阅读说明：本技术 阿苯达唑或其药学上可接受的盐在治疗胆管癌药物中的作用 (Application of albendazole or pharmaceutically acceptable salt thereof in medicaments for treating bile duct cancer ) 是由 李学荣 何晴 吴银娟 殷颖璇 于 2020-07-15 设计创作，主要内容包括：本发明提供阿苯达唑或其药学上可接受的盐在治疗胆管癌药物中的作用。实验验证阿苯达唑能够促进胆管癌细胞凋亡和抑制胆管癌细胞克隆。本发明为胆管癌的药物治疗提供了新方案。(The invention provides the effect of albendazole or a pharmaceutically acceptable salt thereof in a medicament for treating bile duct cancer. Experiments prove that the albendazole can promote the apoptosis of bile duct cancer cells and inhibit the cloning of the bile duct cancer cells. The invention provides a new scheme for the drug treatment of the bile duct cancer.)

1. Use of albendazole or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of cholangiocarcinoma.

2. Use according to claim 1, characterized in that: the pharmaceutically acceptable salt is a salt formed by combining albendazole with an acid, wherein the acid is selected from at least one of hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, aspartic acid and glutamic acid of benzenesulfonic acid.

3. Use according to claim 1, characterized in that: the cholangiocarcinoma is primary or secondary.

4. Application of albendazole in preparation of preparation for promoting bile duct cancer cell apoptosis.

5. Application of albendazole in preparation of preparations for inhibiting bile duct cancer cell clone or preparations for inhibiting proliferation of bile duct cancer cells.

6. A medicament for preventing or treating bile duct cancer, which is characterized by containing albendazole in a preventive or therapeutic effective amount.

7. The medicament of claim 6, wherein: the medicine also comprises a carrier acceptable to human bodies.

8. The medicament of claim 6, wherein: the albendazole is the only effective component or one of the effective components of the medicine.

9. A pharmaceutical composition for treating or preventing bile duct cancer, characterized in that: the pharmaceutical composition contains a prophylactically or therapeutically effective amount of albendazole and at least one other drug for treating or preventing bile duct cancer.

10. A method for preventing or treating non-therapeutic bile duct cancer is to administer an effective amount of albendazole to a subject and/or an effective amount of other drugs for treating bile duct cancer to the subject.

Technical Field

The invention relates to a novel pharmaceutical application of a compound, in particular to an application of albendazole or pharmaceutically acceptable salts thereof in medicaments for treating bile duct cancer.

Background

Drug-assisted chemotherapy is one of the most effective methods for treating bile duct cancer (including ICC and EHCC) after operation at present. Many existing traditional chemotherapy drugs become important factors for preventing poor prognosis chemotherapy effect of intrahepatic bile duct cancer due to their own side effects and drug resistance, for example, gemcitabine and cisplatin, which are most commonly used in treatment of advanced bile duct cancer, still have side effects of easily causing mild-moderate digestive system reaction and liver and kidney dysfunction, and have limitation of clinical drug resistance as a first-line drug administration scheme. It is therefore an important and novel direction of research to improve new treatment regimens by relocating the therapeutic effect of existing non-chemotherapeutic drugs in intrahepatic bile duct cancer.

Albendazole (ABZ) is widely used in clinical treatment as an anthelmintic, but no relevant research reports about its therapeutic effect in bile duct cancer.

Disclosure of Invention

In view of the defects of the prior art, the invention aims to provide the effect of albendazole or the pharmaceutically acceptable salt thereof in the medicine for treating the bile duct cancer, and provides a new idea for treating the bile duct cancer.

To achieve the above and other related objects, the present invention provides the use of albendazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of bile duct cancer.

Albendazole is available in a commercially available form, having the formula:

pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid.

Further, the intrahepatic bile duct cancer may be primary or secondary.

The albendazole has at least one of the following effects:

treating intrahepatic bile duct cancer; inhibiting the proliferation rate of intrahepatic bile duct cancer cells; promoting the apoptosis of intrahepatic bile duct cancer cells; inhibiting the cloning of intrahepatic bile duct cancer cells; affecting the cycle of intrahepatic bile duct cancer cells; inhibiting the development of intrahepatic bile duct cancer.

On the other hand, the invention provides the application of albendazole in preparing a preparation for treating and promoting the apoptosis of intrahepatic bile duct cancer cells.

The invention also provides application of albendazole in preparation of a preparation for inhibiting intrahepatic bile duct cancer cell clone.

In another aspect, the invention provides an application of albendazole in preparing a preparation for inhibiting proliferation of intrahepatic bile duct cancer cells.

In another aspect of the present invention, there is provided a medicament for the prevention or treatment of intrahepatic bile duct cancer, which comprises a prophylactically or therapeutically effective amount of albendazole.

Further, the medicine also comprises a human acceptable carrier. Such vectors include (but are not limited to): saline, buffer, dextrose, water, glycerol, ethanol, powders, and combinations thereof. The pharmaceutical preparation should be compatible with the mode of administration.

Furthermore, the albendazole is the only effective component or one of the effective components of the medicine.

In another aspect, the present invention provides a pharmaceutical composition for treating or preventing intrahepatic bile duct cancer, which comprises a prophylactically or therapeutically effective amount of albendazole and at least one other drug for treating or preventing intrahepatic bile duct cancer.

The pharmaceutical composition may be in any one of the following forms:

firstly), albendazole and other medicines for treating or preventing intrahepatic bile duct cancer are respectively prepared into independent preparations, the preparation forms can be the same or different, and the administration routes can also be the same or different.

Secondly), the albendazole and other medicines for treating or preventing the intrahepatic bile duct cancer are prepared into a compound preparation, and when the albendazole and other medicines for treating the bile duct cancer are administrated by the same administration route and applied simultaneously, the albendazole and the other medicines can be prepared into the compound preparation.

Such other therapeutic or prophylactic agents for cholangiocarcinoma include, but are not limited to: antibody drugs, chemical drugs, targeted drugs, and the like, preferably chemical drugs, and the administration mode may be gastrointestinal administration or parenteral administration.

The form of the drug or the pharmaceutical composition is not particularly limited, and may be in the form of various substances such as solid, liquid, gel, semifluid, aerosol, and the like.

In the case of pharmaceutical compositions, the compositions of the present invention may be prepared in the form of injections, for example, by conventional methods using physiological saline or aqueous solutions containing glucose and other adjuvants. Pharmaceutical compositions, such as tablets and capsules, can be prepared by conventional methods. Pharmaceutical compositions such as injections, solutions, tablets and capsules are preferably manufactured under sterile conditions.

The medicament, preparation or pharmaceutical composition of the present invention can be administered to a desired subject (e.g., human and non-human mammals) by a conventional manner. Representative modes of administration include (but are not limited to): oral administration or injection (including one or more of intravenous injection, intravenous drip, intramuscular injection or subcutaneous injection, etc.), etc. When the pharmaceutical composition is used, a safe and effective amount of the drug is administered to the mammal. Of course, the particular dosage and method will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.

In another aspect of the invention, a non-therapeutic method for preventing or treating bile duct cancer is provided, wherein an effective amount of albendazole is administered to a subject and/or an effective amount of other drug for treating or preventing bile duct cancer is administered to a subject.

As described above, the present invention has the following advantageous effects:

a series of in vitro experiments are carried out to detect the effect of ABZ in two bile duct cancer cell lines, and the results show that the ABZ can obviously inhibit the proliferation of bile duct cancer cells and promote the apoptosis of the bile duct cancer cells, and the ABZ is suggested to have a treatment effect on the bile duct cancer.

Drawings

Fig. 1 shows ABZ cytotoxicity against two bile duct cancer cells.

FIG. 2a shows the effect of ABZ on FRH clonality of cholangiocarcinoma cells.

FIG. 2b shows the effect of ABZ on RBE clonogenic biliary tract cancer cells.

FIG. 3 shows the effect of ABZ on cholangiocarcinoma cell proliferation.

Fig. 4 is a flow cytometry showing the effect of ABZ on bile duct cancer RBE apoptosis.

FIG. 5 shows the effect of ABZ on the expression of apoptosis-related proteins by bile duct cancer RBE.

Detailed Description

The embodiments of the present invention are described below with reference to specific embodiments, and other advantages and effects of the present invention will be easily understood by those skilled in the art from the disclosure of the present specification. The invention is capable of other and different embodiments and of being practiced or of being carried out in various ways, and its several details are capable of modification in various respects, all without departing from the spirit and scope of the present invention.

Before the present embodiments are further described, it is to be understood that the scope of the invention is not limited to the particular embodiments described below; it is also to be understood that the terminology used in the examples is for the purpose of describing particular embodiments, and is not intended to limit the scope of the present invention; in the description and claims of the present application, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise.

When numerical ranges are given in the examples, it is understood that both endpoints of each of the numerical ranges and any value therebetween can be selected unless the invention otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition to the specific methods, devices, and materials used in the examples, any methods, devices, and materials similar or equivalent to those described in the examples may be used in the practice of the invention in addition to the specific methods, devices, and materials used in the examples, in keeping with the knowledge of one skilled in the art and with the description of the invention.

Unless otherwise indicated, the experimental methods, detection methods, and preparation methods disclosed herein all employ techniques conventional in the art of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related arts. These techniques are well described in the literature, see, in particular, Sambrook et al

MOLECULAR CLONING: a LABORATORY MANUAL, Second edition, Cold spring harbor LABORATORY Press, 1989and Third edition, 2001; ausubel et al, CurentProtocols IN MOLECULAR BIOLOGY, John Wiley & Sons, New York, 1987and periodictargets; the series METHODS IN ENZYMOLOGY, Academic Press, San Diego; wolffe, CHROMATIN STRUCTURE AND FUNCTION, Third edition, Academic Press, San Diego, 1998; (iii) METHODS IN ENZYMOLOGY, Vol.304, Chromatin (P.M.Wassarman and A.P.Wolffe, eds.), Academic Press, San Diego, 1999; and METHODS IN MOLECULAR BIOLOGY, Vol.119, chromatography Protocols (P.B.Becker, ed.) Humana Press, Totowa, 1999, etc.

Test materials and reagents

Bile duct cancer cell line RBE: ginie Europe Bio Inc., LOT JNO-20705

Cholangiocarcinoma cell line FRH, LoT, HTX2093, Haodihuatu Biotech Co., Ltd

Hepatocyte LO 2: the Beina biology number: BNCC100012

DMEM medium: GIBCO corporation, LOT 8120064

Pancreatin of EDTA GIBCO Inc., LOT 2042303

Protein lysis mixture CWBIO corporation, LOT 01408/40351

BCA protein concentration kit, TRANS company, LOT: # N20829