-7721 has obvious inhibitory action.
Fig. 2: part A: proton pump inhibitor pantoprazole is on the impact of hepatocellular carcinoma cells HepG2 (A1) and SMMC7721 (A2) growth curve.Inhibit the growth rate of SMMC7721 and HepG2 cell pantoprazole dose-dependant.In often a series of, n=6.Compared with matched group,
# p>0.05, * *
p<0.01.Part B: pantoprazole is on the impact of hepatocellular carcinoma cells HepG2 (B1) and SMMC7721 (B2) clonality.Top panel: the representational figure of Cell clonality.Bottom panel: the comparison of Clone formation quantity between each group.Inhibit the clonality of SMMC7721 and HepG2 cell pantoprazole dose-dependant.160 μMs of groups, the formation that SMMC7721 and HepG2 cell is not all cloned.In often a series of, n=8.Compared with matched group, *
p<0.05, * *
p<0.01.
Experimental example 3: the impact that proton pump inhibitor occurs hepatocellular carcinoma cells tumor growth and hepatocarcinoma:
In order to observe the impact of proton pump inhibitor on the hepatocellular carcinoma cells tumor growth of people.We set up the xenograft model of hepatocarcinoma with nude mice.The hepatocellular carcinoma cells SMMC7721 cell of people is inoculated in the subcutaneous of nude mice back.4 days after the transfer, after the tumor at nude mice model position is formed, nude mice transplanted tumor formed was divided into matched group and proton pump inhibitor pantoprazole 20mg/kg, 40mg/kg and 80mg/kg group at random, often group series 10 nude mices.Pantoprazole is pressed 20mg/kg, 40mg/kg and 80mg/kg or contrast mediator, give in mouse peritoneal, every 12 hours once.Within every 3 days, observe once, measure the size being implanted in the tumor tissues at nude mice back, within 30 days after giving pantoprazole, put to death mice.Our result display proton pump inhibitor pantoprazole be dose-dependant inhibit the growth of hepatocellular carcinoma cells SMMC7721 cell in nude mouse (see Fig. 3 A) of people.
In order to study the impact that proton pump inhibitor occurs hepatocarcinoma further, we apply C57BL6 mice, the hepatocellular carcinoma animal model of chemical induction is set up with two methyl-nitramines (diethylnitrosamine) and carbon tetrachloride, March after Modling model, mice is divided at random matched group and proton pump inhibitor pantoprazole 20mg/kg, 40mg/kg and 80mg/kg group, often group series 20 mices.Pantoprazole is pressed 20mg/kg, 40mg/kg and 80mg/kg or contrast mediator, give in mouse peritoneal, every 12 hours once, after administration 60 days, puts to death mice, and a situation arises to check in mouse liver tumor.Result is presented at matched group to be had in the liver of 16 mices and there occurs tumor, and tumor body is comparatively large, multiple.And in pantoprazole 20mg/kg, 40mg/kg and 80mg/kg group, only have 8,5 and 5 mices to there occurs tumor respectively, and tumor body less (see part B in Fig. 3).
Fig. 3: part A: the impact that proton pump inhibitor pantoprazole grows in vivo on hepatocellular carcinoma cells SMMC7721 cell.Left side: be the image of the tumor body of each group.Right side: be the comparison of each group of tumor size.In every a series of middle n=10.Compared with matched group, * *
p<0.01.Pantoprazole be dose-dependant inhibit the growth of hepatocellular carcinoma cells SMMC7721 in nude mouse of people.Part B: proton pump inhibitor pantoprazole is on the impact of mouse liver cell carcinogenesis.Left side: the presentation graphics occurred for the hepatocarcinoma of each group.Right side: be the comparison of each group of hepatocarcinoma incidence rate.N=20 in each group, compared with matched group, * *
p<0.01.
Experimental example 4: proton pump inhibitor is on the impact of hepatocellular carcinoma cells apoptosis:
In order to understand the impact of proton pump inhibitor on hepatocellular carcinoma cells apoptosis, our impact that is on hepatocellular carcinoma cells SMMC7721 and HepG2 early stage by flow cytomery technology and TUNEL Study on Technology of Dyeing proton pump inhibitor pantoprazole and late apoptic.With the early apoptosis of flow cytomery cell after SMMC7721 and HepG2 cell and pantoprazole 320 μMs act on 24 hours.Detect the late apoptic of cell with TUNEL staining after SMMC7721 and HepG2 cell and pantoprazole 320 μMs act on 48 hours.Result display pantoprazole is significantly induction of the apoptosis (see figure 4) of SMMC7721 and HepG2 cell.
Fig. 4: part A: flow cytomery proton pump inhibitor pantoprazole is on the impact of hepatocellular carcinoma cells HepG2 (A1) and SMMC7721 (A2) early apoptosis.Top panel: the representational flow cytomery figure that matched group and pantoprazole (P) are organized.Bottom panel: matched group and pantoprazole (P) organize the comparison of result.Part B: TUNEL staining detects the impact on hepatocellular carcinoma cells HepG2 (B1) and SMMC7721 (B2) late apoptic of proton pump inhibitor pantoprazole.Top panel: matched group and pantoprazole (P) organize the representational figure of TUNEL dyeing.Bottom panel: matched group and pantoprazole (P) organize the comparison of result.At every a series of middle n=8, compared with matched group, * *
p<0.01.
These results show that proton pump inhibitor pantoprazole can suppress propagation and the growth of hepatocellular carcinoma cells effectively, suppress the generation of hepatocarcinoma, the apoptosis of inducing hepatocyte cancerous cell.It is feasible that proton pump inhibitor prepares the medicine effectively treating hepatocarcinoma.
Claims (1)
1. the application of proton pump inhibitor in preparation treatment hepatocellular carcinoma medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292577A (en) * | 2019-08-19 | 2019-10-01 | 庹必光 | Application of the Pantoprazole in the drug of preparation prevention and treatment nonalcoholic fatty liver |
| CN110522752A (en) * | 2019-08-19 | 2019-12-03 | 庹必光 | Application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis |
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| US20100184807A1 (en) * | 2008-03-04 | 2010-07-22 | Bio-Quant, Inc. | Methods to inhibit tumor cell growth by using proton pump inhibitors |
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2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100184807A1 (en) * | 2008-03-04 | 2010-07-22 | Bio-Quant, Inc. | Methods to inhibit tumor cell growth by using proton pump inhibitors |
Non-Patent Citations (3)
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| 严世芸主编: "《中国中医药学术年鉴》", 31 December 2003 * |
| 常旭等主编: "《原发性肝癌的治疗》", 30 April 1994 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110292577A (en) * | 2019-08-19 | 2019-10-01 | 庹必光 | Application of the Pantoprazole in the drug of preparation prevention and treatment nonalcoholic fatty liver |
| CN110522752A (en) * | 2019-08-19 | 2019-12-03 | 庹必光 | Application of the Pantoprazole in the drug of preparation prevention and treatment liver fibrosis |
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