CN110870879A - Use of PLCE1 inhibitors and recombinant p53 adenoviruses - Google Patents
Use of PLCE1 inhibitors and recombinant p53 adenoviruses Download PDFInfo
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Abstract
The invention provides an application of a PLCE1 inhibitor and a recombinant p53 adenovirus, and particularly relates to an application of a combination of a PLCE1 inhibitor and a recombinant p53 adenovirus in preparation of a medicine for treating esophageal squamous carcinoma. The invention also provides a medicament for treating esophageal squamous carcinoma, which is characterized by comprising a PLCE1 inhibitor and a recombinant p53 adenovirus. The invention belongs to the field of medicines, and provides an application of a combination of a PLCE1 inhibitor and a recombinant p53 adenovirus in preparation of a medicine for treating esophageal squamous cell carcinoma. The invention combines the PLCE1 inhibitor and the recombinant p53 adenovirus, and can effectively inhibit the growth of esophageal squamous carcinoma cells and xenograft tumors. The invention provides a personalized treatment scheme for esophageal squamous carcinoma by using the recombinant p53 adenovirus in combination based on PLCE1 detection, and is easy to use and popularize clinically.
Description
Technical Field
The invention relates to the field of medicines, and relates to an application of a combination of a PLCE1 inhibitor and a recombinant p53 adenovirus in preparation of a medicine for treating esophageal squamous cell carcinoma.
Background
Esophageal Cancer (EC) is a common malignancy of the digestive tract system with a sixth global mortality rate, and the global incidence of Esophageal cancer has increased by 50% from 1990 to 2008. China is a high-incidence region of esophageal cancer in the world, and the tissue type is mainly squamous cell carcinoma (esophageal squamous carcinoma for short). The occurrence of esophageal squamous carcinoma is a complex process involving multifactorial, polygenic variant accumulation and interaction, but the mechanism of occurrence and development of esophageal squamous carcinoma is still unclear. Although the diagnosis and treatment level of the esophageal cancer is greatly improved in recent years, the 5-year survival rate of patients with the esophageal cancer is less than 20%, the existing esophageal squamous carcinoma treatment scheme comprises means such as surgical treatment and chemoradiotherapy, but the long-term use of the drug esophageal cancer cells has drug resistance to the drug, and the finding of the drug resistance of the esophageal cancer cells to the drug has a profound significance.
Phospholipase C Epsilon 1(Phospholipase C Epsilon-1, PLCE1) is a susceptible gene of esophageal squamous carcinoma of Chinese Han nationality and Xinjiang Uygur-Kazak nationality which is firstly proved by genome-wide association studies (GWAS) technology of Wangdong, Abnet, Chen Wu and the like. The activity of PLCE1 is regulated by a variety of intracellular and extracellular signaling molecules, which activate the catalytic center of the conserved domain of PLCE1 to exert its catalytic activity, and thus phosphatidylinositol 4, 5-diphosphate (PIP) on the cell membrane2) Hydrolysis, producing the two second messengers inositol triphosphate (IP3) and Diacylglycerol (DAG). IP3 induced cellsInternal storage of Ca2+And DAG may cause activation of PKC (protein kinase C), causing phosphorylation of serine and threonine residues on various target proteins in the cytoplasm, thereby regulating cellular metabolism and promoting proliferation and differentiation of cells.
p53 is the first cancer suppressor gene found in human, and in most malignant tumors, p53 is mutated and is a gene related to apoptosis, and the invasiveness of tumor cells is increased with the help of other genes, so that the survival time of patients is reduced. The p53 gene includes wild type and mutant. The half-life of the mutant p53 protein is longer than that of the wild p53 protein, so most of the proteins observed by the immunohistochemical method are mutant p53 proteins, and p53 can influence the biological behaviors of tumor cells such as proliferation, apoptosis, autophagy and the like. Please et al found that PLCE1 could inhibit p53 expression and inhibit apoptosis of esophageal carcinoma cells and lung adenocarcinoma A549 cells. The PLCE1 gene was shown to be involved in p 53-mediated tumorigenesis.
Disclosure of Invention
The invention aims to provide new application of a PLCE1 inhibitor and a recombinant p53 adenovirus, and the new application aims to solve the technical problem of poor effect of surgical treatment or drug treatment of esophageal squamous cell carcinoma in the prior art.
In order to achieve the above object, the present invention provides a medicament for treating esophageal squamous carcinoma, which is characterized by comprising a PLCE1 inhibitor and a recombinant p53 adenovirus.
Furthermore, the esophageal squamous carcinoma is a PLCE1 high-expression type.
Further, the PLCE1 inhibitor is shR-PLCE1, or other substances capable of degrading phospholipase C.
Further, the other substance capable of degrading phospholipase C is U73122.
Further, the recombinant p53 adenovirus is rAd-p53 or other substance capable of accumulating wild-type p53 in vivo.
Furthermore, the other shRNAs capable of accumulating the wild-type p53 substance in vivo are proteasome core component proteins or microRNAs for regulating proteasome component proteins.
The invention also provides application of the combination of the PLCE1 inhibitor and the recombinant p53 adenovirus in preparing a medicament for treating esophageal squamous carcinoma.
The invention provides a medicament for treating esophageal squamous carcinoma, which is characterized by comprising a substance capable of degrading phospholipase C and a substance capable of accumulating wild type p53 in vivo.
The combined medicine and the combined medicine are prepared into an injection preparation or an oral preparation according to the conventional technology in the field. Wherein when orally administered, it can be made into conventional solid preparations such as tablet, powder, granule, capsule, etc. Wherein the injection can be made into conventional solution, aqueous or oily suspension, emulsion, liposome, microcapsule, microsphere, nanoparticle, etc., or made into various sustained-release or controlled-release preparations. The pharmaceutical composition is preferably prepared into an oral preparation, preferably an oral capsule, wherein the specific site targeted release preparation is particularly preferred.
In the preferred embodiment of the present invention, the administration of the PLCE1 inhibitor and the recombinant p53 adenovirus includes intravenous injection, oral administration, topical administration, etc.
The application amount of the combined medicament can be properly changed according to different administration objects, administration routes or preparation forms of the medicaments, but the premise is to ensure that the medicinal composition can achieve effective blood concentration in a mammal body.
The effective amount of the present invention may be 0.005-100mg/kg body weight, and preferably the daily dose may be 0.01-100mg/kg body weight, more preferably 0.1-60mg/kg body weight. One or more administrations may be carried out.
Preferably, the weight ratio of the PLCE1 inhibitor to the recombinant p53 adenovirus is 1: 1-10.
The combined medicament is used for treating esophageal squamous carcinoma, and is preferably used for treating esophageal squamous carcinoma with high expression of PLCE 1.
The invention can be used for administering to an esophageal squamous carcinoma patient with high PLCE1 expression by detecting the expression level of PLCE1 in the tumor of the esophageal squamous carcinoma patient and combining a PLCE1 inhibitor and recombinant p53 adenovirus.
The esophageal squamous carcinoma cell line with high PLCE1 expression is dead after the PLCE1 is knocked out by lentivirus, and the PLCE1 can specifically inhibit the expression of p 53.
The combined application of the PLCE1 inhibitor and the recombinant p53 adenovirus can effectively inhibit the proliferation of esophageal squamous carcinoma cells with high expression of PLCE1 and promote the apoptosis of the esophageal squamous carcinoma cells.
Compared with the prior art, the invention has remarkable technical progress. The invention combines the PLCE1 inhibitor and the recombinant p53 adenovirus, and can effectively inhibit the growth of esophageal squamous carcinoma cells and xenograft tumors. The invention provides a personalized treatment scheme for esophageal squamous carcinoma by using the recombinant p53 adenovirus in combination based on PLCE1 detection, and is easy to use and popularize clinically.
Drawings
FIG. 1 shows immunohistochemical staining of PLCE1, p53 in paracancerous normal esophageal tissue and esophageal squamous carcinoma.
FIG. 2 shows the expression of p53 and downstream molecules after inhibition by PLCE 1. The expression of p53 pathway key molecules Bax, p21 and PUMA after silencing PLCE1 was detected by western blot.
FIG. 3 shows the effect on proliferation, apoptosis and autophagy of esophageal squamous carcinoma cell lines Eca109, EC9706, after treatment of PLCE1 and p53 alone and together. Wherein A, B is used for detecting the proliferation capacity of cells after adding inhibitors shR-PLCE1 and rAd-p53, C, D is used for detecting the apoptosis rate after the same treatment, E is the influence on the autophagy level of the cells after the same treatment, F is the expression change of apoptosis-related proteins Bcl-2, Bax and autophagy-related proteins Beclin-1 and p62 after the single inhibition and the joint inhibition.
FIG. 4 shows the therapeutic effect on human esophageal squamous cell carcinoma xenografts following treatment with PLCE1 and p53 alone and in combination. Eca109 cells stably infected with shR-PLCE1 and GFP lentivirus were injected axillary to 6 to 8-week-old nude mice on the left, and when the transplanted tumor grew to about 0.5-1cm in diameter, saline or rAd-p53 was intraperitoneally injected. Wherein A is the tumor taking condition of a nude mouse after death, B is the volume growth curve of the nude mouse, C is the molecule related to the detection of autophagy and apoptosis by WB, and D is the expression level of PLCE1, p53, Bcl2, Beclin-1 and LC3 in the tumor tissue of the nude mouse.
Detailed Description
The embodiments of the present invention will now be described in detail and fully with reference to the accompanying examples, which are provided for illustration of the embodiments of the present invention and are not to be construed as limiting the scope of the invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used are not indicated to the manufacturer, and are considered to be conventional products available through commercial purchase.
Lentiviruses constructed from pSIH1-H1-copGFP/shR-PLCE1 and pSIH1-H1-copGFP plasmids were purchased from Kjekay, Shanghai, Inc.; rAd-p53 adenovirus was purchased from Shanghai rights Yang. The PLCE1 antibody used for immunohistochemistry was purchased from sigma, cat # HPA 015598; the p53 antibody was purchased from Shanghai Gene science and technology, Inc., cat # GM700104, ready-to-use; the PLCE1 antibody used in western blot was purchased from santa, cat # sc-28404, and the p53 antibody was purchased from santa, cat # sc-126. Esophageal squamous carcinoma cell lines Eca-109 and EC9706 were purchased from Shanghai Reineckia Biotech, Inc.
Example 1
Paraffin sections of tissues of 150 patients with esophageal squamous cell carcinoma selected in the invention are all from subsidiary hospitals of medical college of Stone river university, expression levels of PLCE1 protein and p53 protein in esophageal squamous cell carcinoma tissues are detected by an immunohistochemical method, and are scored, which is shown in Wang GH, Ling Y, Hong-Wei XU, et al.identification of MXRA5as a novelbiomar in clinical laboratory cancer, Oncology letters.2013; 5(2):544-8.
Tissue sections are subjected to conventional dewaxing hydration, antigen is repaired for 8 minutes, 5% BSA blocking solution is used for incubation for 30 minutes at 37 ℃, primary antibody is added, and the incubation is carried out overnight at 4 ℃; adding an anti-mouse universal immunohistochemical detection kit (Envision kit) (PV-6000) Envision A liquid labeled secondary antibody, incubating for 30min at 37 ℃, performing DAB color development, performing hematoxylin counterstaining for 3 min, dehydrating, clearing and sealing. The expression levels of PLCE1 and p53 in cancer and paracarcinoma esophageal tissue specimens from patients with esophageal squamous carcinoma were determined according to immunohistochemical method. The method is as follows < 5% cells positive is 0 point; 6% -25% of cells are positive and divided into 1 point; 26% -50% of cells are positive and divided into 2 points; the positive of 51-75% cells is 3 points; > 75% cells were positive for score 4. Staining intensity was scored by the presence or absence of cell coloration and shade: the cell no color development is 0 min; light yellow is 1 point; brown is 2 points; tan was 3 points. Then multiplying and grading by combining the percentage of positive cells and the coloring intensity, wherein the obtained score is 0-1 time minute and is graded as (-) and the result is obtained; 2-4 into (+); 5-8 into (+ +); 9-12 into (+++). Wherein-is negative; + is weakly positive; + + + +/+ + + + was strongly positive (Table 1). We divided all cases into low-expression and high-expression 2 groups, 1 representing the low-expression group and 2 representing the high-expression group, and their cut-off values were determined according to the SPSS20.0 software.
TABLE 1 immunohistochemical staining result scoring criteria
Percentage positive cells and intensity of staining score, total score by two score multiplication
FIG. 1A shows the staining of PLCE1, p53 in esophageal squamous carcinoma tumor tissues, normal tissues being negative and esophageal squamous carcinoma being positive; by immunohistochemical scoring of PLCE1 and p53 on tumor tissues of 150 patients with esophageal squamous carcinoma, 102 samples (68%) of the tumor tissues were found to be positive for expression of PLCE1, which indicates that PLCE1 is highly expressed in esophageal squamous carcinoma, while the p53 protein is highly expressed in esophageal squamous carcinoma tissues at 57.32% (94/150) and in paracarcinoma normal tissues at 11% (11/100). In combination with clinical statistics, Spearman correlation analysis was used to investigate the correlation between P53 protein and PLCE1 protein expression, and fig. 1B shows that P53 protein and PLCE1 protein are positively correlated in esophageal cancer tissues (R0.182P 0.025).
Example 2: western blot analysis of changes in the Signal pathway of the esophageal squamous carcinoma cell line after inhibition by PLCE1
Inoculating tumor cells into a 6-well plate in the number of 10 ten thousand cells per well, culturing in an RPMI 1640 complete culture medium at 37 ℃ incubator, respectively adding 50ul 10^8TU/ml shR-PLCE1 and a control GFP lentivirus when the cell fusion degree reaches 50%, changing the solution after the cells adhere to the wall, adding a new culture medium, and continuing culturing for 48 h; taking out 6-hole plate, removing culture solution by suction, and washing with PBS for 2-3 times; preparing a lysate, wherein RIPA (Solebao, product No. R0010) and PMSF (Solebao, product No. IP0280) are 100: 1, storing on ice; dripping 100ul of prepared lysis solution, and standing on ice for 15 min; collecting cells by using a scraper, and placing the cells in a 1.5ml centrifuge tube; centrifuging at 4 deg.C and 12000g for 15min, collecting supernatant, measuring volume, and detecting protein concentration and OD260/OD280 ratio on computer; adding a sample buffer solution (Biyun day, the product number is P0015), (5 Xthe sample buffer solution: the volume of the protein sample is 1:4, mixing uniformly), and placing in a dry bath kettle at 100 ℃ for 10 minutes; then detecting the expression condition of p53 pathway key molecules Bax, p21 and PUMA through SDS-PAGE electrophoresis and western blot. As shown in FIG. 2, Western blot results show that Bax, p21 and PUMA expressions are obviously increased after PLCE1 is inhibited, which indicates that a p53 channel is activated after PLCE1 is inhibited, and similarly, PLCE1 can inhibit p53 and downstream molecules.
Example 3: effect of combination of PLCE1 inhibitor and recombinant p53 adenovirus on esophageal squamous carcinoma cell line
(1) Esophageal cancer cells were divided into 4 groups (GFP + N.C, shR-PLCE1+ N.C, GFP + rAd-p53, shR-PLCE1+ rAd-p53) each with 3 subpores, and esophageal squamous cancer cell lines Eca109 and EC9706 were administered at 4X 10 per well3The number of individual cells was seeded in a 96-well plate. After the cells are attached to the wall, 1ul shR-PLCE1 lentivirus and control GFP lentivirus (1 x10 ^8TU/ml) are added into each well, and after 24h, the solution is changed, and 4ul rAd-p53(1 x10 ^8IU/ml) and 4ul N.C (normal saline) are respectively added.
(2) After 48h, the cell viability was determined by the MTT method, 20ul of MTT assay reagent (Sigma, cat # 88417) (photophobic) was added to each well, the culture medium was aspirated off by incubation in an incubator at 37 ℃ for 4h, 125ul of DMSO was added to each well, and the cells were shaken on a constant-speed shaker in the dark. After the crystal is fully dissolved, the absorbance value at 490nm is detected on an enzyme-linked immunosorbent assay. The absorbance values measured at each time point were used to plot a growth curve.
(3) Treating the cells in a 24-well plate according to the same steps as in the step (1) by adopting the same groups in the step (1), digesting the cells by using 0.5% pancreatin after treatment, washing the cells by using PBS after centrifugation, adding 10ul PI (20ul/ml) and 5ul FITC (10ul/ml) to stain the cells, centrifuging after 10 minutes, washing the cells by using PBS once, and detecting the cells by using a flow cytometer.
(4) The same groups of cells were treated in 24-well plates according to the same procedure as in step (1), washed 1 time with PBS, fixed in 4% paraformaldehyde for 30 minutes, washed with PBS, incubated with 50ul TUNEL assay solution at 37 ℃ in the dark for 60 minutes, washed with mounting plates, observed with a fluorescent microscope and photographed.
(5) The same groups in 24 hole plate according to the steps of (1) the same steps of treating cells, PBS washing 1 times, after the cell treatment and cultured for 48h, adding 100u L AO staining solution (1 u g/mL), then incubated for 40 minutes; the supernatant was discarded, washed 2 times with 1 × PBS for 5min each, observed with a fluorescent microscope and photographed. In addition, the cells were seeded on a six-well plate, 2ml of a fresh medium of MDC (50. mu.M) was added thereto, incubated at 37 ℃ for 10min in an incubator, and the cells were washed 3 times with 1 XPBS for 5min each, and then observed and photographed under a fluorescence microscope.
(6) The esophageal cancer cells are inoculated into a 6-well plate according to the number of 10 ten thousand cells per well, when the fusion degree of the cells reaches 80%, the proteins are extracted by the same method as the step (1) in the example 2, and the expression of apoptosis and autophagy related molecules is detected after SDS-PAGE electrophoresis and western blot co-treatment.
As shown in FIG. 3A, B, the combined use of the PLCE1 inhibitor and rAd-p53 has a good growth inhibition effect on esophageal squamous carcinoma cell lines Eca109 and EC9706, but the inhibition effect on cells is weak when the inhibitor is used alone; as can be seen from FIG. 3C, D, in Eca109 and EC9706, the apoptosis rate was most significant after the combined use of shR-PLCE1 and rAd-p53, compared with the use of a PLCE1 inhibitor alone and a wild-type p53 adenovirus; FIG. 3E shows that the combined use of PLCE1 inhibitor and rAd-p53 significantly increased the level of esophageal squamous carcinoma cell autophagy, relative to the treatment group alone. FIG. 3F shows that the expression of Bcl-2, p62 is significantly reduced and the expression of Bax, Beclin-1 is significantly increased after the inhibition of technology and rAd-p53 by PLCE1 alone, and the expression of Bcl-2, p62 is lowest and the expression of Bax, Beclin-1 is highest after the combination of PLCE1 inhibitor and rAd-p 53.
Example 4: effect of combination of PLCE1 inhibitor and recombinant p53 adenovirus on esophageal squamous carcinoma tumor growth in vivo.
Puromycin screening of Eca109 cells stably infected with shR-PLCE1 and GFP lentivirus 6 to 8-week-old nude mice (50, animal center, university of Xinjiang medical science) were randomly divided into 4 groups and treated as follows:
(1) group shR-Con + N.S.: left axilla were injected subcutaneously with 0.5ml of shR-Con stable Eca109 cells obtained in example 2 3x10^6 cells, intratumorally with saline (saline volume corresponds to p53 adenovirus volume).
(2) shR-PLCE1 group + N.S. group: left axilla were injected subcutaneously with 0.5ml of shR-Con stable Eca109 cells obtained in example 2 3x10^6 cells, intratumorally with saline (saline volume corresponds to p53 adenovirus volume).
(3) Group shR-Con + rAd-p 53: left axilla was injected subcutaneously with 0.5ml of shR-Con stable Eca109 cells obtained in example 2 3x10^6 cells, intratumorally with rAd-p53 adenovirus, 5 x109VP/mL (tumor diameter 0.2-0.4cm, intratumoral injection 0.1 mL; tumor diameter 0.5-0.7cm, intratumoral injection 0.2 mL; tumor diameter 0.8-1.0cm, intratumoral injection 0.4 mL).
(4) Group shR-PLCE1+ rAd-p 53: left axilla was injected subcutaneously with 0.5ml of shR-Con stable Eca109 cells obtained in example 2 3x10^6 cells, intratumorally with rAd-p53 adenovirus, 5 x109VP/mL (tumor diameter 0.2-0.4cm, intratumoral injection 0.1 mL; tumor diameter 0.5-0.7cm, intratumoral injection 0.2 mL; tumor diameter 0.8-1.0cm, intratumoral injection 0.4 mL).
After the incubation period of the tumors of about 8 to 9 days, tumor masses with the size from mung bean to soybean can be formed at the inoculated part, the tumor formation rate of the four groups reaches 100 percent, and when the transplanted tumors grow to the diameter of about 0.2 to 0.4cm, p53 or physiological saline with the same volume as the transplanted tumors are injected into the tumors.
Tumor diameters were measured every 2 days, and tumor growth curves were plotted after tumor volumes were calculated for each group.
40mg of nude mouse tumor tissue is cut into pieces and ultrasonically treated, 200ul of lysis buffer (Solebao, product number R0010) is added to extract protein, and western blot is used for detecting the expression levels of PLCE1, p53, Bcl2, Beclin-1 and LC 3.
Expression levels of PLCE1, p53, Bcl2, Beclin-1, LC3 in paraffin-embedded nude mouse tumor tissues were examined by immunohistochemical methods.
As shown in fig. 4AB, the tumor size and volume of nude mice were significantly reduced after adding the PLCE1 inhibitor and the wild-type p53 adenovirus recombinant p53 adenovirus, and the tumor size and volume of nude mice were significantly reduced after using the PLCE1 inhibitor and the recombinant p53 adenovirus in combination, compared with the mice treated alone; as shown in fig. 4C, apoptosis and autophagy-related proteins Bcl2, p62 expression were significantly reduced and lower than in the inhibition group alone when a PLCE1 inhibitor was used in combination with recombinant p53 adenovirus; 4D shows that the apoptosis and the expression of autophagy-related proteins bax and Beclin-1 are remarkably increased after adding a PLCE1 inhibitor and recombinant p53 adenovirus.
The above description is only exemplary of the invention and should not be taken as limiting the invention, as any modification, equivalent replacement, or improvement made within the spirit and principle of the invention should be included in the protection scope of the invention.
Claims (10)
1. A medicament for treating esophageal squamous carcinoma, which comprises a PLCE1 inhibitor and a recombinant p53 adenovirus.
2. The medicament for treating esophageal squamous carcinoma according to claim 1, wherein said esophageal squamous carcinoma is high-expression type PLCE 1.
3. The medicament for treating esophageal squamous carcinoma of claim 1, wherein said PLCE1 inhibitor is shR-PLCE1 or other substance capable of degrading phospholipase C.
4. The medicament according to claim 3, wherein the other substance which degrades phospholipase C is U73122.
5. The medicament for treating esophageal squamous carcinoma according to claim 1, wherein the recombinant p53 adenovirus is rAd-p53 or other substance capable of accumulating wild-type p53 in vivo.
6. The medicament for treating esophageal squamous carcinoma according to claim 5, wherein the other substance capable of accumulating wild-type p53 in vivo is shRNA which is a proteasome core component protein or microRNA which regulates proteasome constitutive protein.
Use of a combination of a PLCE1 inhibitor and a recombinant p53 adenovirus in the manufacture of a medicament for the treatment of esophageal squamous carcinoma.
8. A medicament for treating esophageal squamous carcinoma, which comprises a substance capable of degrading phospholipase C and a substance capable of accumulating wild-type p53 in vivo.
9. The medicament for treating esophageal squamous cancer according to claim 1 or 8, which is an injection preparation or an oral preparation.
10. The medicament for treating esophageal squamous carcinoma according to claim 1 or 8, wherein the weight ratio of the PLCE1 inhibitor to the recombinant p53 adenovirus is 1:1-10, and the total effective amount of the two is 0.005-100mg/kg body weight.
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