CN121059813A - Combination and application of anti-tumor drugs with PARG inhibitors - Google Patents
Combination and application of anti-tumor drugs with PARG inhibitorsInfo
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Abstract
本发明公开了联合PARG抑制剂的抗肿瘤药物组合及应用。本发明通过天然产物库筛选和CCK‑8实验，发现PARG敲除的胃癌细胞对人参皂苷CK表现出显著增强的敏感性。进一步的克隆形成实验分析表明，PARG敲除显著增强了人参皂苷CK对胃癌细胞增殖的抑制作用。在体内实验中，利用CDX模型，验证了PARG敲除能够显著增强人参皂苷CK对胃癌的抗肿瘤活性。这些发现为PARG作为胃癌治疗靶点以及人参皂苷CK作为潜在治疗药物的临床应用提供了重要的实验依据。本发明研究发现，PARG抑制剂与人参皂苷CK联合用药对其他多种癌症细胞也具有更好的杀伤效果，说明这种效果的提升是广谱性的。
This invention discloses an antitumor drug combination and its application in conjunction with a PARG inhibitor. Through natural product library screening and CCK-8 assays, this invention found that PARG knockout gastric cancer cells exhibited significantly enhanced sensitivity to ginsenoside CK. Further colony formation assays showed that PARG knockout significantly enhanced the inhibitory effect of ginsenoside CK on gastric cancer cell proliferation. In in vivo experiments, using a CDX model, it was verified that PARG knockout significantly enhanced the antitumor activity of ginsenoside CK against gastric cancer. These findings provide important experimental evidence for the clinical application of PARG as a therapeutic target for gastric cancer and ginsenoside CK as a potential therapeutic drug. This invention also found that the combination of PARG inhibitors and ginsenoside CK has a better killing effect on various other cancer cells, indicating that this enhanced effect is broad-spectrum.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an antitumor drug combination combined with a PARG inhibitor and application thereof.
Background
Gastric cancer is one of the malignant tumors with higher morbidity and mortality worldwide, and despite some progress in diagnosis and treatment in recent years, the treatment of gastric cancer still faces many challenges and drawbacks. The main reason for the difficulty in early diagnosis of gastric cancer is that early symptoms are not obvious, the screening popularity is low, and effective biomarkers are lacked. In recent years, with the progress of technologies such as radiotherapy, chemotherapy, neoadjuvant therapy and the like, the total survival rate of gastric cancer patients is remarkably improved, but the benefits brought by the treatments are still very limited, and drug resistance often occur. In general, the treatment means of gastric cancer are limited, and development of new therapeutic drugs is urgently needed.
Targeting DNA damage repair pathways may provide potential therapeutic strategies for gastric cancer patients. Poly (ADP-ribose) polymerase (PARP) is an important protein for DNA damage repair. PARP inhibitors are a new approach we target DNA repair mechanisms. Since the role of PARG protein in DNA damage repair pathway is similar to that of PARP protein, PARG is likely to be a new target for gastric cancer treatment.
Existing PARG inhibitors (PARGi) are classified as extracts from natural products and small molecule inhibitors. The existing small molecule inhibitors mainly comprise poly (ADP-ribose) analog adenosine diphosphate (hydroxymethyl) pyrrolidine diol (ADP-HPD), compound N-bis- (3-phenylpropyl) 9-oxo-fluorene-2, 7-diamide (GPI 16552), rhodamine-based PARG inhibitor (RBPIs), PDD00017273, COH34, JA2131, IDE161 and the like.
For example, the invention application publication No. CN117486874A discloses a benzo heteroaromatic compound, a pharmaceutical composition and application thereof, wherein the medicine is used for preventing and/or treating cancers or diseases related to PARG, and the cancers are preferably ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or gastric cancer.
The effect of PARG inhibitors as monotherapy for gastric cancer is still limited. Therefore, it is still of practical significance to screen other drugs that can be used in combination with PARG inhibitors to improve the therapeutic effect of gastric cancer.
Ginsenoside CK (Ginsenoside compound K, G C-K), CAS number 39262-14-1, molecular formula C 36H62O8.
The ginsenoside CK shows pharmacological activity in the fields of anti-tumor, liver protection, anti-inflammatory and the like. For example, the invention application with publication number of CN116763799A discloses the application of ginsenoside CK in preparing products for inhibiting the proliferation of ovarian cancer cells, which shows that the ginsenoside CK can inhibit the proliferation of sensitive and drug-resistant ovarian cancer cells.
Disclosure of Invention
The invention provides an anti-tumor pharmaceutical composition combining with a PARG inhibitor and application thereof aiming at the defects in the prior art.
The invention discovers that the ginsenoside CK (Ginsenoside compound K, G C-K) has obvious killing effect on the gastric cancer cells of PARG-KO by screening more than 800 medicines in a natural product library. Therefore, the ginsenoside CK is regarded as a candidate drug used in combination with the PARG inhibitor, and the killing effect of the ginsenoside CK on gastric cancer cells and xenografts of the PARG-KO is further evaluated through in vivo and in vitro experiments, so that a new means is provided for treating gastric cancer. Thus, the combination of PARG inhibitors with ginsenoside CK serves as a new potential clinical therapeutic strategy.
The invention firstly provides an anti-tumor medicine combination combined with a PARG inhibitor, which comprises the PARG inhibitor and ginsenoside CK.
Preferably, the PARG inhibitor is at least one of 6' -thiomethylxanthine derivative JA2131, ADP-HPD, GPI16552, RBPIs, PDD00017273, COH34, JA2131 and IDE 161.
More preferably, the PARG inhibitor is the 6' -thiomethylxanthine derivative JA2131. The structural formula of JA2131 is shown in formula 1:
Formula 1.
The structural formula of the ginsenoside CK (G C-K) is shown in formula 2:
Formula 2.
Preferably, the PARG inhibitor is used at a concentration of 20-80 mu M, and the ginsenoside CK is used at a concentration of 20-80 mu M.
The invention also provides application of the anti-tumor pharmaceutical composition combined with the PARG inhibitor in preparing an anti-cancer drug, wherein the anti-tumor pharmaceutical composition combined with the PARG inhibitor comprises the PARG inhibitor and ginsenoside CK.
Preferably, the PARG inhibitor is at least one of 6' -thiomethylxanthine derivative JA2131, ADP-HPD, GPI16552, RBPIs, PDD00017273, COH34, JA2131 and IDE 161.
More preferably, the PARG inhibitor is the 6' -thiomethylxanthine derivative JA2131.
Preferably, the type of cancer is lung cancer, gastric cancer cells, colon cancer cells, liver cancer, esophageal cancer or pancreatic cancer.
More preferably, the lung cancer is lung adenocarcinoma, the stomach cancer is gastric adenocarcinoma, and the esophageal cancer is esophageal squamous cell carcinoma.
Preferably, the PARG inhibitor is used at a concentration of 20-80 mu M, and the ginsenoside CK is used at a concentration of 20-80 mu M.
Compared with the prior art, the invention has the following beneficial effects.
Through natural product library screening and CCK-8 experiments, the invention discovers that PARG knocked-out gastric cancer cells show obviously enhanced sensitivity to ginsenoside CK. Further clone formation experimental analysis shows that PARG knockout remarkably enhances the inhibition effect of ginsenoside CK on gastric cancer cell proliferation. In vivo experiments, the CDX model is utilized to verify that PARG knockout can remarkably enhance the antitumor activity of ginsenoside CK on gastric cancer. The findings provide important experimental basis for clinical application of PARG as a stomach cancer treatment target and ginsenoside CK as a potential therapeutic drug.
The study of the invention discovers that the PARG inhibitor and the ginsenoside CK have better killing effect on various other cancer cells, and the improvement of the effect is broad-spectrum.
Drawings
Figure 1 is a drug screen looking for potential drugs that may be used in combination with PARG inhibition. A in FIG. 1 is cell plating, drug treatment and CCK8 detection of cell activity, B in FIG. 1 is drug library required for drug screening, and the point indicated by the arrow is ginsenoside CK.
FIG. 2 is a graph showing the effect of a combination of PARG inhibitor (JA 2131) and ginsenoside CK (G C-K) on the antitumor activity of gastric cancer and immunohistochemical staining of G C-K treated tumor tissue in a tumor CDX model study. Wherein A in FIG. 2 is a tumor map of a HGC27 xenograft model after G C-K treatment, B in FIG. 2 is a tumor weight statistical map of a HGC27 xenograft model after G C-K treatment, C in FIG. 2 is a tumor volume growth curve statistical map of a HGC27 xenograft model after G C-K treatment, D in FIG. 2 is an immunohistochemical staining map of tumor tissues of Tunel (TUNEL), ki-67 and H & E, and the scale bar is 50 μm. * Represents p <0.05, <0.001, <0.0001, <0.05, < ns > represents p >0.05, and n=5.
FIG. 3 shows the effect of PARG inhibitors (JA 2131, indicated by PARGi) in combination with ginsenoside CK (G C-K) on cell proliferation activity. Wherein, A in FIG. 3 is the effect of the combined use of PARG inhibitor (JA 2131) and G C-K on HGC27 cell activity, B in FIG. 3 is the effect of the combined use of PARG inhibitor (JA 2131) and G C-K on cell activity, C in FIG. 3 is the statistical histogram of HGC27 cell colony formation under the combined effect of PARG inhibitor (JA 2131) and G C-K, and D in FIG. 3 is the death mode of HGC27 cells under the combined effect of PARG inhibitor (JA 2131) and G C-K. * P <0.0001, P <0.001, ns P >0.05, n=3.
FIG. 4 is the effect of PARG inhibitors (JA 2131, indicated by PARGi in the figure) in combination with G C-K on tumor cell activity of various cancers. Wherein A-F in FIG. 4 is the effect of the combined use of PARG inhibitor (JA 2131) and G C-K on the activity of human lung adenocarcinoma cells A549, human gastric adenocarcinoma cells AGS, human colon carcinoma cells HCT116, human hepatoma cells HepG2, human esophageal squamous cell carcinoma cells KYSE150 and human pancreatic cancer cells PANC-1, respectively. * P <0.0001 and p <0.001, n=3.
Detailed Description
Example 1 drug screening for potential drugs potentially useful in combination with PARG inhibition
A in fig. 1 is an experimental procedure for drug screening, including cell plating, drug treatment, and CCK8 detection of cellular activity.
(1) Construction of PARG knockout cell lines
The knockout plasmid sgRNA fragments were first designed according to the CRISPR-Cas9 system, the corresponding targets are shown in table 1. The target fragment sgRNA is constructed into a CRISPR-Cas9 system, so that the CRISPR-Cas9 plasmid for PARG knockout is constructed.
HEK293T cells in good condition were inoculated in 10cm dishes, and when the cell density reached 80%, washed twice with pre-warmed PBS and replaced with DMEM medium without penicillin-streptomycin. Cell transfection Lipofectamine 3000 transfection reagent the transfection solution was prepared according to the system of Table 2. The solution of group B is slowly dripped into the solution of group A, incubated at room temperature for 10min, then dripped into a HEK293T cell culture dish and incubated at 37 ℃ for 10h. The cells were then washed twice with pre-warmed PBS and replaced with penicillin-streptomycin free DMEM medium. After 48h of culture, the culture medium is collected and centrifuged at 3000rpm for 10min to remove cell debris, and the supernatant is filtered by a 0.45 mu m filter membrane to a sterilized 15mL centrifuge tube to obtain the target virus liquid.
HGC27 and AGS cells in logarithmic phase are digested and inoculated into a 6-well plate, and when the cell density reaches 40% -50%, virus liquid culture medium (1 mL of culture medium+1 mL of virus liquid+1 mu L of polybrene) is added for infection for 24h. After the infection, the cell state was observed, and the medium was changed to medium without double antibody, followed by selection with medium containing puromycin. The gene knockout efficiency was verified by Western Blot and subcultured.
Table 1 PARG sgRNA primers
Table 2 Lipofectamine 3000 transfection System
The PARG knockout cell line obtained using PARG-sg1 was designated KO1 cells, and the PARG knockout cell line obtained using PARG-sg2 was designated KO2 cells.
(2) Cell plating HGC27-WT (wild-type human gastric cancer cells), KO1 cells, KO2 cells were seeded into 96-well plates at 2000 cells per well and cultured overnight.
(3) Drug treatment cells in 96 well plates were drug treated for 48h according to a predetermined experimental design using a constructed natural product library (800 drugs purchased from Targetmol, #L6000), followed by detection of cell activity using CCK-8 detection kit by digestion and counting of target cells, and 200. Mu.L per well of 2X 10 3 HGC27-WT, KO1, KO2 cells were inoculated into 96 well plates, respectively. Culturing in a 37 ℃ and 5% CO 2 incubator for 1-5 days. The medium was discarded every day, fresh medium containing 10% CCK-8 was added and incubation was continued for 2h. After the incubation, the absorbance at 450nm was measured with a microplate reader. Cell viability was calculated as follows:
Survival = (OD experimental group-OD blank)/(OD control group-OD blank) ×100%.
Data were processed using GRAPHPAD PRISM software to calculate survival or to plot survival curves and calculate IC50 values.
(4) Data processing and analysis after obtaining the survival rate data of HGC27-WT and KO1 cells, the difference between the two was calculated, i.e., [ WT (survival rate) -KO (survival rate) ]. As shown in B in fig. 1, the drug more sensitive to PARG knocked out gastric cancer cells was screened out by analyzing the difference data, and the survival rate of drug-treated wild type and PARG knocked out HGC27 cells was detected by CCK8 experiments, which revealed that the survival rate of cells was lower after G C-K (ginsenoside CK) was used, indicating that G C-K had good antitumor activity, providing a reference for subsequent studies.
Example 2 tumor CDX model study G C-K Effect on anti-tumor Activity of PARG-KO (PARG Gene knockout) gastric cancer cells
The effect of PARG knockout enhancement G C-K on the antitumor activity of gastric cancer was further investigated by a PARG-WT (wild-type PARG gene), KO1 (CRISPR-Cas 9 gene editing technique to knock out PARG gene) HGC27 cell xenograft model (as shown in example 1). Four groups were set up, WT (wild type), PARG-KO (PARG knockout), wt+ G C-K (wild type plus G C-K) and PARG-ko+ G C-K (PARG knockout plus G C-K), each 5. When the average tumor diameter exceeds 4mm, intraperitoneal injection of the drug was started at a dose of 30mg/kg for 3 days/time, and the body weight and tumor diameter of the mice were measured.
On day 18, a decrease in tumor size was observed in the PARG-KO and G C-K treated groups compared to the WT group, with the PARG-KO+ G C-K group having significantly smaller tumor size than the other three groups (A in FIG. 2). From the measured tumor volume growth curves, it was found that the tumor weights were reduced in the PARG-KO and WT+ G C-K groups compared to the WT, that the tumor weights were minimal in the PARG-KO+ G C-K groups, significantly lower than in the other three groups (B in FIG. 2), and that the tumor growth rates were reduced in the PARG-KO and WT+ G C-K groups compared to the WT groups, and that the tumor growth rates were more significantly inhibited in the G C-K treated PARG-KO groups (C in FIG. 2). Immunohistochemical staining of TUNEL, ki67 and H & E indicators in tumor tissue showed (D in FIG. 2), that the WT group had the greatest number of Ki67 positive cells, indicating the strongest tumor proliferation capacity, whereas the PARG-KO+ G C-K group had the least number of Ki67 positive cells, and the weakest tumor proliferation capacity. In addition, the WT group had the lowest TUNEL positive rate, suggesting that its tumor anti-apoptotic capacity was the strongest, as compared to the PARG-KO+ G C-K group, which showed that its tumor anti-apoptotic capacity was the weakest.
In conclusion, the in vivo CDX model and the immunohistochemical staining result of tumor tissues show that G C-K can enhance the anti-tumor activity on PARG-KO gastric cancer cells, inhibit the proliferation capacity of tumors and promote the apoptosis activity of tumors.
Example 3 in vitro experimental study of the anti-proliferative Activity of PARG inhibitor (JA 2131) and G C-K in combination against gastric cancer
(1) In order to investigate the killing effect of PARG inhibitors (JA 2131) and G C-K combined on cells, the killing effect of PARG inhibitors (JA 2131) and G C-K with different concentrations on HGC27 cells after being treated for 48 hours singly or in combination was detected by a pharmaceutical combination chessboard method, and the cell survival rate was detected by an SRB method.
Cells of interest were digested into cell suspensions and then counted, and 3×10 3 HGC27 cells per well were seeded into 96-well plates. PARG inhibitor (JA 2131) concentrations of 80, 60, 40, 20, 10, 5, 1 and 0. Mu.M were sequentially added to the 2 th to 7 th rows of 96-well plates, and G C-K concentrations of 80, 60, 40, 20, 10, 5, 1 and 0. Mu.M were sequentially added to the 2 nd to 8 th columns of 96-well plates. A control group without drug and with cells and a blank group without drug and without cells are simultaneously set. mu.L of ice-cold 10% TCA (trichloroacetic acid) was added to each well and gently mixed. Fixing at 4deg.C for 30-60 min. Slowly cleaning with water for 5 times, and air drying. mu.L of 0.4% SRB (Sulfonyl rhodamine B) solution (dissolved in 1% glacial acetic acid) was added to each well and incubated at room temperature for 30 minutes in the absence of light. And (3) rapidly flushing each hole with 1% glacial acetic acid for 4-5 times, removing unbound dye, and airing again. 200. Mu.L of Tris buffer was added to each well and the bound SRB dye was dissolved by shaking. Absorbance per well was measured at 560nm using a microplate reader.
The results of the checkerboard experiments in A in FIG. 3 show that the cell viability of HGC27 cells under the combined treatment of PARG inhibitor (JA 2131) and G C-K is lower than that of either drug alone. The combined treatment of PARG inhibitor (JA 2131) and G C-K had a synthetically lethal effect on HGC27 cells.
(2) After confirming the effect of the combination of PARG inhibitors (JA 2131) and G C-K by a chessboard test, the effect of PARG inhibitors on cell activity under the action of the combined G C-K is further confirmed by an MTS test (cell activity measurement test).
The cells of interest were digested and counted, and 2×10 3 HGC27 cells were seeded into 96-well plates. Incubation was carried out in a 37 ℃ 5% CO 2 incubator for 24 hours until the cell attachment was stable. After the addition, the incubation is continued for 24 to 72 hours, 20 mu L of MTS solution is added into each hole, the mixture is gently and evenly shaken, and the mixture is put back into an incubator to be incubated for 1 to 4 hours, and the mixture is protected from light. Absorbance (OD 490) was read at 490nm using a microplate reader. Cell viability was calculated as follows, viability = (OD experimental group-OD blank group)/(OD control group-OD blank group) ×100%.
As shown in FIG. 3B, HGC27 cell viability was significantly reduced after co-treatment with 20. Mu.M PARG inhibitor (JA 2131) and 20. Mu.M G C-K. Through MTS experiments, the application discovers that the PARG inhibitor (JA 2131) and G C-K combined use has better killing effect on tumor cells.
(3) To investigate the effect of PARG inhibitors (JA 2131) and G C-K in combination on the proliferative capacity of cells, HGC27 cells were evaluated in vitro using a clonogenic assay.
Cells in good cell status and in logarithmic growth phase were inoculated into 6-well plates (500 cells per well) and cultured in an incubator at 37 ℃ with 5% CO 2, 3 multiplex wells per group. After culturing until the cells formed obvious colonies, the medium was discarded, washed 1 time with PBS, and fixed with 4% paraformaldehyde for 15min. After washing again with PBS, the cells were stained with a 0.1% crystal violet solution for 15min. After staining was completed, the 6-well plate was scanned with a scanner to obtain a clone formation Image, which was analyzed with Image software. Cell clone numbers were normalized to the untreated control group.
The results of clone formation showed that when PARG inhibitor (JA 2131) and G C-K were combined, the number of clones of cells was significantly less than that of PARG inhibitor (JA 2131) and G C-K alone, with significant differences (C in FIG. 3)
(4) Subsequently, the mode of death of HGC27 cells under the combined action of PARG inhibitors (JA 2131) and G C-K was examined by MTS assay.
As a result, as shown in D in fig. 3, the addition of the apoptosis inhibitor (Z-VAD-FMK) together with the PARG inhibitor (JA 2131) and G C-K combination treatment significantly rescued cell death, significantly increased cell viability, compared to the PARG inhibitor (JA 2131) and G C-K combination treatment group, whereas no similar effect was observed with the addition of the scorch inhibitor (VX 765), the necrotic apoptosis inhibitor (Nec-1) or the iron death inhibitor (Ferr-1). The above results indicate that PARG inhibitors (JA 2131) further reveal an important role of PARG in regulating apoptosis by promoting apoptosis to enhance G C-K killing effect on tumor cells.
Example 4 in vitro experiments to investigate the anti-proliferative Activity of PARG inhibitors (JA 2131) and G C-K in combination in different cancer species
The drug combination experiments were performed on human lung adenocarcinoma cells A549, human gastric adenocarcinoma cells AGS, human colon carcinoma cells HCT116, human liver carcinoma cells HepG2, human esophageal squamous cell carcinoma cells KYSE150 and human pancreatic carcinoma cells PANC-1.
Target cells were digested and counted, and 2×10 3 a549 cells (human lung adenocarcinoma cells), AGS cells (human stomach adenocarcinoma cells), HCT116 cells (human colon carcinoma cells), hepG2 cells (human liver carcinoma cells), KYSE150 cells (human esophageal squamous cell carcinoma cells), PANC-1 cells (human pancreatic carcinoma cells) were inoculated into 96-well plates, respectively. Cells were treated for 48h in an incubator at 37 ℃ with 5% CO 2 after dosing. The medium in the 96-well plates was then discarded, fresh medium containing 10% CCK-8 was added to each well and incubated with cells for an additional 0.5-4h. After the incubation, the absorbance of each well at 450nm was measured with a microplate reader. Survival was calculated using the following equation, survival= (OD experimental group-OD blank)/(OD control group-OD blank) ×100%. Experimental data were processed and cell viability calculated using GRAPHPAD PRISM software.
As shown in FIG. 4, the survival rate of cells from different carcinoma species was significantly reduced after co-treatment with 20. Mu.M PARG inhibitor (JA 2131) and 20. Mu.M G C-K. Through the experiment, the application discovers that the PARG inhibitor (JA 2131) and G C-K combined use has better killing effect on tumor cells of different cancer species.
Claims (10)
1. An antitumor pharmaceutical combination in combination with a PARG inhibitor, comprising a PARG inhibitor and ginsenoside CK.
2. The antitumor drug combination in combination with a PARG inhibitor according to claim 1, wherein the PARG inhibitor is at least one of the 6' -thiomethylxanthine derivatives JA2131, ADP-HPD, GPI16552, RBPIs, PDD00017273, COH34, JA2131 and IDE 161.
3. The antitumor pharmaceutical combination in combination with a PARG inhibitor according to claim 2, wherein the PARG inhibitor is the 6' -thiomethylxanthine derivative JA2131.
4. The anti-tumor pharmaceutical composition combined with the PARG inhibitor according to claim 1, wherein the use concentration of the PARG inhibitor is 20-80 mu M, and the use concentration of the ginsenoside CK is 20-80 mu M.
5. The application of an anti-tumor pharmaceutical composition combined with a PARG inhibitor in preparing an anti-cancer drug is characterized in that the anti-tumor pharmaceutical composition combined with the PARG inhibitor comprises the PARG inhibitor and ginsenoside CK.
6. The use according to claim 5, wherein the PARG inhibitor is at least one of the 6' -thiomethylxanthine derivatives JA2131, ADP-HPD, GPI16552, RBPIs, PDD00017273, COH34, JA2131 and IDE 161.
7. The use according to claim 6, wherein the PARG inhibitor is the 6' -thiomethylxanthine derivative JA2131.
8. The use according to claim 5, wherein the cancer type is lung cancer, gastric cancer cells, colon cancer cells, liver cancer, esophageal cancer or pancreatic cancer.
9. The use according to claim 8, wherein the lung cancer is lung adenocarcinoma, the stomach cancer is gastric adenocarcinoma, and the esophageal cancer is esophageal squamous cell carcinoma.
10. The use according to claim 5, wherein the PARG inhibitor is used at a concentration of 20 to 80 μm and the ginsenoside CK is used at a concentration of 20 to 80 μm.
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| US20180311264A1 (en) * | 2015-10-23 | 2018-11-01 | Agency for Science,Technology and Research | Composition for modulating irak1 |
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