阅读说明：本技术 绿原酸、同分异构体或药学上可接受的盐在制备肿瘤化疗增敏药物中的应用 (Application of chlorogenic acid, isomer or pharmaceutically acceptable salt in preparing tumor chemotherapy sensitization medicine ) 是由 刘玉琳 王强 颜泽萱 向卓 于 2020-05-28 设计创作，主要内容包括：本发明涉及绿原酸、同分异构体或药学上可接受的盐在制备肿瘤化疗增敏药物中的应用,提供了绿原酸、同分异构体或药学上可接受的盐的新医学用途,即诱导肿瘤干细胞分化,削减肿瘤干细胞的生物学特征,作为肿瘤化疗的增敏剂,用于提高化疗药物的治疗敏感性。本发明与传统肿瘤治疗方案联合应用,可以显著减少细胞毒性药物的用量,从而减少传统治疗毒副反应的发生率,增加肿瘤化疗的安全性和治疗效应,削减化疗导致的肿瘤干性增强,从而增强肿瘤化疗敏感性。(The invention relates to application of chlorogenic acid, an isomer or a pharmaceutically acceptable salt in preparing a tumor chemotherapy sensitizing medicament, and provides new medical application of the chlorogenic acid, the isomer or the pharmaceutically acceptable salt, namely inducing differentiation of tumor stem cells and reducing biological characteristics of the tumor stem cells, and the chlorogenic acid, the isomer or the pharmaceutically acceptable salt is used as a sensitizing agent for tumor chemotherapy for improving the treatment sensitivity of the chemotherapy medicament. The invention is combined with the traditional tumor treatment scheme for application, can obviously reduce the dosage of cytotoxic drugs, thereby reducing the incidence rate of toxic and side effects of the traditional treatment, increasing the safety and treatment effect of tumor chemotherapy, and reducing the dryness enhancement of tumors caused by the chemotherapy, thereby enhancing the sensitivity of the tumor chemotherapy.)

1. Application of chlorogenic acid, isomer or pharmaceutically acceptable salt in preparing tumor stem cell inhibitor medicine is provided.

2. Application of chlorogenic acid, isomer or pharmaceutically acceptable salt in preparing tumor chemotherapy sensitization medicine is provided.

3. Chlorogenic acid, isomers or pharmaceutically acceptable salts can be combined with other antitumor drugs for preparing tumor chemotherapy drugs.

4. A tumor chemotherapy sensitization medicine is characterized in that the effective component of the medicine is chlorogenic acid, isomer or pharmaceutically acceptable salt.

5. A tumor chemotherapy medicine is characterized in that the effective components of the medicine are chlorogenic acid, isomer or pharmaceutically acceptable salt and other antitumor medicines.

Technical Field

The invention belongs to the technical field of biological medicines, and relates to application of chlorogenic acid, an isomer or pharmaceutically acceptable salt in preparing tumor chemotherapy sensitizing drugs.

Background

Chemotherapy is an important approach to the treatment of malignant tumors. The traditional Chinese medicine composition plays an important role in treating digestive tract tumors, lung cancers, three-yin breast cancers and gynecological tumors. Clinical routine chemotherapy regimens, usually platinum based combination chemotherapy regimens, inhibit tumor progression through cytotoxicity. However, malignant tumors often develop drug resistance, which is a key factor limiting the effectiveness of traditional chemotherapy treatments. How to improve the chemotherapy effect through a proper sensitization scheme is an important strategy for improving the treatment prognosis of malignant tumor patients.

Tumor stem cells (CSCs) represent only a very small proportion of the heterogeneous tumor cell population, but play a critical role in tumorigenesis and progression. CSCs are defined as "cells that have self-renewal ability and can initiate tumors", and their stem-like nature, which differentiate into high proliferation potential daughter cells, leads to heterogeneous tumor stem cells of tumors to maintain their survival advantage in the tumor killing environment through the self-renewal cell property, and are the root of tumor progression and recurrence, playing a key role in tumor resistance. The combined chemotherapy scheme based on platinum drugs cannot inhibit or kill tumor stem cells and becomes the root cause of drug-resistant relapse of tumors. How to induce killing of CSCs is critical to improving drug sensitivity of traditional chemotherapeutic regimens.

Chlorogenic acid (also known as 3-O-caffeoylquinic acid) belongs to the phenylpropanoid class of compounds. The isomer of neochlorogenic acid is also called trans-5-O-caffeoyl quinic acid and cryptochlorogenic acid is also called 4-O caffeoyl quinic acid. The compounds have wide pharmacological action, and can reduce blood lipid, resist oxidation, reduce blood glucose, resist ultraviolet light and radiation, resist bacteria, regulate immunity, etc. Chlorogenic acid and derivatives also show certain activity of inhibiting tumor proliferation in tumor treatment, but generally depend on higher drug concentration. Chlorogenic acid has low solubility in water and poor bioavailability, so that the clinical application value of chlorogenic acid is limited. In addition, chlorogenic acid molecules contain unstable structures such as ester bonds, polyphenol and unsaturated double bonds, the structures of the chlorogenic acid can be damaged by heat and light, the stability is poor, the quality guarantee period is short, and the clinical application of the chlorogenic acid is limited. Therefore, the application of chlorogenic acid in tumor treatment is still in an exploration stage, and the application of chlorogenic acid in preparing chemosensitization medicines is not reported.

Disclosure of Invention

In view of the above, one of the objectives of the present invention is to provide the application of chlorogenic acid, isomers or pharmaceutically acceptable salts in the preparation of tumor chemosensitization drugs; the second purpose of the invention is to provide the application of the chlorogenic acid, the isomer or the pharmaceutically acceptable salt in preparing the tumor chemotherapy medicament in combination with other anti-tumor medicaments; the third purpose of the invention is to provide a tumor chemotherapy sensitizing medicament; the fourth purpose of the invention is to provide a tumor chemotherapy medicament.

In order to achieve the purpose, the invention provides the following technical scheme:

1. application of chlorogenic acid, isomer or pharmaceutically acceptable salt in preparing tumor stem cell inhibitor medicine is provided.

Preferably, the isomer is neochlorogenic acid (5-O-caffeoyl quinic acid) or cryptochlorogenic acid (4-O-caffeoyl quinic acid).

Further preferably, the isomer is neochlorogenic acid.

Preferably, the pharmaceutically acceptable salt includes, but is not limited to, a sodium salt, a magnesium salt, or a calcium salt.

Preferably, the tumor includes, but is not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer or liver cancer.

2. Application of chlorogenic acid, isomer or pharmaceutically acceptable salt in preparing tumor chemotherapy sensitization medicine is provided.

Preferably, the isomer is neochlorogenic acid (5-O-caffeoyl quinic acid) or cryptochlorogenic acid (4-O-caffeoyl quinic acid).

Further preferably, the isomer is neochlorogenic acid.

Preferably, the pharmaceutically acceptable salt includes, but is not limited to, a sodium salt, a magnesium salt, or a calcium salt.

Preferably, the tumor includes, but is not limited to, breast cancer, gastric cancer, colorectal cancer, lung cancer, ovarian cancer or liver cancer.

3. Chlorogenic acid, isomers or pharmaceutically acceptable salts can be combined with other antitumor drugs for preparing tumor chemotherapy drugs.

Preferably, the other anti-tumor drugs include, but are not limited to, cisplatin, adriamycin, paclitaxel, 5-fluorouracil, vincristine, trastuzumab, sorafenib, or gefitinib.

Further preferably, the other antitumor drug is cisplatin.

4. A tumor chemotherapy sensitizing medicine contains chlorogenic acid, isomer or pharmaceutically acceptable salt as effective component.

Preferably, the drug further comprises a pharmaceutically acceptable carrier, an absorption enhancer and an excipient, wherein the pharmaceutically acceptable carrier includes, but is not limited to, microcapsules, microspheres, nanoparticles, liposomes, and the like, and the absorption enhancer includes, but is not limited to, cholic acid and salts thereof (such as sodium deoxycholate), surfactants (such as poloxamer), polymeric materials (such as carbomer), and the like.

Preferably, the dosage form of the medicament is oral dosage form or parenteral dosage form, and specifically includes but is not limited to tablets, capsules, solutions, suspensions, granules, injections, transdermal preparations or implants.

5. A chemotherapeutic medicine for treating tumor contains chlorogenic acid, isomer or pharmaceutically acceptable salt and other antineoplastic agents as effective components.

Preferably, the mass ratio of the chlorogenic acid, the isomer or the pharmaceutically acceptable salt to other antitumor drugs is 0.2-11.5: 1.

preferably, the other anti-tumor drugs include, but are not limited to, cisplatin, adriamycin, paclitaxel, 5-fluorouracil, vincristine, trastuzumab, sorafenib, or gefitinib.

Further preferably, the other antitumor drug is cisplatin.

Preferably, the drug further comprises a pharmaceutically acceptable carrier, an absorption enhancer and an excipient, wherein the pharmaceutically acceptable carrier includes, but is not limited to, microcapsules, microspheres, nanoparticles, liposomes, and the like, and the absorption enhancer includes, but is not limited to, cholic acid and salts thereof (such as sodium deoxycholate), surfactants (such as poloxamer), polymeric materials (such as carbomer), and the like.

Preferably, the dosage form of the medicament is oral dosage form or parenteral dosage form, and specifically includes but is not limited to tablets, capsules, solutions, suspensions, granules, injections, transdermal preparations or implants.

The invention has the beneficial effects that:

the invention provides a new medical application of chlorogenic acid, an isomer or a pharmaceutically acceptable salt, namely inducing differentiation of tumor stem cells, reducing biological characteristics of the tumor stem cells, and serving as a sensitizer for tumor chemotherapy for improving treatment sensitivity of chemotherapeutic drugs. The invention is combined with the traditional tumor treatment scheme for application, can obviously reduce the dosage of cytotoxic drugs, thereby reducing the incidence rate of toxic and side effects of the traditional treatment, increasing the safety and treatment effect of tumor chemotherapy, and reducing the dryness enhancement of tumors caused by the chemotherapy, thereby enhancing the sensitivity of the tumor chemotherapy.

Drawings

In order to make the object, technical scheme and beneficial effect of the invention more clear, the invention provides the following drawings for explanation:

FIG. 1 is a structural formula of chlorogenic acid and isomers thereof, wherein a is chlorogenic acid, b is neochlorogenic acid, and c is cryptochlorogenic acid;

FIG. 2 shows that chlorogenic acid and isomers thereof reduce the balling capacity of tumor cells, wherein a to f are gastric cancer cell line SGC7901, liver cancer cell line HepG2, colon cancer cell line SW480, lung cancer cell line A549, breast cancer MDA-MB231 and ovarian cancer cell line SKOV-3 cells in sequence;

FIG. 3 shows the ratio of chlorogenic acid and its isomers to decrease CSCs in tumor cell lines;

FIG. 4 is a graph showing the effect of different concentrations of chlorogenic acid and its isomers in combination with cisplatin on breast cancer cell proliferation;

FIG. 5 shows the effect of chlorogenic acid and its isomers in combination with cisplatin on the proliferation potency of tumor cells;

FIG. 6 shows the effect of chlorogenic acid and its isomers in combination with cisplatin on the growth of subcutaneous transplantable tumor of nude mouse, wherein a-f are stomach cancer cell line SGC7901, liver cancer cell line HepG2, colon cancer cell line SW480, lung cancer cell line A549, breast cancer MDA-MB231, ovarian cancer cell line SKOV-3 cells in sequence;

FIG. 7 shows the effect of chlorogenic acid and its isomers in combination with cisplatin on the body weight of nude mice, wherein a-f are gastric cancer cell line SGC7901, liver cancer cell line HepG2, colon cancer cell line SW480, lung cancer cell line A549, breast cancer MDA-MB231, and ovarian cancer cell line SKOV-3 cells in sequence.

Detailed Description

Preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings.