CN115887473A - Application of verbascoside compound or derivative thereof in preparation of bladder cancer resistant medicines - Google Patents
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Abstract
The invention discloses an application of a verbascoside compound or a derivative thereof in preparing anti-bladder cancer medicaments. In addition, the invention also discloses a pharmaceutical composition, which comprises a component A and a component B; wherein component A is selected from: verbascoside compounds and/or derivatives thereof; the component B is selected from: lapatinib or other chemical drugs used clinically for the treatment of bladder cancer. In addition, the invention also discloses a kit, which comprises a kit A and a kit B; wherein, the kit A comprises a verbascoside compound and/or a derivative thereof, and the kit B comprises lapatinib. Moreover, the invention also discloses a kit and a drug delivery device. The invention firstly provides the therapeutic action of the verbascoside compound on the bladder cancer, thereby being beneficial to actively searching a safer and more effective perfusion method of the bladder cancer, reducing the recurrence of the bladder cancer, improving the therapeutic effect of patients with the bladder cancer and improving the life quality of the patients with the bladder cancer.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an application of a verbascoside compound or a derivative thereof in preparation of bladder cancer resistant medicines, in particular to an anti-tumor effect of the verbascoside compound on bladder cancer.
Background
Bladder Cancer (BC) is a common urological malignancy worldwide, with the prevalence of men being about three times that of women in some areas (see: korea soviet, tensor, chen wan et al [ J ] cancer progression. 2013,11 (01)), exposure to chemical carcinogens, smoking, etc., all factors that induce or promote bladder tumorigenesis. Bladder cancer can be classified as non-muscle invasive bladder cancer (NMIBC) and Muscle Invasive Bladder Cancer (MIBC) depending on whether the tumor invades the muscle tissue. At the time of initial diagnosis, 70% -75% of patients were diagnosed as NMIBC, the remaining 25% -30% were MIBC or had distant metastasis (see: kates M, date A, yoshida T, et al. Predictive Evaluation of intraspecific peptides for Non-human-invader blade Cancer. Clin Cancer Res.2017;23 (21): 6592-6601. And Fang D, kitamura H. Cancer stem cells and epithelial-sensory transport in epithelial Cancer. Int. J. Urol. 8;25 (1): 7-17).
Transurethral resection of bladder tumor (TURBT) is currently the standard treatment for NMIBC, with a bladder perfusion treatment protocol determined post-operatively based on risk of recurrence (see Nason GJ, ajib K, tan GH, kulkarni GS. Radiator-spraying treatment in localized muscle-innovative radiator. Expert Rev Anticancer. Ther. 2020, 20 (3): 179-188.. MIBC surgery is mainly radical cystectomy, and it is determined whether to be assisted by systemic chemotherapy and/or radiation therapy according to the high risk factors of pathological outcome after surgery (see: kates M, matoso A, choi W, et al. Adaptive Immune response to intensive BCG in Non-Muscle animal active blower Cancer: immunological for productive BCG-nonresponsive Trials. Clin Cancer Res.2020;26 (4): 882-891.). Most of NMIBC patients after TURBT progress to MIBC or develop distant urinary metastasis due to incomplete primary tumor resection, tumor cell engraftment or new tumor development, etc., resulting in higher recurrence and mortality (see Prasad SM, decastro GJ, steinberg GD; medscape. Urotheca of the blader: definition, treatment and future efforts. Nat Rev Urol.2011;8 (11): 631-642.). The current first line regimen for bladder cancer is a cisplatin-based chemotherapy regimen, however, about 50% of patients are clinically resistant to this regimen. Postoperative Bladder perfusion treatment with drugs such as BCG can effectively improve patient recurrence and progression, but is not suitable for all patients due to its large toxic side Effects (see: koch GE, smelser WW, chang SS. Side Effects of intensive BCG and Chemotherapy for blower Cancer: at the same arm and How to Manage the. Urology.2021; 149-20.. The human epidermal growth factor receptor (epidermal growth factor receptor family) comprises 4 main members, namely ErbB1 (EGFR/HER 1), erbB2 (HER 1), erbB3 (HER 3) and ErbB4 (HER 4), wherein the EGFR and the HER2 play a central role in participating in the development of bladder Cancer tumors (see: cancer Genome Atlas Research network. Comprehensive molecular characterization of urothelial blank receptor Cancer. Nature.2014;507 (7492): 315-322.). Lapatinib is a dual small molecule reversible tyrosine kinase inhibitor against HER2 and EGFR, approved for the treatment of HER 2-positive recurrent or advanced metastatic breast cancer. Based on effective preclinical and clinical evidence, several clinical trials for anti-HER 2 therapy in bladder cancer have been performed today. A single-arm open phase 2 clinical trial using lapatinib (an ErbB family oral irreversible inhibitor) for treatment OF HER2 or HER3 positive metastatic bladder cancer resulted in significantly longer progression-free survival (see: afatinib Is Active in Platinum-reflective ERBB-Mutant oral Carcinoma. Cancer Discov.2016;6 (6): 13.). However, in a Phase 3 clinical Trial Lapatinib Maintenance treatment for HER1 and or HER2 Positive Metastatic Bladder cancer Patients following platinum Chemotherapy, no significant survival benefit was achieved (see: chang SS. Re: phase III, double-bind, random triple that shared Maintane Lapatinib versicolor Placebo after First-Line Chemotherapy in Patients with Human epitopic Growth Factor Receptor 1/2-Positive allergic adaptive blast cancer cell cancer.J. 2018;199 (4): 891-892.).
Therefore, it is highly important to actively search for a safer and more effective perfusion method for bladder cancer, reduce the recurrence of bladder cancer, improve the therapeutic effect of bladder cancer patients, and improve the quality of life of bladder cancer patients.
Furthermore, it will be appreciated by those skilled in the art that an anti-tumor drug is effective, being related to the characteristics of the targeted tumor. Drugs effective against some non-bladder cancers, such as oral cancer and liver cancer, are not necessarily suitable for bladder cancer. For example: sorafenib, indicated for hepatocellular carcinoma, renal cell carcinoma or differentiated thyroid carcinoma (head and neck tumors of the same genus as oral cancer), is not effective in bladder cancer.
Disclosure of Invention
Aiming at the current situations that bladder cancer is easy to relapse and poor in prognosis and the current treatment means has limited effect of improving the treatment effect of bladder cancer patients, the invention aims to provide the application of the verbascoside compound or the derivative thereof in the preparation of anti-bladder cancer drugs.
In order to achieve the above object, the present invention is achieved by the following aspects:
in a first aspect, the invention provides the use of verbascoside compounds or derivatives thereof in the preparation of anti-bladder cancer medicaments.
Acteoside (A01) is called acteoside and verbascoside, and is a phenylethanoid glycoside compound. A01 has a variety of pharmacological activities including anti-inflammatory, antioxidant and antitumor effects (see: alipieva K, korkina L, orhan IE, georgiev MI. Verbasco- -a review of its ocurrence, (bio) synthesis and pharmacological design. Biotechnol. Adv. 2014 32 (6): 1065-1076). In previous studies, A01 was found to have some tumor growth inhibition in oral and liver cancers (see: zhang Y, yuan Y, wu H, et al. Effect of very basic on apoptosis and metastasis in human organic cell cancer. Int J cancer.2018;143 (4): 980-991. And Ma D, wang J, liu L, chen M, wang Z. Acidity a porous thermal analysis for primary refractory. BMC cancer.2020;20 (1): 936.), but no report on the effect of A01 on bladder cancer was found.
The inventor discovers that the therapeutic effect of the verbascoside compound on the bladder cancer is provided for the first time through a large number of experimental researches. In addition, since a01 can be adapted for bladder instillation, it has no significant toxic side effects that may result from systemic use, i.e., it has the advantage of not exacerbating clinical drug regimen toxicity.
It is noted that the statement that a01 can be applied to bladder instillation does not exclude other modes of administration, for example a01 can also be administered systemically.
Preferably, the derivative is selected from a salt, ester, prodrug or solvate;
and/or, the verbascoside compound has the following structure:
and/or the verbascoside compound or the derivative thereof is used in an amount of 50-5000 mug/ml;
preferably, the verbascoside compound or derivative thereof is infused into the bladder.
In the above scheme, bladder perfusion is preferably adopted, and the total volume of clinical bladder perfusion is about 30-50ml, so the total dosage for bladder perfusion is 1.5-250mg, and can also be used for conventional systemic administration, oral administration or injection dosage, and the skilled person can convert the dosage according to the body surface area of a patient and the like as required, and therefore, the details are not repeated herein.
Preferably, the verbascoside compound or the derivative thereof is added with conventional auxiliary materials according to the conventional process to prepare clinically acceptable tablets, capsules, powder, mixtures, granules, syrups, plasters, suppositories, aerosols, ointments or injections.
In a second aspect, the present invention provides a pharmaceutical combination comprising component a and component B;
wherein component A is selected from: verbascoside compounds and/or derivatives thereof;
the component B is selected from: lapatinib and/or other chemical drugs clinically used for the treatment of bladder cancer, such as one or more of carboplatin and doxorubicin.
Preferably, the pharmaceutical combination further comprises a pharmaceutically acceptable carrier.
In the scheme, lapatinib is originally used for treating Her 2-expressing breast cancer, and researches show that the breast cancer has Her2 expression, so that when the Her2 positive bladder cancer is treated by lapatinib in the clinical stage 2, the effective treatment can enter the stage 3, and no obvious survival benefit exists in the current stage 3 clinical test. However, the use of lapatinib in combination with verbascoside bladder instillation, which does not induce systemic effects, increases the efficacy of lapatinib in treating Her 2-positive bladder cancer. Thus, the verbascoside compound has an epitaxial effect, and can be combined with other medicaments for treating bladder cancer to generate a common bladder cancer resisting effect.
In a third aspect, the invention provides an application of the pharmaceutical composition in preparing an anti-bladder cancer medicament.
In a fourth aspect, the present invention provides a kit comprising a kit a and a kit B;
wherein kit A comprises a verbascoside compound and/or a derivative thereof and kit B comprises lapatinib;
preferably, the administration of kit a and kit B is not sequential or preceded by administration of kit a; and/or, the kit further comprises kit C, which comprises a further therapeutic agent;
more preferably, the administration of kit a, kit B and kit C is not sequential or preceded by administration of kit a.
In a fifth aspect, the present invention provides a kit comprising the pharmaceutical combination described above.
In a sixth aspect, the present invention provides a drug delivery device comprising:
an infusion module for administering the above-described drug combination to a subject in need thereof.
Preferably, the drug delivery device further comprises a drug efficacy monitoring module.
It should be noted that, in the technical scheme of the invention, the description of the component A and the component B is only used for distinguishing the description and should not be taken as the adding sequence, and the existence of the alternative method, the improvement method and the transformation method is obvious to the ordinary skilled person in the art, and all the alternative method, the improvement method and the transformation method are considered to be included in the invention.
It should be noted that, in the technical scheme of the invention, the description of the kit A and the kit B is only used for distinguishing the description, and the description should not be taken as an adding sequence, and the existence of the alternative method, the improvement method and the change method is obvious for a person with ordinary skill in the art, and all the alternative method, the improvement method and the change method are considered to be included in the invention.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the invention firstly provides the therapeutic action of the verbascoside compound or the derivative thereof on the bladder cancer, thereby being beneficial to actively searching a safer and more effective perfusion method for the bladder cancer, reducing the recurrence of the bladder cancer, improving the therapeutic effect of patients with the bladder cancer and improving the life quality of the patients with the bladder cancer.
Drawings
FIG. 1 shows the HE staining and growth of bladder cancer tissue and bladder cancer organoids;
fig. 2 to 4 are fitting curves of the drug sensitivity test results of bladder cancer organoids, wherein fig. 2 is a fitting curve of the drug sensitivity test results of No. 1 bladder cancer organoids, in which a01 refers to a01 administration alone, lapatinib refers to a Lapatinib administration alone, and a01& Lapatinib refer to a01 and Lapatinib administration in combination;
FIG. 3 is a graph of the drug sensitivity test results for bladder cancer organoid No. 2, wherein A01 refers to A01 alone, lapatinib alone refers to Lapatinib alone, A01& Lapatinib refers to A01 and Lapatinib in combination;
FIG. 4 is a graph fitted with drug sensitivity test results for bladder cancer organoids No. 3, in which A01 refers to A01 alone, lapatinib refers to Lapatinib alone, and A01& Lapatinib refers to A01 and Lapatinib in combination.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected in accordance with conventional methods and conditions, or in accordance with the instructions for commercial products.
1. Test sample
A01 was purchased from qiangtai pharmaceutical limited, jiang su, lot No.: 100581; the purity is more than or equal to 99 percent (HPLC).
2. Instrumentation apparatus
Superclean bench: suzhou purification equipment Limited, SW-CJ-2FD model, meitian and whirly Gentle MACS Ocot eight channel band heating fully automated tissue processor, full wavelength multifunctional microplate reader, cell culture box, inverted microscope.
3. Experimental methods
The tumor cell line with stable passage is the most widely applied in vitro model in the tumor research field at present, but has the problems of single cell type, lack of heterogeneity of original tumor and the like, and due to the difference between the tumor cell line and clinical tumor, the potential of the tumor cell line as a preclinical anti-tumor model is limited to a certain extent. A tumor organoid (PDO) is a multicellular mass which is obtained by three-dimensional culture of somatic stem cells in tumor tissues and retains multiple characteristics of original tumors (see: drost J, developers H. Organic in cancer research. Nat Rev cancer.2018;18 (7): 407-418). Compared with a traditional cell line and a human tumor animal transplanted tumor PDX model, the PDO has the advantages of high proliferation speed, short culture period, high establishment rate and high consistency with the original tumor tissues, and has a wide application prospect in-vitro tumor research, particularly in an anti-cancer drug development platform and individualized precise treatment. The drug evaluation center of the State drug administration has listed organoids as one of the technical guidelines of non-clinical research and technical evaluation of genetically modified cell therapy products.
Preparation of bladder cancer organoids:
the tumor specimen is placed in a sterile culture dish, washed by PBS for a plurality of times and then cut into small pieces with the diameter of less than 2mm by using a sterilized surgical instrument. According to Gentle
Preparing a certain amount of enzymolysis liquid according to the weight of a tumor specimen, and then mixing the enzymolysis liquid and the tumor specimenTransferred together into C-tubes and different programs of the Gentle MACS tissue processor were selected according to the tumor texture. After the procedure was completed, the C tube was removed, the suspension transferred to a 15mL centrifuge tube, the erythrocytes were removed by lysis with erythrocyte lysate, washed several times, the cell pellet was suspended with medium to the desired volume, mixed with a certain amount of Matrigel gel, inoculated into an opaque 96 well plate, placed at 37 ℃ and 5% CO 2 Is incubated in the incubator of (1).
Test grouping and drug intervention:
dividing the cultured bladder cancer organoids into a lapatinib monotherapy group, an A01 lapatinib combined medication group and a blank control group. Wherein, in the lapatinib single traditional Chinese medicine, the lapatinib administration concentrations are respectively as follows: 10. 1 and 0.1 mu M, and the dosage concentration of A01 in the A01 single medicine group is respectively as follows: 1000. 100 and 10. Mu.M; in the A01 Lapatinib combined medicine group, the concentration of Lapatinib is 10, 1 and 0.1 mu M respectively, and the concentration of A01 is 250 mu M. And after the organoids in the holes successfully grow out, removing the original culture medium, and adding a corresponding medicine-containing culture medium for continuous culture for 72 hours.
Detection index and method
By using
The 3D luminescence method cell viability detection kit is used for measuring the cell viability of 3D cultured cells by quantifying ATP. After the drug acts on the bladder cancer organoids for 72 hours, CTL solution is added into each hole, and after incubation for 90 minutes, the chemiluminescence OD value is measured at 570nm by using a full-wavelength multifunctional microplate reader. Tumor inhibition (IR%) was calculated according to the following formula: IR% = (1-dose absorbance/control absorbance) × 100%, curves were plotted and fitted with Graphpad, and half inhibitory concentration (IC 50) of drug was calculated.
The results are shown in table 1:
table 1.
As can be seen from table 1: the growth conditions before and after the organoids are administrated in the experimental process are shown in figure 1, a plurality of spherical and transparent bladder cancer organoids can be observed before the organoids are administrated, and after 72 hours of administration, the organoids of different groups of administration medicines collapse and disintegrate. And (3) detecting the cell viability after treatment of the drugs with different concentrations, drawing a scatter diagram by taking the logarithm value of the drug concentration as an X axis and the cell viability as a Y axis, and performing curve fitting by using Graphpad software to calculate the drug IC50. As the drug concentration increases, the tumor cell viability (chemiluminescence value) decreases. The experiment comprises a No. 1 bladder cancer organoid sensitive to lapatinib, a No. 2 bladder cancer organoid sensitive to lapatinib and a No. 3 bladder cancer organoid insensitive to lapatinib, and after the A01 combined drug is added, the inhibition effect on the bladder cancer organoids is stronger than that of the single drug administration.
It is noted that organoid No. 3 is resistant to multiple drugs, and although not shown in the IC50 value, it is seen from the curve in fig. 4 that the combination enhances the antitumor ability, i.e., the percentage increase in IR% inhibition.
The results show that the verbascoside compound has a certain inhibition effect on bladder cancer, and when the A01 and lapatinib are combined for use, the inhibition effect on tumor cells is better than that of the A01 and lapatinib which are used independently. Although acteoside is present in higher concentrations than common chemotherapeutic drugs, it is better to produce local anti-tumor effects in the treated area given that bladder perfusion can use higher concentrations to achieve high local drug levels.
In conclusion, the verbascoside compound has obvious inhibition effect on the growth of bladder cancer tumor, can enhance the anti-tumor effect of lapatinib when being used together with lapatinib, and can be applied to bladder perfusion treatment.
In the technical scheme, the inventor firstly proposes the therapeutic effect of the verbascoside compound on the bladder cancer, and the verbascoside compound has important research value and application prospect on the postoperative perfusion treatment of the bladder cancer.
It should be noted that the features and effects described in the various aspects of the present invention may be applied to each other, and are not described in detail herein.
Reference throughout this specification to the description of "one embodiment," "another embodiment," or the like, means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.
Moreover, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. Application of verbascoside compound or its derivative in preparing anti-bladder cancer medicine is provided.
2. The use according to claim 1, wherein the derivative is selected from a salt, an ester, a prodrug or a solvate;
and/or, the verbascoside compound has the following structure:
and/or the verbascoside compound or the derivative thereof is used in an amount of 50-5000 mug/ml;
preferably, the verbascoside compound or derivative thereof is infused into the bladder.
3. The use according to claim 1 or 2, wherein the verbascoside compound or the derivative thereof is prepared into clinically acceptable tablets, capsules, powders, mixtures, granules, syrups, plasters, suppositories, aerosols, ointments or injections by adding conventional adjuvants according to a conventional process.
4. A pharmaceutical combination comprising a component a and a component B;
wherein component A is selected from: verbascoside compounds and/or derivatives thereof;
the component B is selected from: lapatinib and/or other chemical drugs clinically used for the treatment of bladder cancer, such as one or more of carboplatin and doxorubicin.
5. The pharmaceutical combination of claim 4, further comprising a pharmaceutically acceptable carrier.
6. Use of a pharmaceutical combination according to claim 4 or 5 in the manufacture of an anti-bladder cancer medicament.
7. A kit comprising a kit a and a kit B;
wherein the kit A comprises a verbascoside compound and/or a derivative thereof and the kit B comprises lapatinib;
preferably, the administration of kit a and kit B is not sequential or preceded by administration of said kit a; and/or, the kit further comprises kit C, which comprises a further therapeutic agent;
more preferably, the administration of kit a, kit B and kit C is not sequential or preceded by administration of kit a.
8. A kit comprising the pharmaceutical combination of claim 4 or 5.
9. A drug delivery device, characterized in that the drug delivery device comprises:
an infusion module for administering the pharmaceutical combination of claim 4 or 5 to a subject in need thereof.
10. The drug delivery device of claim 9, further comprising a drug efficacy monitoring module.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219102A (en) * | 2007-12-11 | 2008-07-16 | 山东蓝金生物工程有限公司 | Lapatinib sustained-release implantation agent for treating solid tumors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101219102A (en) * | 2007-12-11 | 2008-07-16 | 山东蓝金生物工程有限公司 | Lapatinib sustained-release implantation agent for treating solid tumors |
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| 何春锋 等: "蟾毒灵对人膀胱癌T24细胞增殖及细胞凋亡的影响", 中医药导报, vol. 25, no. 8, pages 31 - 34 * |
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