Application of compound or derivative thereof in preparation of medicine for treating pancreatic cancer

Abstract

The invention discloses application of a compound or a derivative thereof in preparation of a medicine for treating pancreatic cancer. The tumor cell supernatant and the macrophages are co-cultured, and the result shows that the tumor cell supernatant can induce the macrophages to express a large amount of IL-1beta and CXCL2. A plurality of macrophage receptors are utilized to knock out mice, and cellular pathways activated by mediating macrophages are found. A mouse pancreatic cancer tumor model is utilized, and a result shows that compared with a control group, the small molecule compound or the derivative thereof can activate macrophages in a tumor microenvironment and remarkably inhibit the growth of pancreatic cancer tumors, so that a new thought and a targeting drug are provided for treatment of pancreatic cancer.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and in particular relates to the application of a compound or a derivative thereof in the preparation of a drug for treating pancreatic cancer. Background Art

[0002] The human immune cells are always monitoring the cells around them. Once foreign cells are found, they will immediately launch immune mechanisms to eliminate these "bad cells" to ensure the safety of the human body. However, cunning cancer cells can evade the body's immune surveillance through various mechanisms in some cases, continue to proliferate in the body and eventually form tumor tissue. The tumor microenvironment (TME for short) is mainly composed of tumor cells and their surrounding immune and inflammatory cells, tumor-associated fibroblasts, and nearby interstitial tissues, microvessels, and various cytokines and chemokines. It is a complex integrated system that can be divided into an immune microenvironment dominated by immune cells and a non-immune microenvironment dominated by fibroblasts. The lymphocytes inside the tumor tissue are called tumor infiltrating lymphocytes (TILs for short), including T lymphocytes, B lymphocytes, macrophages, natural killer cells, myeloid-derived suppressor cells and dendritic cells that play an antigen presenting role. The lymphocytes infiltrating into the tumor mediate the immunosuppressive tumor microenvironment, helping tumor cells to achieve immune escape and promote the malignant development of the tumor, among which tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) play a major role. The core of this immunosuppressive environment (TIME) established by the tumor is oncogenes and abnormal pathway signals, which lead to the production of potent cytokines and chemokines.

[0003] Generally speaking, an acute myeloid response occurs when the body fights against infection and tumors. In the case of acute infection, strong activation signals mediated by PAMPs lead to a large number of myeloid precursor cells proliferating and differentiating to form mature monocytes and granulocytes to fight infection. Relatively speaking, tumor growth is relatively slow, and tumor-derived growth factors, cytokines, and DAMPs are continuously released into the blood circulation, giving the body a continuous low-level stimulation. In this case, myeloid precursor cells proliferate moderately, but differentiation is blocked, so myeloid precursor cells with immunosuppressive and tumor-promoting functions are formed, which are also called myeloid-derived suppressor cells (MDSCs). The MDSCs of mice and humans are mainly mononuclear MDSCs (M-MDSCs) and granulocyte-like MDSCs (PMN-MDSCs), whose morphology and phenotype are similar to monocytes and granulocytes, respectively. Among them, monocytes or M-MDSCs enter the blood circulation from the bone marrow, and tumor cells recruit them into the tumor microenvironment by secreting chemokines.

[0004] CXCL2, also known as Gro-beta or MIP-2, is a proinflammatory cytokine that has chemotactic activity for neutrophils. CXCL2 is produced by activated monocytes and neutrophils and expressed at sites of inflammation. CXCL2 is involved in many immune responses, including wound healing, cancer metastasis, and angiogenesis. Inflammation is one of the seven characteristics of malignant tumors and is closely related to the occurrence and development of tumors. Studies have found that proinflammatory factors in the tumor microenvironment, such as IL-6, IL-1β, TNF-α, and IL-8, can induce inflammation, and chemotactic inflammatory cells (such as T cells and tumor-infiltrating macrophages) secrete cytokines to promote tumor proliferation, induce immune tolerance, and secrete proangiogenic factors such as VEGF to participate in tumor angiogenesis. Tumors can escape the attack of the immune system by promoting the differentiation or activation of immunosuppressive cell subsets, such as high levels of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs). Tumor cells can also secrete chemokines such as CCL22 and CCL2 to recruit the above-mentioned immunosuppressive cells into the tumor microenvironment, thereby greatly weakening the anti-tumor immune response. Preclinical research results also show that the elimination of immunosuppressive cell subsets can enhance endogenous anti-tumor immunity.

[0005] Cancer has always been a difficult problem that has plagued mankind. With the increasing incidence of cancer and the trend of younger patients, new treatment technologies are also constantly developing and innovating. In recent years, the development of tumor immunotherapy technology has made great contributions to the expansion of precision oncology medicine. According to research, the tumor microenvironment (TME) plays an important role in promoting the occurrence and development of tumors. Myeloid-derived suppressor cells (MDSCs) widely present in the TME are the main effector cell population mediating tumor immune escape. The immune microenvironment is an important factor affecting the effect of immunotherapy, and it plays an important role in tumor progression and mobilizing anti-tumor immunity. With the advancement of technology, people have gradually come to understand the complexity and diversity of the immune environment of the tumor microenvironment and its important impact on immunotherapy. Further analysis and understanding of the tumor immune microenvironment will help improve the responsiveness of immunotherapy. Therefore, it is of great significance to deeply study the composition of various immune cells and factors in TIME and their intrinsic mechanisms of action, and to find measures that are conducive to improving the anti-tumor ability of the immune system. Summary of the invention

[0006] In order to solve at least some of the technical problems in the above-mentioned prior art, the present invention discloses the use of a compound or its derivatives in the preparation of a drug for treating or improving pancreatic cancer. The small molecule compound of the present invention can activate macrophages in the tumor microenvironment, thereby providing a new idea and targeted drug for the treatment of pancreatic cancer. Specifically, the present invention includes the following contents.

[0007] In one aspect of the present invention, a compound or a derivative thereof is provided for use in preparing a drug for treating or improving pancreatic cancer, wherein the compound has a structure shown in Formula I: Formula I, Wherein, R1, R2 and R3 are each independently selected from H, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy.

[0008] In certain embodiments, the compounds or derivatives thereof according to the present invention are used in the preparation of drugs for treating or improving pancreatic cancer, wherein, in Formula I, R1 is hydroxyl, R2 is C1-C4 alkoxy, and R3 is hydroxyl.

[0009] In certain embodiments, the compounds or derivatives thereof according to the present invention are used in the preparation of drugs for treating or improving pancreatic cancer, wherein, in Formula I, R1 is hydroxyl, R2 is methoxy, and R3 is hydroxyl.

[0010] In certain embodiments, the use of the compound or its derivative according to the present invention in the preparation of a drug for treating or improving pancreatic cancer, wherein the treatment or improvement of pancreatic cancer includes at least one of the following: (1) Inhibit the proliferation or growth of tumor cells; (2) Killing tumor cells or inducing apoptosis of tumor cells; (3) reduce or decrease tumor cell volume and / or weight; (4) Increase or enhance the number of immune cells and induce immune cells to enter the tumor microenvironment; (5) Promote or enhance the tumor-killing function of immune cells; (6) Modulating the immunosuppressive microenvironment; (7) Inhibit pancreatic cancer metastasis; (8) Prolong survival time.

[0011] In certain embodiments, the compounds or derivatives thereof according to the present invention are used in the preparation of drugs for treating or improving pancreatic cancer, wherein the immune cells include one or more of natural killer cells, cytotoxic T lymphocytes, tumor infiltrating lymphocytes, macrophages, cytokine-induced killer cells, dendritic cells combined with cytokine-induced killer cells, chimeric antigen receptor T cells and T cell receptor chimeric T cells.

[0012] In certain embodiments, the compound or derivative thereof according to the present invention is used in the preparation of a drug for treating or improving pancreatic cancer, wherein the drug further comprises a pharmaceutically acceptable carrier.

[0013] In certain embodiments, the use of the compound or its derivative according to the present invention in the preparation of a drug for treating or improving pancreatic cancer, wherein the pharmaceutically acceptable carrier includes at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative and an antioxidant.

[0014] In certain embodiments, the use of the compound or its derivative according to the present invention in the preparation of a drug for treating or improving pancreatic cancer, wherein the dosage of the compound or its derivative is 0.01-500 mg / Kg.

[0015] In certain embodiments, the use of the compound or its derivative according to the present invention in the preparation of a drug for treating or improving pancreatic cancer includes: preparing a drug for treating pancreatic cancer in combination with other drugs.

[0016] In certain embodiments, the compounds or derivatives thereof according to the present invention are used in the preparation of drugs for treating or improving pancreatic cancer, wherein the other drugs include chemotherapeutic agents and / or immune checkpoint inhibitors.

[0017] The present invention co-cultures tumor cell supernatant with macrophages, and the results show that tumor cell supernatant can induce macrophages to express IL-1β and CXCL2 in large quantities. Using multiple macrophage receptor knockout mice, the cell pathways that mediate macrophage activation were discovered. Using a mouse pancreatic cancer tumor model, the results show that compared with the control group, the compound of the present invention or its derivative can significantly inhibit the growth of pancreatic cancer tumors. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It was shown that various mouse and human tumor cell supernatants were able to activate macrophage IL-1β and CXCL2 expression.

[0019] Figure 2 It was shown that the stimulatory factors secreted by tumor cells are proteins and are able to activate macrophages across species.

[0020] Figure 3 The figure shows that the supernatant of pancreatic cancer cell Pan02 induces the expression of IL-1β and CXCL2.

[0021] Figure 4 The inhibition of breast cancer cell proliferation by small molecule compounds is shown.

[0022] Figure 5-6 Small molecule compounds were shown to be able to inhibit pancreatic cancer tumor growth. DETAILED DESCRIPTION

[0023] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as limiting the present invention, but should be understood as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0024] It should be understood that the terms described in the present invention are only for describing special embodiments and are not intended to limit the present invention. In addition, for the numerical range in the present invention, it should be understood that the upper and lower limits of the scope and each intermediate value therebetween are specifically disclosed. Each smaller range between the intermediate value in any stated value or stated range and any other stated value or intermediate value in the described range is also included in the present invention. The upper and lower limits of these smaller ranges can be independently included or excluded in the scope.

[0025] Unless otherwise indicated, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention belongs. Although the present invention describes only preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the documents. In the event of a conflict with any incorporated document, the content of this specification shall prevail.

[0026] application In one aspect of the present invention, a compound or a derivative thereof is provided for use in preparing a drug for treating or improving pancreatic cancer, wherein the compound has a structure shown in Formula I: Formula I, Wherein, R1, R2 and R3 are each independently selected from H, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy.

[0027] In a preferred embodiment, the compound of the present invention or its derivative has a structure shown in Formula I, and R1 is hydroxyl, R2 is C1-C4 alkoxy, and R3 is hydroxyl. In a specific embodiment, the compound of the present invention or its derivative has a structure of Formula II (molecular weight 285.29, molecular formula C 16 H 15 NO4), that is, R1 is hydroxyl, R2 is methoxy, and R3 is hydroxyl: Formula II.

[0028] In the present invention, "derivative" refers to a product derived from a compound of Formula I or Formula II in which a hydrogen atom or group is replaced by another atom or group, and the derivative has the same or even increased function, for example, the derivative has a better effect in treating or improving pancreatic cancer.

[0029] The compounds used in the present invention can be obtained from commercially available products or synthesized by known methods, and are not particularly limited.

[0030] In the present invention, the treatment or improvement includes at least one of the following: (1) Inhibit the proliferation or growth of tumor cells; (2) Killing tumor cells or inducing apoptosis of tumor cells; (3) reduce or decrease tumor cell volume and / or weight; (4) Increase or enhance the number of immune cells and induce immune cells to enter the tumor microenvironment; (5) Promote or enhance the tumor-killing function of immune cells; (6) Modulating the immunosuppressive microenvironment; (7) Inhibit pancreatic cancer metastasis; (8) Prolong survival time.

[0031] In the present invention, the term "treat or improve" refers to therapeutic treatment or preventive measures, the purpose of which is to prevent or slow down (reduce) undesirable physiological changes or disorders, such as the progression of pancreatic cancer. Beneficial or desired clinical results include, but are not limited to, the following, whether detectable or undetectable, including relief of symptoms, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or alleviation of the disease state, and relief (whether partial or complete). Those in need of treatment include those who already have cancer or tumor-related diseases or those in need of treatment or improvement of cancer or tumor-related diseases.

[0032] In the present invention, the immune cells include natural killer cells (such as but not limited to NK cells), cytotoxic T lymphocytes (such as but not limited to CD8 + T cells), tumor infiltrating lymphocytes, macrophages, cytokine-induced killer cells, dendritic cells combined with cytokine-induced killer cells, chimeric antigen receptor T cells and T cell receptor chimeric T cells.

[0033] The compound of the present invention or its derivatives can be administered to a subject in need in a therapeutically effective amount, such as a mammal (such as a human). The mode of administration is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration. Accordingly, the compound of formula I or the compound of formula II of the present invention can be prepared into various clinically acceptable dosage forms, including oral dosage forms, injection dosage forms, topical dosage forms or external dosage forms, etc.

[0034] The therapeutically effective amount of the present invention refers to the effective dosage considered in medicine, that is, the amount of the active compound (i.e., the compound of formula I or the compound of formula II) is sufficient to significantly improve the condition without causing serious side effects. The daily dosage of the compound or its derivative is usually 0.01-500 mg / Kg, preferably 0.5-200 mg / Kg or 0.5-180 mg / Kg, or 0.5-150 mg / Kg, or 0.5-120 mg / Kg, or 0.5-100 mg / Kg, or 0.5-50 mg / Kg, or 0.5-40 mg / Kg, or 0.5-30 mg / Kg, most preferably 0.5-25 mg / Kg. Exemplary effective dosages are, for example, 0.5 mg / Kg, 0.75 mg / Kg, 0.95 mg / Kg, 1 mg / Kg, 1.25 mg / Kg, 1.5 mg / Kg, 1.75 mg / Kg, 2 mg / Kg, 2.5 mg / Kg, 2.75 mg / Kg, 3 mg / Kg, 3.25 mg / Kg, 3.5 mg / Kg, 3.75 mg / Kg, 4 mg / Kg, 4.25 mg / Kg, 4.5 mg / Kg, 4.75 mg / Kg, 5 mg / Kg, 5.25 mg / Kg, 5.5 mg / Kg, 5.75 mg / Kg, 6 mg / Kg, 6.25 mg / Kg, 6.5 mg / Kg, 6.75 mg / Kg, 7 mg / Kg, 7.25 mg / Kg, 7.5 mg / Kg, 7.75 15 mg / Kg, 16 mg / Kg, 17 mg / Kg, 18 mg / Kg, 19 mg / Kg, 20 mg / Kg, 21 mg / Kg, 22 mg / Kg, 23 mg / Kg, 24 mg / Kg, 25 mg / Kg. It can be administered as a single dose once a day, can be administered multiple times a day, or can be used at intervals.

[0035] In the present invention, the drug comprising the compound or its derivative may further comprise a pharmaceutically acceptable carrier. In the present invention, a pharmaceutically acceptable carrier is involved in carrying or transporting a drug from one organ or part of the body to another organ or part of the body. Each carrier is "acceptable" in that it is compatible with the other ingredients of the formulation (e.g., the compound of formula I or the compound of formula II) and does not harm the patient.

[0036] In the present invention, "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition or medium, which includes at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative and an antioxidant. Examples of diluents include, but are not limited to, physiological saline, aqueous buffer solutions, solvents, dispersion vehicles, etc.; fillers include, but are not limited to starch, lactose, mannitol, microcrystalline cellulose, etc.; absorbents include, but are not limited to, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents include, but are not limited to, water, ethanol, etc.; binders include, but are not limited to, hydroxypropyl methylcellulose, povidone, microcrystalline cellulose, etc.; disintegrants include, but are not limited to, cross-linked sodium carboxymethyl cellulose, cross-linked povidone, surfactants, low-substituted hydroxypropyl cellulose, etc.; lubricants include, but are not limited to, magnesium stearate, talc, polyethylene glycol, sodium lauryl sulfate, micropowdered silica gel, talc, etc.; sweeteners include, but are not limited to, sucralose, acesulfame, saccharin, sucrose, xylitol, mannitol, sorbitol, glucose, fructose, aspartame, etc.; preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, etc.; antioxidants include, but are not limited to, ascorbic acid, methionine, etc.

[0037] Joint Application One aspect of the present invention provides use of a compound or a derivative thereof in the preparation of a drug for treating pancreatic cancer in combination with other drugs.

[0038] In the present invention, the other drugs include at least one of chemotherapeutic agents, immune checkpoint inhibitors, anti-tumor drugs and immunomodulators. Among them, chemotherapeutic agents include but are not limited to cisplatin, etoposide, floxuridine, capecitabine, mitomycin, methotrexate, vinblastine, cyclophosphamide, dacarbazine, ifosfamide, topotecan, docetaxel, temozolomide, paclitaxel, doxorubicin, camptothecin, etc.; immune checkpoint inhibitors include but are not limited to BK1 inhibitors, PDK1 inhibitors, CTLA-4 inhibitors, anti-PD-1 antibodies, etc.; anti-tumor drugs include but are not limited to gemcitabine, irinotecan, fluorouracil, oxaliplatin, carboplatin, etc.; immunomodulators include but are not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, etc.

[0039] Example 1 This example shows the effect of Transwell co-cultured cancer cell lines on macrophage IL-1β and inflammatory factors The Transwell co-culture system was used for the study. The upper chamber of the Transwell chamber was inoculated with cancer cell lines of different species and types, and the lower chamber was inoculated with mouse monocyte macrophage RAW264.7. After the two culture media were co-cultured for 24 hours, the RAW264.7 cells were collected, and then the expression of IFN-β and inflammatory factors CXCL1 / CXCL2 was detected at the RNA level.

[0040] The results are as follows Figure 1 As shown, mouse pancreatic cancer cells PAN02 and lymphoma cells EL4 can activate IL-1β ( Figure 1 A), the supernatants of human colon cancer cells HCT116 and HT29, human breast cancer cells MDAMB231, and human liver cancer cells HEPG2 can also strongly induce IL-1β expression ( Figure 1 B), and the activation of macrophage IL-1β by tumor cell supernatant reached its peak after 12 hours of co-culture ( Figure 1 C).

[0041] The results of the relative expression of mRNA genes in mononuclear macrophages showed that mouse pancreatic cancer cells PAN02 and lymphoma cells EL4 can also activate IL-1β, indicating that the activation effect is universal; the supernatants of human colon cancer cells HCT116 and HT29, human breast cancer cells MDAMB231, and human liver cancer cells HEPG2 can strongly induce IL-1β expression. In summary, the results prove that there is a certain stimulating factor in the supernatant of tumor cells, which has a specific regulatory function for macrophages and can activate macrophages to produce IL-1β.

[0042] The experiment on the activation degree of IL-1β at different time points of co-culture showed that the activation of macrophage IL-1β by tumor cell supernatant reached its peak after 12 hours of co-culture, indicating that the stimulating factors secreted by tumor cells in the tumor cell supernatant reached the strongest effect of activating macrophage IL-1β expression after 12 hours of co-culture with macrophages, and may be degraded afterwards.

[0043] Example 2 This example shows the validation of tumor cell-derived stimulatory factors that activate macrophages.

[0044] In order to determine whether this tumor cell-derived stimulatory factor that can activate macrophages is a protein, we first verified whether it is a protein. The results showed that after the supernatant of tumor cells was inactivated by high temperature (100°C, 10 minutes), the effect of activating macrophages to express IL-1β and CXCL2 was significantly reduced ( Figure 2 A). Similarly, high salt solution can also significantly inhibit the induced expression of IL-1β and CXCL2 in macrophages ( Figure 2At the same time, in order to verify whether this stimulator can activate macrophages across species, the supernatant of human colon cancer cell HT29 cultured for 24 hours was transferred to mouse mononuclear macrophage RAW264.7, and the induced expression of IL-1β and CXCL2 in RAW264.7 was detected after 2 hours of co-culture ( Figure 2 C); Similarly, the supernatant of mouse colon cancer cell CT26 after 24 hours of culture was transferred to human monocyte THP1, and the induced expression of IL-1β and CXCL2 of THP1 was detected after 2 hours of co-culture ( Figure 2 D).

[0045] The results of macrophage gene expression after heat inactivation and high salt denaturation treatment on tumors suggest that the stimulating factors derived from tumor cells are proteins. After co-culturing tumor cells and macrophages across species, the results of IL-1β and CXCL2 gene expression detection in macrophage mRNA suggest that the stimulating factors secreted by tumor cells can activate macrophages across species, indicating that the regulatory effect of tumor cells on macrophages is universal.

[0046] Example 3 This example shows the mechanism by which stimulatory factors activate macrophages.

[0047] In order to further study the mechanism of macrophage activation by this stimulatory factor, peritoneal macrophages from Tlr2 knockout mice were co-cultured with the supernatant of mouse pancreatic cancer cells Pan02, and DMEM medium was used as a blank control. The induced expression of IL-1β and CXCL2 in mouse peritoneal macrophages was then detected. The results showed that after TLR2 receptor knockout, macrophages could not be induced to express IL-1β and CXCL2 ( Figure 3 ).

[0048] Next, the mouse breast cancer model was used for further verification. After inoculating C57BL / 6 mice with 4T-1, the first round of intraperitoneal injection of Formula II compound was performed from the first to the fifth day, 3 mg / g per mouse per day, and the control group was treated with PBS. Then the second round of administration of the same dose was performed from the eighth to the twelfth day. During this period, when the tumor grew to a size that could be touched, the tumor volume was measured every other day. The results showed that blocking TLR2 in the breast cancer cell model did not inhibit cancer cell proliferation ( Figure 4 ).

[0049] Example 4 This example shows the tumor inhibitory effect of the small molecule compound of formula II.

[0050] In this embodiment, a small molecule compound of formula II is used for blocking in a mouse pancreatic cancer tumor model, and its tumor suppressor effect is monitored to verify that the small molecule compound inhibits the communication between tumor cells and macrophages in the tumor microenvironment, and enhances the immunosuppression of the tumor microenvironment by recruiting MDSCs. After inoculating C57BL / 6 mice with pancreatic cancer cells Pan02, the first round of intraperitoneal injection of the small molecule compound of formula II was performed from the first to the fifth day, 3 mg / g per mouse per day, and the control group was treated with PBS. Then a second round of administration of the same dose was performed from the eighth to the twelfth day. During this period, the tumor volume was measured every other day when the tumor grew to a touchable size. The results show that the small molecule compound of formula II can significantly inhibit the proliferation of pancreatic cancer cells ( Figure 5-6 ).

[0051] In summary, the present invention co-cultures tumor cell supernatant with macrophages, and the results show that tumor cell supernatant can induce macrophages to express IL-1β and CXCL2 in large quantities. Using multiple macrophage receptor knockout mice, it was found that TLR2 receptor mediated the activation of macrophages. Using a mouse pancreatic cancer tumor model, it was found that compared with the control group, the small molecule compound of formula II can significantly inhibit the growth of pancreatic cancer tumors.

[0052] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit them; although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the above embodiments, or replace some of the technical features therein by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of a compound or a derivative thereof in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The compound has a structure shown in Formula I: Formula I, Wherein, R1, R2 and R3 are each independently selected from H, hydroxyl, C1-C4 alkyl or C1-C4 alkoxy.

2. Use of the compound or its derivative according to claim 1 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: In formula I, R1 is a hydroxyl group, R2 is a C1-C4 alkoxy group, and R3 is a hydroxyl group.

3. Use of the compound or its derivative according to claim 1 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: In formula I, R1 is hydroxyl, R2 is methoxy, and R3 is hydroxyl.

4. Use of the compound or its derivative according to claim 1 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The treatment or improvement of pancreatic cancer includes at least one of the following: (1) Inhibit the proliferation or growth of tumor cells; (2) Killing tumor cells or inducing apoptosis of tumor cells; (3) reduce or decrease tumor cell volume and / or weight; (4) Increase or enhance the number of immune cells and induce immune cells to enter the tumor microenvironment; (5) Promote or enhance the tumor-killing function of immune cells; (6) Modulating the immunosuppressive microenvironment; (7) Inhibit pancreatic cancer metastasis; (8) Prolong survival time.

5. Use of the compound or its derivative according to claim 4 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The immune cells include one or more of natural killer cells, cytotoxic T lymphocytes, tumor infiltrating lymphocytes, macrophages, cytokine-induced killer cells, dendritic cells combined with cytokine-induced killer cells, chimeric antigen receptor T cells and T cell receptor chimeric T cells.

6. Use of the compound or its derivative according to claim 1 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The medicament further comprises a pharmaceutically acceptable carrier.

7. Use of the compound or its derivative according to claim 6 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The pharmaceutically acceptable carrier includes at least one of a diluent, a filler, an absorbent, a wetting agent, a binder, a disintegrant, a lubricant, a sweetener, a preservative and an antioxidant.

8. Use of the compound or its derivative according to claim 1 in the preparation of a drug for treating or improving pancreatic cancer, characterized in that: The dosage of the compound or its derivative is 0.01-500 mg / Kg.

9. Use of the compound or its derivative according to claim 1 in preparing a drug for treating or improving pancreatic cancer, characterized in that: The application includes: preparing a drug for treating pancreatic cancer in combination with other drugs.

10. Use of the compound or its derivative according to claim 9 in preparing a drug for treating or improving pancreatic cancer, characterized in that: The other drugs include chemotherapeutic agents and / or immune checkpoint inhibitors.

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