Application of nicotinamide ribose in preparation of medicine for treating pancreatic ductal adenocarcinoma and / or delaying occurrence and development process of pancreatic ductal adenocarcinoma

Abstract

The invention provides application of nicotinamide ribose in preparation of a medicine for treating pancreatic ductal adenocarcinoma and / or delaying the occurrence and development process of pancreatic ductal adenocarcinoma, and belongs to the technical field of biological medicine. Researches find that nicotinamide ribose (NR) treatment can effectively improve the sensitivity of pancreatic ductal adenocarcinoma tumor (PDAC) cells to gemcitabine, and NR and gemcitabine are combined to show a remarkable synergistic effect and remarkably promote tumor cell death. In a spontaneous PDAC model, NR single-drug treatment also shows an inhibition effect on the occurrence and development process of PDAC precancerous lesions. Specifically, the area of precancerous lesions such as acinus-catheter metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) is effectively reduced, and the tumor-related fibrosis degree is relieved.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, specifically the application of nicotinamide ribose in the preparation of drugs for treating pancreatic ductal adenocarcinoma and / or delaying the occurrence and development of pancreatic ductal adenocarcinoma. Background Technology

[0002] Pancreatic ductal adenocarcinoma is a highly malignant tumor of the digestive system, with a five-year survival rate of only about 10%. The lethality of this disease stems primarily from two key challenges. First, early diagnosis is extremely difficult; over 80% of patients are diagnosed at a locally advanced stage or with metastasis, thus missing the opportunity for radical surgical treatment. Second, treatment outcomes are generally unsatisfactory. For patients eligible for radical surgery, the high incidence of postoperative complications means that nearly half cannot receive timely adjuvant chemotherapy. For advanced-stage patients, the current standard first-line treatment is gemcitabine combined with albumin-bound paclitaxel. While this regimen can extend median survival to some extent, it also comes with severe hematologic toxicity and the problem of rapid acquired resistance in tumor cells.

[0003] To address the treatment bottlenecks of PDAC, natural products with multi-target regulatory properties have shown potential (such as triptolide, curcumin, and resveratrol). However, existing treatment strategies using natural products or their derivatives still need to overcome problems such as limited efficacy, unclear mechanisms of action, or obstacles to clinical translation. There is an urgent need to discover safer, more effective, and clearly defined intervention targets and drugs.

[0004] Nicotinamide ribose (NR), a natural vitamin B3 derivative, is highly efficient at converting into intracellular nicotinamide adenine dinucleotide (NAD). + Its ability to participate in energy metabolism and redox balance has attracted widespread attention in the fields of anti-aging and disease intervention. Studies have shown that NR, as a highly efficient NAD+,... + The precursor exerts anti-tumor or adjuvant therapeutic effects in various tumor models (such as melanoma, colon cancer, and liver cancer) by improving immune cell function and regulating specific metabolic axes, and can alleviate cancer cachexia and promote recovery after radiotherapy and chemotherapy.

[0005] Despite the progress made in the study of nicotinamide ribose in the field of tumor metabolic regulation, the therapeutic value of nicotinamide ribose for pancreatic ductal adenocarcinoma itself remains unclear, and there is a lack of direct evidence and mechanistic explanation as to whether it can delay the carcinogenesis process or inhibit tumor progression. Summary of the Invention

[0006] In view of this, the purpose of the present invention is to provide the application of nicotinamide ribose in the preparation of a drug for treating pancreatic ductal adenocarcinoma.

[0007] Another object of the present invention is to provide the application of nicotinamide ribose in the preparation of a drug for delaying the development and progression of pancreatic ductal adenocarcinoma.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides the application of nicotinamide ribose in the preparation of drugs for treating pancreatic ductal adenocarcinoma.

[0009] This invention also provides the application of nicotinamide ribose in the preparation of drugs that delay the development and progression of pancreatic ductal adenocarcinoma.

[0010] Preferably, delaying the development of pancreatic ductal adenocarcinoma includes inhibiting precancerous lesions of pancreatic ductal adenocarcinoma and / or reducing fibrosis of pancreatic ductal adenocarcinoma.

[0011] More preferably, the inhibition of precancerous lesions of pancreatic ductal adenocarcinoma includes the inhibition of acinar-ductal metaplasia and / or pancreatic intraepithelial neoplasia.

[0012] More preferably, the active ingredient of the drug includes nicotinamide ribose.

[0013] More preferably, the active ingredient of the drug also includes gemcitabine.

[0014] More preferably, the concentration of the nicotinamide ribose solution is 0.5 mg / mL to 10 mg / mL.

[0015] More preferably, the injectable concentration of gemcitabine is 30 mg / kg to 80 mg / kg.

[0016] The present invention also provides a medicament for treating and / or delaying the development of pancreatic ductal adenocarcinoma, wherein the active ingredient of the medicament includes nicotinamide ribose.

[0017] Preferably, the active ingredient of the drug also includes gemcitabine.

[0018] Compared with the prior art, the present invention has the following advantages: This invention discovers that nicotinamide riboside (NR) exhibits unique therapeutic potential in intervening in the progression of pancreatic ductal adenocarcinoma (PDAC), with its core advantages manifested in the following two synergistic effects: (1) Significantly enhanced efficacy of the standard chemotherapy drug gemcitabine (GEM): NR treatment effectively increased the sensitivity of PDAC tumor cells to gemcitabine. This was assessed through dose gradient synergistic antitumor effect evaluation (e.g., IC50). 50 Measurements confirmed that the combination of NR and gemcitabine exhibited a significant synergistic effect, significantly promoting tumor cell death. The core technological advantage lies in NR's effective enhancement of intracellular NAD+. +Level. This NAD + The increased levels of these enzymes partly overcome chemotherapy resistance and enhance gemcitabine cytotoxicity by activating the mitochondrial deacetylase SIRT3.

[0019] (2) Independently delays the progression of PDAC and precancerous pathological changes: In spontaneous PDAC models (such as KPC, KC), NR monotherapy also showed an inhibitory effect on the development of PDAC. Specifically, it effectively reduced the area of ​​precancerous lesions such as acinar-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN); and reduced the degree of tumor-related fibrosis.

[0020] The fundamental reason for these core advantages lies in NR's effective improvement of damaged mitochondrial function in PDAC by activating the SIRT3 pathway. This improvement in mitochondrial function forms the common basis for achieving dual therapeutic advantages. By restoring mitochondrial health, tumor cells become more tolerant to therapeutic stress, effectively mitigating excessive oxidative damage induced by chemotherapy drugs such as gemcitabine, thereby synergistically enhancing the killing efficacy of gemcitabine against tumor cells. Healthy mitochondrial function directly counteracts the oxidative stress damage that drives the development of PDAC. This effectively blocks the persistent abnormal tissue damage, regeneration / chemoradiogenesis signaling, and pro-fibrosis and proliferation signaling pathways driven by metabolic imbalance and oxidative damage, ultimately resulting in a delay in the formation and development of precancerous lesions (ADM / PanIN) and a reduction in the degree of tumor-associated fibrosis. Attached Figure Description

[0021] Figure 1 To illustrate the effect of NR on pancreatic pathological changes in KPC mice, Figure A shows the H&E staining results of pancreatic tissue (400× magnification, scale bar: 50μm); B shows the Masson staining and quantitative analysis results of fibrotic areas in pancreatic tissue (400× magnification, scale bar: 50μm); and C shows the Ki-67 staining and proliferation index statistical results (400× magnification, scale bar: 50μm). The sample size was 5 mice per group, and the results represent at least 3 independent experiments. Unpaired t-tests were used for intergroup comparisons. All data are presented as mean ± standard error. p<0.01, p<0.001; Figure 2To illustrate the effect of NR on pancreatic pathological changes in KC mice, Figure A shows the H&E staining results of pancreatic tissue from 16-week-old KC mice (400× magnification, scale bar: 50μm); B shows the Masson staining results of pancreatic tissue from 16-week-old KC mice (400× magnification, scale bar: 50μm); C shows the H&E staining results of pancreatic tissue from 20-week-old KC mice (400× magnification, scale bar: 50μm); and D shows the Masson staining results of pancreatic tissue from 20-week-old KC mice (400× magnification, scale bar: 50μm). The sample size was 5 mice per group, and the results represent at least 3 independent experiments. Unpaired t-tests were used for inter-group comparisons. All data are presented as mean ± standard error. p<0.05, p<0.01, p<0.001; Figure 3 To demonstrate the synergistic antitumor effect of gemcitabine enhanced by NR in vitro, Figure A shows the dose-response curves and IC50 values ​​of mouse KPC1199 and mouse Panc02 cells. 50 Value; B is the dose-response curve and IC50 of human PDAC cells SW1990 and human PDAC cells PANC-1. 50 Values; all data are presented as mean ± standard error; Figure 4 To enhance the antitumor effect of gemcitabine on subcutaneous tumors using NR, the figure shows: A) a schematic diagram of the subcutaneous tumor model treatment; B) tumor morphology photographs and growth curves of mice in different treatment groups; C) final tumor weight of mice in different treatment groups; D) immunohistochemical staining and quantitative analysis of PCNA in mice in different treatment groups; and E) survival curves of mice in different treatment groups. The sample size was 7 mice per group, and the results represented at least three independent experiments. One-way ANOVA with Tukey's or Dunnett's test was used for comparisons among multiple groups. Two-way ANOVA with Bonferroni correction was used for tumor growth curve analysis. All data are presented as mean ± standard error. p<0.05, p<0.01, p<0.001, p < 0.0001, ns = no significant difference; Figure 5To enhance the antitumor effect of gemcitabine in a xenograft model NR, Figure A shows tumor morphology photographs and growth curves in mice of different treatment groups; B shows the final tumor weight in mice of different treatment groups; C shows immunohistochemical staining of PCNA in mice of different treatment groups; and D shows quantitative analysis of PCNA immunohistochemical staining in different groups. The sample size was 7 mice per group, and the results represent at least 3 independent experiments. One-way ANOVA with Tukey's or Dunnett's test was used for comparisons among multiple groups, and two-way ANOVA with Bonferroni correction was used for tumor growth curve analysis. All data are presented as mean ± standard error. p<0.05, p<0.01, p < 0.0001, ns = no significant difference; Figure 6 To demonstrate the therapeutic effect of SIRT3 deficiency blocking NR, A in the figure represents LSL- Kras G12D / + ; Pdx1 -cre; Sirt3 - / - Schematic diagram of mouse model construction; Figure B shows agarose gel electrophoresis analysis of PCR products (mutant Sirt3 allele fragment: 200bp; wild-type allele fragment: 562bp), HO is Sirt3 - / - HE is Sirt3 + / - WT is Sirt3 + / + Figure C shows the detection of LSL- by Western blotting. Kras G12D / + ; Pdx1 -cre; Sirt3 - / - SIRT3 knockout efficiency in mouse pancreatic tissue, D represents LSL- Kras G12D / + ; Pdx1 -cre;Sirt3 - / - H&E staining results of mouse pancreatic tissue (400× magnification, scale bar: 50μm); E indicates LSL- Kras G12D / + ; Pdx1 -cre;Sirt3 - / - Masson staining results of mouse pancreatic tissue (400× magnification, scale bar: 50μm); sample size: 7 mice per group; results represent at least 3 independent experiments; unpaired t-test was used for intergroup comparisons; all data are presented as mean ± standard error. p<0.01, p<0.001. Detailed Implementation

[0022] This invention provides the application of nicotinamide ribose in the preparation of drugs for treating pancreatic ductal adenocarcinoma.

[0023] This invention also provides the application of nicotinamide ribose in the preparation of drugs that delay the development and progression of pancreatic ductal adenocarcinoma.

[0024] In this invention, delaying the development of pancreatic ductal adenocarcinoma includes inhibiting precancerous lesions of pancreatic ductal adenocarcinoma and / or reducing fibrosis of pancreatic ductal adenocarcinoma. Inhibition of precancerous lesions preferably includes inhibiting acinar-ductal metaplasia and / or pancreatic intraepithelial neoplasia. Experimental results show that, in a spontaneous PDAC model, nicotinamide riboside monotherapy exhibits an inhibitory effect on the development of PDAC. Specifically, it effectively reduces the area of ​​precancerous lesions such as acinar-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN), while also reducing the degree of tumor-related fibrosis.

[0025] In this invention, the active ingredient of the drug is preferably nicotinamide ribose. As a preferred embodiment, nicotinamide ribose is used as the sole active ingredient of the drug to treat pancreatic ductal adenocarcinoma and / or delay the progression of pancreatic ductal adenocarcinoma. In this invention, the purity of the nicotinamide ribose is preferably not less than 95% (w / w), more preferably not less than 98% (w / w). In this invention, the physical form of the nicotinamide ribose is crystalline or amorphous powder, which can be directly dissolved in drinking water or a solvent. In this invention, when nicotinamide ribose is the sole active ingredient of the drug, the preferred method of administration is to dissolve the nicotinamide ribose powder in animal drinking water to form a homogeneous solution. In this invention, the concentration of the nicotinamide ribose solution is preferably 0.5 mg / mL-10 mg / mL, more preferably 1 mg / mL-6 mg / mL. Experimental verification shows that the nicotinamide ribose solution can significantly delay precancerous lesions (ADM / PanIN), reduce fibrosis, and inhibit proliferation.

[0026] In this invention, the active ingredient of the drug preferably also includes gemcitabine. In this invention, nicotinamide ribose can also be combined with other active ingredients for the treatment of pancreatic ductal adenocarcinoma and / or for delaying the progression of pancreatic ductal adenocarcinoma. As a preferred embodiment, nicotinamide ribose combined with gemcitabine is used to treat pancreatic ductal adenocarcinoma and / or for delaying the progression of pancreatic ductal adenocarcinoma. In this invention, when nicotinamide ribose and gemcitabine are used in combination, the preferred administration method is to dissolve nicotinamide ribose powder in drinking water, while simultaneously administering injectable gemcitabine. In this invention, the solution concentration of nicotinamide ribose is preferably 0.5 mg / mL-10 mg / mL, more preferably 1 mg / mL-6 mg / mL. The injection concentration of gemcitabine is preferably 30 mg / kg-80 mg / kg, more preferably 50 mg / kg-60 mg / kg; the injection frequency of gemcitabine is preferably 1-3 times per week, more preferably 2 times per week. After dose gradient experiments (IC50-IC50-IC50), the drug is further evaluated. 50 Measurements and subcutaneous tumor burden experiments in mice confirmed that the combination of NR and gemcitabine significantly enhanced the tumor cell killing efficacy and promoted tumor cell death. This invention does not specifically limit the sources of nicotinamide riboside and gemcitabine; any product known in the art or commercially available may be used.

[0027] The present invention also provides a medicament for treating and / or delaying the development and progression of pancreatic ductal adenocarcinoma, wherein the active ingredient of the medicament comprises nicotinamide ribose. As a preferred embodiment, nicotinamide ribose is used as the sole active ingredient of the medicament for treating pancreatic ductal adenocarcinoma and / or delaying its development and progression.

[0028] In this invention, the active ingredient of the drug also includes gemcitabine. In this invention, nicotinamide ribose can also be combined with other active ingredients to treat pancreatic ductal adenocarcinoma and / or delay its progression. As a preferred embodiment, nicotinamide ribose combined with gemcitabine is used to treat pancreatic ductal adenocarcinoma and / or delay its progression.

[0029] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0030] Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods. Unless otherwise specified, the experimental materials used in the following embodiments are commercially available products.

[0031] Example 1: NR delays PDAC progression in KPC mice Test methods KPC mice (LSL) -Kras G12D / + LSL -Trp53R172H / + ; Pdx1 Mice were randomly divided into an NR treatment group and a control group, with 5 mice in each group. The NR treatment group received NR dissolved in drinking water at a concentration of 3 mg / mL. The water bottles were kept away from light and changed every 2 days for more than 2 weeks. The control group mice were fed ordinary drinking water.

[0032] Test results The effect of NR on pancreatic pathological changes in KPC mice is shown in the figure. Figure 1 . Figure 1 In the figure, A represents H&E staining. The pancreatic tissue of the control group mice showed typical malignant pathological features of PDAC, including acinar atrophy, ductal structural disorder, and ADM and PanIN lesions. Compared with the control group, the ADM and PanIN lesion areas in the NR treatment group were significantly reduced. Figure 1 B in the figure represents Masson staining and quantitative analysis of fibrotic areas. In the control group, large areas of blue collagen deposition were visible in the interstitial area, while in the NR treatment group, collagen fibers were broken and sparse, and the proportion of fibrotic areas was significantly reduced. Figure 1 C in the figure represents Ki-67 staining and proliferation index statistics. In the control group, Ki-67 strongly positive cells were densely distributed; in the NR treatment group, Ki-67... + The number of cells was significantly reduced.

[0033] Example 2: NR delays PDAC progression in KC mice Test methods 16-week-old KC mice (LSL- Kras G12D / + ; Pdx1 KC mice were randomly divided into an NR treatment group and a control group, with 5 mice in each group. The NR treatment group received NR dissolved in drinking water at a concentration of 3 mg / mL. The water bottles were protected from light, and the solution was changed every 2 days for at least 2 weeks. The control group mice were fed regular drinking water.

[0034] Test results The effect of NR on pancreatic pathological changes in KC mice is shown in the figure. Figure 2 . Figure 2 Images A and C show H&E staining in 16-week and 20-week-old KC mice, respectively. The control groups showed extensive acinar-ductal metaplasia, disordered ductal structure, and early pancreatic intraepithelial neoplasia. The ADM / PanIN lesion area was significantly reduced in the NR treatment group. Figure 2 B and D in the image show Masson staining of 16-week and 20-week-old KC mice, respectively. Large areas of blue collagen deposition were visible in the interstitial region of the control group, while the NR treatment group showed a significant reduction in the proportion of fibrotic areas.

[0035] Example 3: NR enhances the synergistic antitumor effect of gemcitabine (in vitro) Test methods Human PDAC cells (PANC-1, SW1990) and mouse PDAC cells (KPC1199, Panc02) were used in the experiments. Each cell type was randomly divided into the following treatment groups: gemcitabine monotherapy group: gradient concentrations (5 nM, 10 nM, 100 nM, 500 nM, 1 μM, 10 μM); NR + gemcitabine combination group: fixed NR concentrations (0.5 mM, 1 mM, 2 mM, 10 mM) combined with the above gemcitabine gradients; control group: drug-free culture medium. After treating the cells in different groups at 37℃ in a 5% CO2 incubator for 48 hours, cell viability was detected using the CCK-8 assay, and the IC50 of each group was calculated. 50 value.

[0036] Test results The in vitro NR-enhanced gemcitabine synergistic antitumor effect is shown in [reference needed]. Figure 3 . Figure 3 Image A shows the dose-response curves and IC50 curves of mouse-derived cells (KPC1199 and Panc02). 50 Comparing the data, Figure 3 The results for cell line B correspond to those of human PDAC cells (PANC-1 and SW1990). All cell models showed a consistent trend, with gemcitabine monotherapy showing an IC50 concentration of [missing value]. 50 The value was significantly higher than that of the NR+gemcitabine combination group, indicating that the NR+gemcitabine combination group can significantly enhance the killing efficacy of tumor cells.

[0037] Example 4: NR enhances the antitumor effect of gemcitabine (subcutaneous tumor) Test methods The antitumor effect of NR combined with gemcitabine was evaluated using a Panc02 cell subcutaneous xenograft tumor model. Eight-week-old male C57BL / 6 mice were randomly divided into four groups (n=7 per group): a control group, an NR monotherapy group, a gemcitabine monotherapy group, and an NR + gemcitabine combination group. 5 × 10⁵ g of NR was injected subcutaneously into the right flank. 5 Panc02 cells were used. NR intervention was initiated immediately after injection. Gemcitabine treatment was initiated when the tumor reached 3×3 mm. Both the gemcitabine monotherapy group and the NR + gemcitabine combination group received 50 mg / kg intraperitoneally twice weekly. The control group and the NR monotherapy group received an equal volume of normal saline. The tumor's long diameter (L) and short diameter (W) were measured every two days using calipers, calculated using the formula V = π / 6 × L × W. 2 Monitor volume. After 21 days, the tumor was removed and weighed. The survival group was observed for the survival period of the model mice. The survival status of the mice was observed and recorded daily. Death was taken as the event, and the survival time was recorded and Kaplan-Meier survival curves were plotted to assess long-term survival benefits.

[0038] Test results The enhanced gemcitabine antitumor effect of NR in subcutaneous tumors is shown in [reference needed]. Figure 4 . Figure 4 A in the diagram is a schematic of NR intervention in a subcutaneous tumor model. Figure 4 The morphological images of tumor B in mice showed that the control group had the largest tumor volume and surface angiogenesis, the NR monotherapy group showed no change in tumor volume, the gemcitabine monotherapy group reduced tumor volume, and the NR + gemcitabine combination group had the smallest tumor volume. Tumor growth curves in mice indicated that the NR monotherapy group showed no change in tumor volume growth, the gemcitabine monotherapy group reduced tumor volume, and the NR + gemcitabine combination group had the smallest tumor volume. Figure 4 The final weight data of tumors in the C group were consistent, and the changes in tumors in the NR + gemcitabine combination group were more significant than those in the gemcitabine monotherapy group. Figure 4 Immunohistochemical images and quantitative analysis of PCNA in the D group showed that the number of PCNA-positive cells remained unchanged in the NR group, while the number of PCNA-positive cells was significantly reduced in the NR + gemcitabine combination group. Figure 4 The survival curve results from the study indicate that the NR + gemcitabine combination group had the best survival prognosis.

[0039] Example 5 Test methods The antitumor effect of NR combined with gemcitabine was evaluated using a PANC-1 cell xenograft subcutaneous xenograft model. Male, 8-week-old nude mice were randomly divided into four groups (n=7 per group): a control group, a NR monotherapy group, a gemcitabine monotherapy group, and a NR + gemcitabine combination group. 5 × 10⁵ cells were injected subcutaneously into the right flank. 5 PANC1 cells. NR intervention was initiated immediately after injection. Gemcitabine treatment was initiated when the tumor reached 3×3 mm. Both the gemcitabine monotherapy group and the NR + gemcitabine combination group received 50 mg / kg intraperitoneally twice weekly. The control group and the NR monotherapy group received an equal volume of normal saline. The tumor's long diameter (L) and short diameter (W) were measured every two days using calipers, calculated using the formula V = π / 6 × L × W. 2 Monitor volume. After 21 days, remove the tumor and weigh it.

[0040] Test results The enhanced gemcitabine antitumor effect of NR in subcutaneous tumors is shown in [reference needed]. Figure 5 . Figure 5 Figure A shows photographs of tumor morphology and tumor growth curves in mice from different treatment groups. The results show that the control group had the largest tumor volume and surface angiogenesis, the NR monotherapy group showed no change in tumor volume, the gemcitabine monotherapy group reduced tumor volume, and the NR + gemcitabine combination group had the smallest tumor volume. The tumor growth curves in mice indicate that the NR monotherapy group showed no change in tumor volume growth, the gemcitabine monotherapy group reduced tumor volume, and the NR + gemcitabine combination group had the smallest tumor volume. Figure 5 The final weight data of tumors in the middle B group were consistent, and the changes in tumors in the NR + gemcitabine combination group were more significant than those in the gemcitabine monotherapy group. Figure 5 C and Figure 5 The images in the middle and D sections are immunohistochemical images and quantitative analysis of PCNA, respectively. There was no change in PCNA-positive cells in the NR group, while the number of PCNA-positive cells was significantly reduced in the NR + gemcitabine combination group.

[0041] Example 6: SIRT3 deficiency blocks NR therapeutic effect Test methods KC mice and Sirt3 mice were used - / - LSL- was obtained by mating gene knockout mice. Kras G12D / + ; Pdx1 -cre;Sirt3 - / - Mouse model (hereinafter referred to as KC; Sirt3) - / - Mice were divided into two groups: KC+NR group and KC; Sirt3 - / - +NR group. The area ratio of ADM and PanIN was quantified by H&E staining, and the percentage of fibrotic area was calculated by Masson staining.

[0042] Test results SIRT3 deficiency blocks NR efficacy (see [link]). Figure 6 . Figure 6 A in the diagram is a schematic of the model construction, showing KC; Sirt3 - / - Genetic background of mice. Figure 6 China B and Figure 6 The efficiency of SIRT3 knockout was verified by C, indicating that KC; Sirt3 - / - SIRT3 protein was completely absent in mouse pancreatic tissue. Figure 6 H&E staining of D showed that the ADM / PanIN lesion area was significantly reduced in the KC+NR group, while that in the KC; Sirt3 group was significantly reduced. - / - The +NR group showed widespread ADM and PanIN lesions. Figure 6 Masson staining results from E showed that the fibrotic area was localized in the KC+NR group, and KC; Sirt3 - / - In the +NR group, the fibrotic area was expanded.

[0043] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Application of nicotinamide ribose in the preparation of drugs for the treatment of pancreatic ductal adenocarcinoma.

2. Application of nicotinamide ribose in the preparation of drugs that delay the development and progression of pancreatic ductal adenocarcinoma.

3. The application according to claim 2, characterized in that, The process of delaying the development of pancreatic ductal adenocarcinoma includes inhibiting precancerous lesions of pancreatic ductal adenocarcinoma and / or reducing fibrosis of pancreatic ductal adenocarcinoma.

4. The application according to claim 3, characterized in that, The inhibition of precancerous lesions of pancreatic ductal adenocarcinoma includes the inhibition of acinar-ductal metaplasia and / or pancreatic intraepithelial neoplasia.

5. The application according to any one of claims 1 to 4, characterized in that, The active ingredient of the drug includes nicotinamide ribose.

6. The application according to any one of claims 1 to 4, characterized in that, The active ingredient in the drug also includes gemcitabine.

7. The application according to claim 5, characterized in that, The concentration of the nicotinamide ribose solution is 0.5 mg / mL to 10 mg / mL.

8. The application according to claim 6, characterized in that, The injectable concentration of gemcitabine is 30 mg / kg-80 mg / kg.

9. A medicament for treating and / or delaying the progression of pancreatic ductal adenocarcinoma, characterized in that, The active ingredient of the drug includes nicotinamide ribose.

10. The medicament according to claim 9, characterized in that, The active ingredient in the drug also includes gemcitabine.

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