Application of polyamination modification in preparation of agent for treating cancer

Abstract

The invention belongs to the field of cancer treatment, particularly relates to application of polyamination modification in preparation of a reagent for treating cancer, and more particularly relates to application of polyamination modification in preparation of a reagent for treating pancreatic cancer. The invention provides an application of polyamination modification in preparation of an agent for treating cancer. The inventor creatively discovers that polyamination modification plays an important role in cancers, particularly pancreatic cancer, and inhibition of polyamination modification can be used for treating cancers.

Description

Technical Field

[0001] The present invention belongs to the field of cancer treatment, and in particular, relates to the use of polyvalent modification in preparing a reagent for treating cancer, and more particularly, relates to the use of polyvalent modification in preparing a reagent for treating pancreatic cancer. Background Art

[0002] Pancreatic cancer is a highly malignant digestive system tumor that is difficult to diagnose and treat. The main type is pancreatic ductal adenocarcinoma (PDAC), which has an extremely poor prognosis, with a five-year survival rate of less than 10%.

[0003] Abnormal proliferation of the stroma is one of the important characteristics of pancreatic cancer. The large amount of extracellular matrix deposition reduces the distribution of blood vessels in pancreatic cancer tissue, forming a hypoxic and nutrient-deficient tumor microenvironment. In order to adapt to the nutrient-deficient microenvironment and meet the needs of rapid proliferation, pancreatic tumor cells often reshape their intracellular metabolic pathways. Therefore, metabolic remodeling plays an important role in the occurrence and development of tumors.

[0004] Previous studies on the regulation of metabolic remodeling have mostly focused on changes in popular metabolic pathways, such as glycolysis, fatty acid oxidation, glutamine, and branched-chain amino acid metabolism. Relatively little attention has been paid to the remodeling of pathways other than the three major metabolic pathways in the occurrence and development of tumors.

[0005] Therefore, there is a need in the art to study the remodeling of other metabolic pathways as new targets for pancreatic cancer treatment. Summary of the invention

[0006] In view of this, in a first aspect, the present invention provides the use of polyamine modification in the preparation of agents for treating cancer.

[0007] Furthermore, the agent for treating cancer is a polyamine modification inhibitor.

[0008] The applicant creatively discovered that polyamination modification plays an important role in cancer, in particular, pancreatic cancer, and inhibiting its polyamination modification can be used to treat cancer.

[0009] Furthermore, the polyamination modification inhibitor is a polyamination modification inhibitor of QARS protein.

[0010] Furthermore, the polyamination modification inhibitor is a polyamination modification inhibitor at position 216 of the QARS protein.

[0011] Furthermore, the polyamine modification inhibitor may be a polyamine synthesis inhibitor or a polyamine modification enzyme inhibitor.

[0012] Furthermore, the polyamine synthesis inhibitor includes, for example, DFMO and BSPM.

[0013] Furthermore, polyamine modification enzyme inhibitors include, for example, transglutaminase inhibitors.

[0014] In a specific embodiment, the polyamine modification inhibitor is a cell penetrating peptide having a sequence as shown in SEQ ID NO.1:

[0015] HLYVSPWGG-NGETADQTLSLME.

[0016] Based on the important role of polyamine modification in cancer development, the applicant further discovered that the polyamine modification of QARS protein in pancreatic cancer cells has a significant relationship with the proliferation of cancer cells and the development of cancer. In particular, the polyamine modification of site 216 has a significant relationship with the proliferation of cancer cells and the development of cancer. Based on this, the applicant designed the cell-penetrating peptide of the present invention, which can compete with intracellular QARS, inhibit polyamine modification and inhibit the activity of QARS protein, thereby inhibiting the proliferation and progression of cancer cells.

[0017] Furthermore, the polyamines in the polyamine modification are spermine, spermidine, and putrescine.

[0018] In a specific embodiment, the agent for treating cancer is a spermination inhibitor.

[0019] In a specific embodiment, the agent for treating cancer is a putrescination inhibitor.

[0020] Furthermore, the cancer is pancreatic cancer.

[0021] According to the present invention, the cancer treatment agent has one or more of the following functions: inhibiting the proliferation rate of cancer cells, changing the cycle distribution of cancer cells, promoting cancer cell apoptosis, and inhibiting cancer cell clone formation.

[0022] Preferably, according to the present invention, the cancer treatment drug necessarily includes a polyamine modification inhibitor, and the polyamine modification inhibitor is used as the only effective ingredient or one of the effective ingredients for the aforementioned function.

[0023] In a second aspect, the present invention provides a cell penetrating peptide, which specifically has a sequence as shown in SEQ ID NO.1.

[0024] In a third aspect, the present invention provides a drug for treating cancer, comprising the cell penetrating peptide as described above.

[0025] Furthermore, the cancer is pancreatic cancer.

[0026] Preferably according to the present invention, the cell penetrating peptide is the sole active ingredient or one of the active ingredients of the drug for treating pancreatic cancer.

[0027] The form of the drug for treating cancer is not particularly limited, and can be in the form of solid, liquid, gel, semi-fluid or aerosol. The dosage form of the drug is any dosage form that is clinically or pharmaceutically acceptable. For example, but not limited to, the dosage form of the drug is powder, injection, capsule, oral solution, tablet, pill, spray.

[0028] Furthermore, the medicine also includes instructions.

[0029] Furthermore, the instructions contain information on the use of the drug for treating cancer, such as the effective amount required for treating cancer, the number of doses, the interval time, etc.

[0030] In a fourth aspect, the present invention provides a combination of cancer therapeutic drugs, comprising a polyamine modification inhibitor and at least one other cancer therapeutic drug.

[0031] Furthermore, the drug is paclitaxel, gemcitabine, various targeted antibodies, etc.

[0032] Furthermore, the drug is gemcitabine.

[0033] Furthermore, the cancer is pancreatic cancer.

[0034] Furthermore, the agent for treating cancer is a polyamine modification inhibitor.

[0035] Furthermore, the polyamine modification inhibitor may be a polyamine synthesis inhibitor or a polyamine modification enzyme inhibitor.

[0036] Furthermore, the polyamine synthesis inhibitor includes, for example, DFMO and BSPM.

[0037] Furthermore, polyamine modification enzyme inhibitors include, for example, transglutaminase inhibitors.

[0038] In a specific embodiment, the polyamine modification inhibitor is a cell penetrating peptide having the sequence shown in SEQ ID NO.1.

[0039] Furthermore, the polyamines in the polyamine modification are spermine, spermidine, and putrescine.

[0040] In a specific embodiment, the agent for treating cancer is a spermination inhibitor.

[0041] In a specific embodiment, the agent for treating cancer is a putrescination inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 :A. Differential metabolites of non-targeted metabolomics analysis of 20 paired pancreatic cancer and adjacent tissues. B. Levels of polyamine metabolites in normal pancreatic tissue (K), pancreatic ductal intraepithelial neoplasia (KC) and pancreatic cancer (KPC) in mice. C. mRNA expression of polyamine metabolism-related enzymes in pancreatic cancer and adjacent tissues. D. Immunohistochemical detection results of polyamine metabolism-related enzymes in pancreatic cancer and adjacent tissues. E. Survival curve of polyamine metabolism-related enzyme expression levels and overall survival of pancreatic cancer patients in the TCGA pancreatic cancer cohort;

[0043] Figure 2 :A. Spermine levels in normal pancreas and pancreatic cancer cell lines. B. Spermine levels in pancreatic cancer cells treated with ODC inhibitor DFMO and polyamine metabolism inhibitor BSPM and control pancreatic cancer cells. C. Tumor cell clone formation ability and statistical results under DFMO and BSPM treatment of pancreatic cancer cells. D. EUD staining and statistical results of pancreatic cancer cells under DFMO and BSPM treatment. E. Three-dimensional growth of primary pancreatic cancer cells under DFMO and BSPM treatment;

[0044] Figure 3 :A. Subcutaneous tumors established by injection of PATU8988 cells were treated with BSPM and control. B. Changes in the growth curves of subcutaneous tumors in the control group and BSPM-treated group. C. Statistical results of subcutaneous tumor weights in the control group and BSPM-treated group. D. Immunohistochemical staining of PCNA and Cleaved caspase3 in subcutaneous tumors in the interference group and control group; the scale is 100μm.EG. In situ small animal imaging results of the pancreas of C57BL6 / J mice in the control group, BSPM-treated group, gemcitabine chemotherapy group, and BSPM-treated group combined with chemotherapy group (E), overall small animal imaging statistics (F) and overall survival curve (G);

[0045] Figure 4:A. Heat map of differential metabolites in pancreatic cancer and paired adjacent tissues by non-targeted metabolomics. B. Levels of spermine and its metabolic precursors in mouse pancreatic precancerous lesions and pancreatic cancer measured by targeted metabolomics. C. Growth of pancreatic cancer cell lines PATU8988 and PANC-1, and pancreatic cancer primary cells PDA-1 and PDA-2 in the control group and under 5μM and 10μM spermine treatment conditions, respectively. D. Growth curves of pancreatic cancer primary cells PDA-1 and PDA-2 in the control group and under 5μM spermine, TGM inhibitor GK591, and 5μM spermine combined with TGM inhibitor GK591 treatment groups. E. Clone formation and statistical analysis results of pancreatic cancer cells PATU8988 and PANC-1 in the control group and under 5μM spermine, TGM inhibitor GK591, and 5μM spermine combined with TGM inhibitor GK591 treatment groups. F. 3D-ontopgrowth growth of pancreatic cancer primary cells. G. Representative growth and statistical results of pancreatic cancer organoids under control, 5 μM spermine, TGM inhibitor GK591, and 5 μM spermine combined with TGM inhibitor GK591 treatment;

[0046] Figure 5 :A. mRNA expression levels of key enzymes of spermine metabolism in pancreatic cancer and non-cancerous pancreatic tissues. B. Immunohistochemical results of key enzymes of spermine metabolism in pancreatic cancer and paired adjacent cancer tissues. C. Survival curves of the expression of key enzymes of spermine metabolism and the prognosis of pancreatic cancer patients. D. Levels of spermine and its precursor metabolites in pancreatic cancer and its paired adjacent cancer tissues determined by targeted metabolomics. E. Growth of pancreatic cancer cells PATU8988 and PANC-1 under the treatment of the control group DFMO and BSPM. F. Growth curves of pancreatic cancer cells PATU8988 and PANC-1 in the control group and the groups treated with 5μM spermine, TGM inhibitor GK591, and 5μM spermine combined with TGM inhibitor GK591;

[0047] Figure 6 :A. Screening process of sperminated proteins in pancreatic cancer and protein Coomassie Brilliant Blue staining results.B. Detection of QARS protein levels in 5-BP binding proteins by WB.C. In the in vitro MDC modification experiment, spermine, TGM and TGM inhibitor Cystamine were added to detect the modification of QARS by MDC.D. After pancreatic cancer cells were treated with control, DFMO and BSPM, the level of Gln-tRNA that was not aminoacylated in the cells was detected by PCR.E. The results of puromycin uptake by pancreatic cancer cells after being treated with control, DFMO and BSPM.F. The results of puromycin uptake by pancreatic cancer cells after being treated with control, spermine and spermine-linked sperminated modification enzyme inhibitor;

[0048] Figure 7 :A. Mass spectrometry identification of QARS spermination modification sites. B. Effect of QARS spermination site mutation on Gln-tRNA aminoacylation efficiency. C. Molecular dynamics docking evaluation of the effect of spermination modification on the stability of QARS-Gln-tRNA complex;

[0049] Figure 8 :A. Subcutaneous tumors established by injection of PATU8988 cells were treated with Q216CPP and control. B. Changes in the growth curves of subcutaneous tumors in the control group and Q216CPP-treated group. C. Statistical results of subcutaneous tumor weights in the control group and Q216CPP-treated group. DF. In situ small animal imaging results of the pancreas of C57BL6 / J mice in the control group and Q216CPP-treated group (D), overall small animal imaging statistics (E) and overall survival curve (F). DETAILED DESCRIPTION

[0050] The present invention will be described in detail below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly presented. It should be understood by those skilled in the art that these specific embodiments and examples are used to illustrate the present invention, rather than to limit the present invention.

[0051] The term "QARS protein" is a full name for Glutaminyl-TRNA Synthetase 1, i.e., glutamine-tRNA synthetase, which has the following amino acid sequence (SEQ ID NO.2):

[0052] .

[0053] Example 1: Polyamine metabolism is significantly enhanced in pancreatic cancer tissue

[0054] In order to screen the metabolic pathways that pancreatic cancer depends on, we collected 20 pairs of human pancreatic cancer and paired adjacent tissues for non-targeted metabolomics analysis. The metabolomics results showed that the levels of spermine (SPM) and putrescine in polyamine metabolism in human pancreatic cancer tissues were significantly increased ( Figure 1A). To verify this result, we further collected normal pancreatic tissue, pancreatic ductal intraepithelial neoplasia (PanIN) and pancreatic cancer tissues of mice for polyamine targeted metabolomics analysis. Similarly, the levels of spermine and putrescine in pancreatic cancer tissues of mice were also significantly upregulated, and showed a trend of gradual increase from normal pancreatic tissue to pancreatic ductal intraepithelial neoplasia (PanIN) and pancreatic cancer tissues. The level of spermidine in tumor tissues was significantly lower than that in precancerous lesions and normal pancreatic tissues ( Figure 1 B). Subsequently, we analyzed the expression levels of polyamine metabolism-related metabolic enzymes. Using the integrated data of GTEx and TCGA, we found that except for spermidine synthase, the expression of other polyamine metabolism-related enzymes was significantly enhanced, and the expression of polyamine degradation enzyme PAOX was significantly reduced ( Figure 1 C). These results suggest that in pancreatic tumor cells, polyamine metabolism is disordered, spermidine synthesis in tumor cells is significantly reduced, spermine synthesis is significantly increased, and spermine degradation is also reduced. To further verify the expression of polyamine synthases, we collected human pancreatic cancer sample tissues for immunohistochemical staining, and the results showed that the expression of these proteins at the protein level was also significantly increased ( Figure 1 D). Subsequently, we analyzed the expression of polyamine metabolic enzymes and the prognosis of pancreatic cancer patients. We found that ODC1, AMD1 and SRM expression were not correlated with pancreatic cancer prognosis, while high expression of SMS, which promotes polyamine production, predicted a poor prognosis, and high expression of PAOX, which mediates polyamine degradation, showed a longer overall survival time. Figure 1 E). These results suggest that polyamine metabolism is disturbed in pancreatic tumor cells, spermidine synthesis is significantly reduced, spermine synthesis is significantly increased, and spermine degradation is also reduced. The entire polyamine metabolic pathway is remodeled to promote the accumulation of spermine in tumor cells. These results suggest that spermine accumulation in pancreatic cancer tissue is positively correlated with the progression of pancreatic cancer.

[0055] Example 2: Targeting polyamine metabolism to inhibit the proliferation of pancreatic cancer tumor cells

[0056] Firstly, targeted metabolomics was used to detect the levels of spermine in pancreatic cancer cell lines AsPC-1, BxPC-3, Capan-1, MIAPaCa-2, Patu8988, PANC-1 and control cell lines HPNE and HPDE. The results showed that the levels of spermine in pancreatic cancer cell lines were significantly higher than those in pancreatic ductal immortalized cells ( Figure 2A). Subsequently, the applicant selected Patu8988 and PANC-1 cells with the highest spermine levels for subsequent functional experiments. The polyamine metabolic pathway in tumor cells was inhibited by using DFMO, an inhibitor of the first rate-limiting enzyme in polyamine metabolism, and BSPM, an inhibitor of pan-polyamine metabolic enzymes. The spermine levels in the polyamine inhibitor-treated cells and the control group were further detected by mass spectrometry, and it was found that both inhibitors could significantly reduce the spermine levels in tumor cells ( Figure 2 B). Then the clone formation experiment found that the clone formation ability of Patu8988 and PANC-1 cells after polyamine metabolism inhibition was significantly lower than that of the control group ( Figure 2 C). The applicant further used the EdU fluorescence kit to detect the changes in the EdU dye uptake rate of Patu8988 and PANC-1 cells in the polyamine inhibitor treatment group and the control group, and found that blocking polyamine metabolism can significantly inhibit the EdU dye uptake rate of pancreatic ductal adenocarcinoma cells ( Figure 2 F). To further evaluate the role of polyamine metabolism in the growth of pancreatic cancer cells, the applicant isolated two primary pancreatic cancer cells and cultured them in three dimensions, then blocked polyamine metabolism. It was also found that inhibiting polyamine metabolism significantly weakened the growth ability of primary pancreatic tumor cells. The results of the above in vitro cell experiments suggest that polyamine metabolism is closely related to the proliferation and cloning of pancreatic ductal adenocarcinoma cells.

[0057] Example 3: Targeting polyamine metabolism to inhibit the progression of pancreatic cancer in mice

[0058] Based on the results of previous in vitro functional experiments, the applicant further evaluated the role of polyamine metabolism in the development of pancreatic cancer in an in vivo pancreatic cancer mouse model. The applicant first used Patu8988 cells to construct a subcutaneous tumor model of pancreatic cancer in nude mice, and inoculated Patu8988 cells into the subcutaneous tissue around the groin of nude mice by subcutaneous implantation. After three weeks, the mice were evenly divided into two groups according to the size of the tumor. After 4 weeks of treatment with the polyamine inhibitor BSPM, the subcutaneous tumors were observed and it was found that the tumors in the polyamine metabolism inhibition group were significantly smaller than those in the control group ( Figure 3 A). By plotting the tumor volume change curve, it was found that the tumor growth of mice given polyamine metabolic inhibitors was significantly slower than that of subcutaneous tumors in control mice ( Figure 3 B). Further weighing of subcutaneous tumors revealed that the number of tumors in the interference group mice was significantly reduced ( Figure 3 C). Staining of the tumor sections revealed that PCNA (Proliferating Cell Nuclear Antigen), a tumor cell proliferation marker, in the interference group was also significantly weaker than that in the control group, while the proportion of apoptotic cells was significantly higher than that in the control group. Figure 3D). Subsequently, the applicant constructed an orthotopic pancreatic cancer model, using the pancreatic orthotopic implantation method to inoculate mouse pancreatic cancer cell KPC1199 cells into the pancreatic tissue of C57BL6 / J mice through an insulin needle. Afterwards, the progression of the orthotopic tumor was regularly detected by small animal imaging. The results showed that targeting polyamine metabolism was able to significantly inhibit the progression of orthotopic pancreatic cancer ( Figure 3 F). Afterwards, the orthotopic model mice were treated with gemcitabine chemotherapy (50 mg / kg, once every five days) and the progression of pancreatic cancer in the mice was observed. It was found that the inhibition of polyamine metabolism by BSPM and gemcitabine chemotherapy could show a synergistic effect, further inhibiting the progression of orthotopic tumors and prolonging the overall survival time of mice ( Figure 3 F). These results further confirm that polyamine metabolism plays a very important role in the occurrence and development of pancreatic ductal adenocarcinoma, suggesting that intervening in polyamine metabolism can inhibit the progression of pancreatic cancer in vivo.

[0059] Example 4: Spermine promotes the growth of pancreatic cancer cells through spermination modification

[0060] Non-targeted metabolomics analysis was performed on PDAC (pancreatic ductal adenocarcinoma) and its paired adjacent tissues. The results showed that the level of spermine in PDAC tissues was significantly increased compared with non-tumor tissues, and putrescine, a spermine precursor metabolite, also showed a similar trend ( Figure 4 A~B). This finding was further verified by targeted metabolomics analysis of PDAC samples, as well as PaINs and PDAC tissues of KC and KPC mice. Spermine detection results showed that spermine levels were elevated in the early stages of PDAC. To determine the role of spermine in PDAC, we treated two PDAC cell lines, PATU8988 and PANC-1, with different doses of spermine. The data showed that spermine promoted the proliferation of PDAC cells ( Figure 4 C). In contrast, depletion of spermine in PDAC cells by spermine synthesis inhibitors DFMO and BSPM inhibited the survival of PDAC cells. Given that spermine can affect cell survival directly or through protein spermination, to determine whether it is dependent on spermination, we simultaneously treated PDAC cells with spermine and a TGM inhibitor (TGMi) ( Figure 4 D). The results showed that inhibition of spermidation in PDAC cells could reverse the spermine-mediated growth promotion effect, which was further confirmed in the PDAC clone formation experiment ( Figure 4 E). In addition, three-dimensional growth experiments showed that TGMi treatment inhibited spermine-induced primary cell spheroid formation ability ( Figure 4F). In PDAC tumors, we found that TGMi treatment inhibited spermine-induced spheroid formation in primary cancer cells isolated from PDAC tumors. In addition, spermine promoted the growth of PDAC organoids, and blocking spermidation attenuated these effects ( Figure 4 G). Next, we examined spermidation levels in mouse and human PDAC tissues. Hematoxylin-eosin (H&E) and immunohistochemistry (IHC) staining showed that spermidation levels in PDAC tissues were significantly enhanced compared with adjacent non-tumor tissues ( Figure 5 A~C). Tissue chip analysis found that the overall survival rate of patients with high spermatination levels was much lower than that of patients with low spermatination levels ( Figure 5 D~E).

[0061] Example 5: Spermine promotes the synthesis of new proteins in pancreatic cancer through QARS spermination

[0062] To investigate how spermine modification regulates pancreatic cancer progression, we first used spermine analogs to identify potential spermine-modified proteins in pancreatic cancer cells. Among the results obtained by mass spectrometry analysis, we found previously reported cytoskeletal proteins and EIF4E and noticed that the QARS scores were high ( Figure 6 A). Subsequently, we performed WB identification on the IP product and found that QARS was indeed modified with spermine. To verify whether QARS had undergone spermine modification, we further used QARS antibodies and found that QARS was indeed present in 5-BP binding protein ( Figure 6 B). Next, we designed a spermine competition experiment and found that when TGM2 transferase activity was inhibited, MDC could not bind to QARS. Similarly, after adding spermine to compete with MDC, MDC was also unable to modify QARS ( Figure 6 C). Given that aminoacyl-tRNA is responsible for the connection between amino acids and specific tRNA, we first evaluated the synthesis efficiency of the two glutamine-tRNAs in cells under spermine depletion. The results showed that inhibiting spermine synthesis could reduce the level of glutamine-tRNA in cells ( Figure 6 D). Because aminoacyl-tRNA is used for protein synthesis. Next, we sought to determine whether QARS spermidation affects new protein synthesis by multimer analysis. We measured protein synthesis rates in PDAC by puromycin incorporation and consistently found that spermine depletion or spermidation inhibition could significantly reduce new protein synthesis in PDAC cells ( Figure 6 E~F).

[0063] Then, to determine the specific sites of spermine modification on QARS, we performed spermine modification experiments in vitro using recombinant QARS protein and identified the specific sites by mass spectrometry analysis ( Figure 7A). The results showed that QARS can be modified by spermine at positions 41, 86, and 216 of Q. To evaluate the effect of spermine modification on QARS activity, we mutated these three sites and examined their effects on tRNA aminoacylation. The results showed that only the mutation at position 216 significantly inhibited the activity of QARS ( Figure 7 B). To further clarify the effect of spermination modification at position Q216 on QARS, we then performed protein dynamics simulation ( Figure 7 C), the results show that after tRNA and modified QARS protein bind, the modified QARS protein exhibits high structural flexibility in the 190-210AA residue region. The RMSF values ​​of the original 50-90AA and 90-110AA residue regions decreased, indicating that the stability of the QARS protein increased significantly after the spermine modification of 216Q. tRNA and modified QARS protein are relatively stable after 40ns, and the system is in equilibrium. The wild type requires 75ns to reach a stable state, which indicates that after the QARS protein Q216 undergoes spermine modification, the binding of tRNA and QARS protein can reach a stable state earlier, and the maximum RMSD value drops from 5.5 angstroms to 4.0 angstroms. In order to further clarify the effect of spermine modification on QARS enzyme activity, we conducted an in vitro tRNA aminoacylation experiment, and the results showed that spermine modification can significantly enhance the activity of the QARS enzyme, and blocking spermine modification by TGM inhibition or Q216 site mutation can reverse the spermine modification-mediated enzyme activity enhancement.

[0064] Example 6: Cell-penetrating peptides inhibit the growth of pancreatic cancer cells

[0065] We constructed a shuttle peptide modified with spermination at position Q216 of QARS (Q216 CPP, as shown in SEQ ID NO.1) and evaluated its role in the development of pancreatic cancer in an in vivo pancreatic cancer mouse model. The applicant first constructed a subcutaneous tumor model of pancreatic cancer in nude mice using Patu8988 cells, and inoculated Patu8988 cells into the subcutaneous tissue around the groin of nude mice by subcutaneous implantation. After three weeks, the mice were evenly divided into two groups according to the size of the tumor. After 4 weeks of treatment with Q216 CPP, the subcutaneous tumor was observed and it was found that the tumor in the Q216CPP group was significantly smaller than that in the control group ( Figure 8 A). By drawing the tumor volume change curve, it was found that the tumor growth of mice treated with Q216 CPP was significantly slower than that of subcutaneous tumors in control mice ( Figure 8 B). Further weighing of subcutaneous tumors revealed that the number of tumor-bearing mice treated with Q216 CPP was significantly reduced ( Figure 8C). Subsequently, the applicant constructed an orthotopic pancreatic cancer model, using the pancreatic orthotopic implantation method to inoculate mouse pancreatic cancer cell KPC1199 cells into the pancreas of C57BL6 / J mice via insulin needle. The progression of orthotopic tumors was then regularly monitored by small animal imaging. The results showed that Q216 CPP could significantly inhibit the progression of orthotopic pancreatic cancer and prolong the overall survival of mice ( Figure 8 D~F).

Claims

1. Use of polyamine modification in the preparation of agents for treating cancer.

2. The use according to claim 1, characterized in that The agent for treating cancer is a polyamine modification inhibitor.

3. The use according to claim 1, characterized in that The polyamination modification inhibitor is a polyamination modification inhibitor of QARS protein.

4. The use according to claim 3, characterized in that The polyamine modification inhibitor of QARS protein is a cell penetrating peptide having a sequence as shown in SEQ ID NO.

1.

5. The use according to any one of claims 1 to 4, characterized in that: The cancer is pancreatic cancer.

6. A cell penetrating peptide having the sequence shown in SEQ ID NO.

1.

7. A drug for treating cancer, comprising the cell penetrating peptide according to claim 6.

8. A cancer combination therapy drug combination, comprising a polyamine modification inhibitor and at least one other cancer treatment drug.

9. The therapeutic drug combination according to claim 8, characterized in that: The polyamine modification inhibitor of QARS protein is a cell penetrating peptide having a sequence as shown in SEQ ID NO.

1.

10. The therapeutic drug combination according to claim 9, characterized in that: The other cancer treatment drugs are paclitaxel, gemcitabine, or various targeted antibodies.

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