CN114848651A - Application of GUSB active inhibiting substance in preparing medicine for improving anticancer effect - Google Patents
Application of GUSB active inhibiting substance in preparing medicine for improving anticancer effect Download PDFInfo
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- CN114848651A CN114848651A CN202210452809.2A CN202210452809A CN114848651A CN 114848651 A CN114848651 A CN 114848651A CN 202210452809 A CN202210452809 A CN 202210452809A CN 114848651 A CN114848651 A CN 114848651A
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
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Abstract
The invention finds that the targeted inhibition and/or the reduction of the GUSB activity can improve the anticancer curative effect, and specifically can improve the hepatocellular carcinoma curative effect, more specifically, the combination of in vivo knockout of the GUSB and the PD1 monoclonal antibody can enhance the immunotherapy curative effect of hepatocellular carcinoma, further, a subject group provides the application of a raw material drug capable of in vivo knockout of the GUSB and a raw material drug of the PD1 monoclonal antibody in the preparation of a drug for enhancing the effect of the PD1 monoclonal antibody in hepatocellular carcinoma by inhibiting the GUSB activity, and also provides a new application of amoxapine, and the combination of the amoxapine and the PD1 monoclonal antibody can enhance the immunotherapy curative effect of hepatocellular carcinoma. The invention not only finds a new target point of PD1 resistance, but also finds an effective way for inhibiting the target point by using the old drug amoxapine. Has important significance for improving the prognosis of patients with advanced HCC.
Description
Technical Field
The invention relates to the field of life health, in particular to the application field of substances for inhibiting GUSB (glucuronidase B) activity in preparing a medicine for improving anticancer curative effect.
Background
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer-related death worldwide. Since most patients have entered an advanced stage at the time of diagnosis, there is a lack of effective treatment. Immunotherapy, particularly immune checkpoint blockade therapy, has achieved significant efficacy in clinical treatment. Wherein PD1 and its ligand PD-L1 play an important role in tumor immunity, and the main functions played after the combination are to generate inhibitory signals, inhibit the activation and proliferation of T cells and the secretion of cytotoxic factors, thereby inhibiting the anti-tumor immunity. Although PD1 monoclonal antibody enhances the patient's own immune system and makes obvious progress in treating various advanced malignant tumors by blocking the inhibitory activity, and has achieved great success, many preclinical and clinical studies show that anti-PD 1 treatment often generates drug resistance, resulting in treatment failure and tumor recurrence of liver cancer patients. Therefore, finding a treatment regimen resistant to PD1 is of great interest for improving the prognosis of patients with advanced HCC.
Disclosure of Invention
In order to solve the above technical problems, and in order to find potential biomarkers or targets of anti-PD 1 therapeutic response, a subject group collected 10 anti-PD 1 pre-treatment tumor tissues and analyzed gene expression at the first subsidiary hospital of the university of medical science, Nanjing, and compared the sequencing results of the reaction group and the non-reaction group. Occasionally, it was found that β -Glucosidase (GUSB) was expressed significantly higher in the non-reacted group than in the reacted group. This suggests that the subject group, GUSB, may play an important role in HCC immunotherapy resistance.
GUSB is an enzyme expressed in most tissues and is actively involved in the degradation of proteoglycans in lysosomes. By catalyzing the fifth step of degradation of GAGs, it plays an important role in the degradation of dermatan sulfate and keratin. GUSB is also involved in the cationic binding and interconversion of various metabolites such as pentoses, gluconate, chlorophyll, porphyrins, starch and sucrose. Under physiological and inflammatory conditions, GUSB plays an important role in the reconstitution of extracellular matrix components.
In order to prove the guess of the subject group, the subject group was intensively studied and tested for GUSB.
First, the subject group constructed a GUSB lentiviral packaging plasmid for mouse HCC cells (Genechem, china).
Mouse HCC cells (Hepa1-6) were supplied from Cell Bank of Type Culture Collection (Chinese academy of sciences) and were cultured in RPMI 1640 medium (BI, USA) plus 10% Fetal Bovine Serum (FBS) (Gibco, USA) at 37 ℃ in a 5% CO2 incubator.
GUSB in mouse HCC cells (Hep1-6) was down-regulated by shRNA (Genechem, China).
Specifically, Polybrene (Sigma-Aldrich, USA) and lentivirus are added into a culture dish with HCC cells, and the culture medium is added and mixed well. And after incubation in an incubator at 37 ℃ for 3 days, obtaining GUSB-knocked-down mouse HCC cells, namely sh-GUSB cells. The same method was used to obtain control sh-NC cells.
Next, the subject group constructed the first partial mouse model, C57BL/6 mice injected subcutaneously with Hepa1-6 cells. The mice were divided into four groups of 5 mice each, sh-NC + PD1 monoclonal antibody, sh-GUSB + PD1 monoclonal antibody (bisoxcell, USA). The sh-GUSB + PD1 monoclonal antibody group and the sh-NC + PD1 monoclonal antibody group were injected intraperitoneally with 200ug PD1 on day 8, and every 3 days thereafter.
In the first part of the mouse tumor model, the tumor growth was found to be fastest in the mice of the challenge group, and slow in the tumor growth in the sh-GUSB group. When PD1 mab was injected on day 8, tumor growth tended to slow. At day 20, when the mice were sacrificed, the subjects found that the tumor volume and weight of the sh-GUSB group was significantly less than those of the sh-NC group, and the tumor volume and weight of the sh-GUSB + PD1 monoclonal antibody group was significantly less than those of the sh-NC + PD1 monoclonal antibody group.
Therefore, the invention provides the application of the bulk drug capable of inhibiting and/or reducing GUSB activity in a targeted manner in the preparation of the drug for improving the anticancer curative effect.
Further, the application of the raw material medicine capable of inhibiting and/or reducing the activity of GUSB in the preparation of the medicine for improving the curative effect of hepatocellular carcinoma is provided.
Further, the bulk drug comprises C17H16ClN3O, and the molecular structural formula of C17H16ClN3O is as follows:
furthermore, the invention provides application of the raw material medicine for the targeted inhibition of amoxapine and/or the reduction of GUSB activity in the preparation of the medicine for improving the curative effect of hepatocellular carcinoma.
Furthermore, the invention provides the application of the amoxapine in preparing the medicine for improving the anticancer curative effect through targeted inhibition andor reduction of GUSB activity.
Further specifically, the invention provides an application of a bulk drug capable of knocking down GUSB in vivo and a bulk drug of PD1 monoclonal antibody in preparing a drug for enhancing the effect of PD1 monoclonal antibody in hepatocellular carcinoma by inhibiting the activity of GUSB.
Further, the bulk drug capable of knocking down GUSB in vivo comprises C17H16ClN3O, and the molecular structural formula of C17H16ClN3O is as follows:
further, the bulk drug capable of knocking down GUSB in vivo is amoxapine.
The invention has the beneficial effects that the invention discovers that the GUSB activity is targeted and inhibited or reduced, the anticancer curative effect can be improved, specifically, the hepatocellular carcinoma curative effect can be improved, more specifically, the curative effect of the hepatocellular carcinoma immunotherapy can be enhanced by combining in-vivo knocking-down GUSB and PD1 monoclonal antibody, further, the subject group provides a new application of amoxapine, and the curative effect of the hepatocellular carcinoma immunotherapy can be enhanced by combining the amoxapine and the PD1 monoclonal antibody. The invention not only finds a new target point of PD1 resistance, but also finds an effective way of inhibiting the target point by using the old drug amoxapine (antidepressant). Has important significance for improving the prognosis of patients with advanced HCC.
Drawings
FIG. 1 is a time-varying line graph of tumor volume for each group (sh-NC, sh-NC + PD1 mAb, sh-GUSB + PD1 mAb);
FIG. 2 is a scattergram of tumor volumes of groups (sh-NC, sh-NC + PD1 monoclonal antibody, sh-GUSB + PD1 monoclonal antibody) on the twentieth day;
FIG. 3 is a scattergram of tumors from each group (sh-NC, sh-NC + PD1 monoclonal antibody, sh-GUSB + PD1 monoclonal antibody) on the twentieth day;
FIG. 4 is a time-varying line graph of tumor volume for each group (control, amoxapine, PD1 monoclonal antibody, amoxapine + PD1 monoclonal antibody);
FIG. 5 is a scattergram of tumor volumes of groups on the twentieth day (control group, amoxapine group, PD1 monoclonal antibody group, amoxapine + PD1 monoclonal antibody group);
FIG. 6 is a scattergram of tumor weights of groups on the twentieth day (control group, amoxapine group, PD1 monoclonal antibody group, amoxapine + PD1 monoclonal antibody group);
FIG. 7 is a graph showing that the expression of GUSB in the amoxapine group is remarkably reduced after PBS (Ctrl) and amoxapine (Amox) are added into human hepatoma cell Hep-3b and HCC-LM3 cells.
Detailed Description
Example 1:
this example, in combination with experimental data, further demonstrates that in vivo knockdown of GUSB in combination with PD1 mab enhances the therapeutic efficacy of immunotherapy for hepatocellular carcinoma in accordance with the present invention.
The first test name: whether the combination of in vivo knock-down GUSB and PD1 monoclonal antibody can enhance the immune therapeutic effect of hepatocellular carcinoma in mice.
Secondly, the purpose of experiment is as follows: the expression of GUSB in mice is changed, and whether the combination of the GUSB with PD1 monoclonal antibody can enhance the curative effect of hepatocellular carcinoma immunotherapy is observed.
Thirdly, experimental principle: mouse hepatocellular carcinoma models can be constructed by injecting mouse hepatocellular carcinoma cells subcutaneously, and the change trend of the weight and the volume of tumors among different groups is observed by changing the expression of GUSB in mice.
Fourth, experimental materials
(1) Laboratory animal
C57BL/6 mouse with weight of 15-20g, provided by the laboratory animal center of Nanjing university of medical science
(2) Experimental drugs and reagents
PD1 monoclonal antibody (Bioxcell), amoxapine (Cayman), phosphate buffer (Thermofisher), Hepa1-6(The Cell Bank of Type Culture Collection)
The amoxapine (Cayman) is an antidepressant, the chemical molecular formula of the main component is C17H16ClN3O, and the molecular structural formula of the C17H16ClN3O is as follows:
(3) feed for experiment
Complete nutrition pellet feed is provided by Nanjing cooperative animal feed factory.
(4) Experimental statistical method
Statistical analysis is carried out by SPSS19.0 statistical software, results are expressed by mean + -standard deviation (X + -s), variance analysis is adopted, and LSD-t test is adopted for pairwise comparison among groups. Differences of P <0.05 were statistically significant.
(5) Conditions of the experiment
(6) Equipment for experiments
FA1004 electronic balance: shanghai Jingke balance plant;
MNT-150T vernier caliper: meinaite in Germany.
Fifth, Experimental method
Taking 20C 57BL/6 mice, and randomly dividing the mice into four groups, wherein the mice are kept for longer life and 15-20 g:
(1) sh-NC group: each subcutaneous injection was 2x10 6 sh-NC hpa 1-6 cells.
(2) sh-NC + PD1 monoclonal antibody group: subcutaneous injection 2x10 6 sh-NC hepa1-6 cells, and PD1 mAb 200ug per peritoneal, eight days after injection. Injections were given every three days thereafter.
(3) sh-GUSB group: each subcutaneous injection was 2x10 6 sh-GUSB hepa1-6 cells.
(4) sh-GUSB + PD1 monoclonal antibody group: each subcutaneous injection was 2x10 6 sh-GUSB hepa1-6 cells, and PD1 mAb 200ug per peritoneal, eight days after injection. Injections were given every three days thereafter.
Mice were observed daily for activity, mental and dietary status. Tumor major and minor diameters A (mm) and B (mm) were measured every 4 days with vernier calipers at V = AB 2 The tumor volume (V) of the mice was calculated and the tumor growth curve was plotted. After 20 days, the mice were sacrificed, the tumors removed and weighed, and the volume calculated.
And (II) taking 20C 57BL/6 mice, and randomly dividing the mice into four groups, namely, overlapping the mice and 15-20 g:
(1) control group: each subcutaneous injection was 2x10 6 hpa 1-6 cells, 100ul PBS per intraperitoneal injection on day 2 after injection, and once every 2 days thereafter
(2) Amoxapine group: each subcutaneous injection was 2x10 6 hpa 1-6 cells, and 5mg/kg amoxapine per intraperitoneal injection the following day after injection, every two days thereafter.
(3) PD1 mab group: each subcutaneous injection was 2x10 6 hpa 1-6 cells, and 200ug of PD1 mAb per abdominal cavity on the eighth day after injection. Injections were given every three days thereafter.
(4) Amoxapine + PD1 monoclonal antibody group: each subcutaneous injection was 2x10 6 hpa 1-6 cells, 5mg/kg amoxapine per intraperitoneal injection the day after injection, every two days thereafter. And about 200ug of PD1 mAb was injected into each abdominal cavity on the eighth day after injection. Injections were given every three days thereafter.
Mice were observed daily for activity, mental and dietary status. Tumor major and minor diameters A (mm) and B (mm) were measured every 4 days with vernier calipers at V = AB 2 The tumor volume (V) of the mice was calculated and the tumor growth curve was plotted. After 20 days, the mice were sacrificed, the tumors removed and weighed, and the volume calculated.
Sixth, experimental results
The combination of in vivo knock-down GUSB and PD1 monoclonal antibody can enhance the curative effect of immune therapy of hepatocellular carcinoma.
In the first partial mouse tumor model, the tumors in the mice of the challenge group were found to grow fastest in sh-NC group, while those in the sh-GUSB group grew slowly (FIG. 1). When PD1 mab was injected on day 8, tumor growth tended to slow. At day 20, when the mice were sacrificed, the subjects found that the tumor volume and weight of the sh-GUSB group was significantly less than those of the sh-NC group, and the tumor volume and weight of the sh-GUSB + PD1 monoclonal group was significantly less than those of the sh-NC + PD1 monoclonal group (fig. 2, 3).
The (bi) amoxapine can enhance the effect of PD1 monoclonal antibody in hepatocellular carcinoma by inhibiting the expression of GUSB.
In the second part of mouse tumor models, the subject group found that compared with the PBS group, the amoxapine group had a slow tumor growth, while the amoxapine + PD1 monoclonal group had a slow tumor growth (fig. 4 and 5). At day 20, when the mice were sacrificed, the tumors of the amoxapine group were found to be significantly smaller in volume and weight than those of the PBS group, and the tumors of the amoxapine + PD1 monoclonal antibody group were found to be significantly smaller in volume and weight than those of the amoxapine group and PD1 monoclonal antibody group (fig. 6, 7). The amoxapine can be used as an effective means for treating HCC, and the sensitivity of anti-PD 1 treatment is improved.
The advantage of the embodiment is that amoxapine is found in the subject group as a GUSB inhibitor, can be used as an effective means for treating liver cancer, and improves the sensitivity of anti-PD 1 treatment. The subject group not only finds a new target point of PD1 resistance, but also finds an effective way for inhibiting the target point by using the old drug amoxapine. Amoxapine, an ancient drug, has been widely accepted for its properties and toxicity, but it has great clinical application potential and can be transferred to the human body because it can prevent irinotecan-induced diarrhea with minimal side effects and can improve the effectiveness of chemotherapy. The research of the subject group provides a new way for HCC patients to enhance anti-PD 1 treatment.
Example 2: test and experimental data for targeted inhibition and/or reduction of GUSB (glucuronidase B) activity of amoxapine
In the subject group, PBS (Ctrl) and amoxapine (Amox) are added into human hepatoma cell Hep-3b and HCC-LM3 cells, and then the expression of GUSB in the amoxapine group is found to be remarkably reduced, as shown in FIG. 7, the fact that the amoxapine remarkably inhibits the expression of GUSB in the hepatoma cell is suggested.
Claims (7)
1. An application of a raw material drug capable of inhibiting and/or reducing GUSB activity in a targeted manner in preparing a drug for improving anticancer curative effect.
2. Use according to claim 1, characterized in that: the cancer is hepatocellular carcinoma.
3. Use according to claim 1, characterized in that: the bulk drug comprises C17H16ClN3O, and the molecular structural formula of C17H16ClN3O is as follows:
4. use according to claim 1, characterized in that: the raw material medicine is amoxapine.
5. An application of a bulk drug capable of knocking down GUSB in vivo and a bulk drug of PD1 monoclonal antibody in preparing a drug for enhancing the effect of PD1 monoclonal antibody in hepatocellular carcinoma by inhibiting the activity of GUSB.
6. Use according to claim 5, characterized in that: the bulk drug capable of knocking down GUSB in vivo comprises C17H16ClN3O, and the molecular structural formula of C17H16ClN3O is as follows:
7. use according to claim 5, characterized in that: the bulk drug capable of knocking down GUSB in vivo is amoxapine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009148623A2 (en) * | 2008-06-05 | 2009-12-10 | Stc.Unm | Methods and related compositions for the treatment of cancer |
| CN107970243A (en) * | 2017-10-30 | 2018-05-01 | 江苏理工学院 | A kind of new application of Norclozapine |
| WO2019097078A1 (en) * | 2017-11-20 | 2019-05-23 | Tolremo Therapeutics Ag | Diagnostic method |
| CN113599527A (en) * | 2021-08-27 | 2021-11-05 | 江苏省人民医院（南京医科大学第一附属医院） | Application of APOE inhibitor and PD-1 monoclonal antibody in preparation of medicine for treating digestive tract tumor |
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- 2022-04-27 CN CN202210452809.2A patent/CN114848651A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009148623A2 (en) * | 2008-06-05 | 2009-12-10 | Stc.Unm | Methods and related compositions for the treatment of cancer |
| CN107970243A (en) * | 2017-10-30 | 2018-05-01 | 江苏理工学院 | A kind of new application of Norclozapine |
| WO2019097078A1 (en) * | 2017-11-20 | 2019-05-23 | Tolremo Therapeutics Ag | Diagnostic method |
| CN111417730A (en) * | 2017-11-20 | 2020-07-14 | 托雷莫治疗股份公司 | Diagnostic method |
| CN113599527A (en) * | 2021-08-27 | 2021-11-05 | 江苏省人民医院（南京医科大学第一附属医院） | Application of APOE inhibitor and PD-1 monoclonal antibody in preparation of medicine for treating digestive tract tumor |
Non-Patent Citations (3)
| Title |
|---|
| KONG R，等: ""Old Drug New Use-Amoxapine and Its Metabolites as Potent Bacterial beta-Glucuronidase Inhibitors for Alleviating Cancer Drug Toxicity"", 《CLINICAL CANCER RESEARCH》, vol. 20, no. 13, pages 3521 * |
| KONG XY，等: ""Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma"", 《 FRONTIERS IN IMMUNOLOGY》, vol. 13, pages 1 - 13 * |
| 吴蓉蓉，等: ""靶向抑制肠道菌β-葡萄糖醛酸苷酶在肿瘤预防和治疗中的应用"", 《中国临床药理学与治疗学》, vol. 1997, no. 8, pages 964 - 974 * |
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