CN112142684A - Analog AC1MJE7Y of NAT10 inhibitor Remodelin and application thereof - Google Patents
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Abstract
The invention provides an analogue AC1MJE7Y of a NAT10 inhibitor Remodelin and application thereof, relating to the technical field of biological medicines. Experiments prove that the apoptosis rate of cells gradually increases along with the gradual increase of the dosage of AC1MJE7Y, and the cell apoptosis rate is in a dose-dependent relationship; the AC1MJE7Y can obviously increase the activity of Caspase-3, 9 and is in a dose-dependent relationship; the AC1MJE7Y can obviously increase Bax mRNA expression and reduce Bcl-2mRNA expression in a dose-dependent relationship.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to an analogue AC1MJE7Y of a NAT10 inhibitor Remodelin and application thereof.
Background
Hepatocellular carcinoma (HCC) is one of the major malignant tumors threatening human health today, and its incidence rate is the sixth place in malignant tumors worldwide, and the second place in our country. Is the third cancer-related death cause in the world[1]. About 50 million patients are diagnosed with liver cancer each year, and the incidence is still increasing year by year, and the long-term prognosis is still not optimistic[2]. There is an urgent need to find a new therapeutic target to solve this problem.
N-acetyltransferase 10(NAT10) is the only lysine acetyltransferase identified as acting on microtubules and histones[3]. NAT10 is present in the kernel. NAT10 (N-acetyltransferase 10) is a 872 amino acid nucleolin containing an acetyltransferase domain and a lysine-rich C-terminus. NAT10 enhances telomerase activity by stimulating human telomerase reverse transcriptase (hTERT) transcription[4]And are involved in important biological processes such as DNA damage response, rRNA transcriptional activation, cytokinesis and microtubule acetylation[5-7]. NAT10 has been reported to be involved in the development of several human cancers, including colorectal and hepatocellular carcinomas[8-11]. In addition, Ma et al demonstrate that NAT10 can modulate EMT of liver cancer[12]. Meanwhile, the influence of the expression level of NAT10 on the survival rate of clinical liver cancer patients is found to have significant difference through database query (p is 0.0016), and the survival time of the NAT10 high-expression patients is obviously shortened.
The small molecule remodelain is a NAT10 inhibitor discovered for the first time in 2014 by Larrieu et al[13]。
It was found that inhibition of NAT10 could reduce doxorubicin resistance in breast cancer cells by reversing EMT. In addition, Remodelin can inhibit invasion and migration of hepatoma carcinoma cells under hypoxic conditions[12]. The NAT10 inhibitor remodelain can be a potential anticancer drug[14]。
Reference documents:
[1]Ferlay J,Shin HR,BrayF,etal.Estimates ofworldwide burden ofcancer in2008:GLOBOCAN 2008.IntJ Cancer2010；127:2893-2917.
[2]Simard EP,Ward EM,Siegel R,etal..Cancers with increasing incidence trends inthe United States:1999through 2008.CACancerJ Clin 2012.
[3]Larrieu D,Britton S,Demir M,et al.Chemical inhibition of NAT10corrects defects of laminopathic cells.Science,2014,344(6183):527-532.
[4]Shen Q,Zheng X,McNutt MA,etal.NAT10,a nucleolar protein,localizes to the midbody and regulates cytokinesis and acetylation of microtubules.Exp Cell Res 2009；315:1653-1667.
[5]Ito S,Horikawa S,Suzuki T,Kawauchi H,etal.Human NAT10 is an ATP-dependent RNA acetyltransferase responsible for N4-acetylcytidine formation in 18S ribosomal RNA(rRNA).J Biol Chem 2014；289:35724-35730.
[6]Liu H,Ling Y,Gong Y,etal.DNA damage induces N-acetyltransferase NAT10 gene expression through transcriptional activation.Mol Cell Biochem2007；300:249-258.
[7]Chi YH,Haller K,Peloponese JM Jr,etal.Histone acetyltransferase hALP and nuclear membrane protein hsSUN1 function in decondensation of mitotic chromosomes.J Biol Chem 2007；282:27447-27458.
[8]Ma R,Chen J,Jiang S,etal.Up regulation of NAT10 promotes metastasis of hepatocellular carcinoma cells through epithelial-to-mesenchymal transition.Am J Transl Res 2016；8:4215-4223.
[9]Liu X,Tan Y,Zhang C,etal.NAT10 regulates p53 activation through acetylating p53 at K120 and ubiquitinating Mdm2.EMBO Rep 2016；17:349-366.
[10]Zhang X,Liu J,Yan S,etal.High expression ofN-acetyltransferase 10:a novel independent prognostic marker of worse outcome in patients with hepatocellular carcinoma.Int J Clin Exp Pathol 2015；8:14765-14771.
[11]Zhang H,Hou W,Wang HL,etal.GSK-3beta-regulated N-acetyltransferase 10 is involved in colorectal cancer invasion.Clin Cancer Res2014；20:4717-4729.
[12]Wu J,Zhu H,Wu J,etal.Inhibition of N-acetyltransferase 10 using remodelin attenuates doxorubicin resistance by reversing the epithelial-mesenchymal transition in breast cancer.Am J Transl Res.2018；10(1):256-264.Published 2018 Jan 15.
[13]Ma R,Chen J,Jiang S,etal.Up regulation of NAT10 promotes metastasis of hepatocellular carcinoma cells through epithelial-to-mesenchymal transition.Am J Transl Res 2016；8:4215-4223.
[14]Larrieu D,Britton S,Demir M,etal.Chemical inhibition of NAT10corrects defects oflaminopathic cells.Science 2014；344:527-532。
disclosure of Invention
In view of the above, the present invention aims to provide an analog AC1MJE7Y of a NAT10 inhibitor Remodelin and an application thereof, which can inhibit liver cancer cell proliferation, reduce the expression of anti-apoptotic protein Bcl-2mRNA, increase the content of the pro-apoptotic protein Caspase-3, 9 and the expression of Bax mRNA, thereby achieving the effect of treating liver cancer.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an analogue AC1MJE7Y of a NAT10 inhibitor Remodelin, wherein the structural formula of the AC1MJE7Y is shown as a formula I;
preferably, the Compound CID of AC1MJE7Y is 3136076, and the chemical formula is C20H21N3S, molecular weight 335.469 g/mol.
The invention also provides application of the AC1MJE7Y in preparing a medicament for inhibiting liver cancer cell proliferation and promoting liver cancer cell apoptosis.
The invention also provides application of the AC1MJE7Y in preparing a medicament for treating liver cancer.
The invention also provides a medicament for inhibiting the proliferation of the liver cancer cells and promoting the apoptosis of the liver cancer cells, and the effective component of the medicament comprises the AC1MJE 7Y.
The invention also provides a medicament for treating liver cancer, and the effective component of the medicament comprises the AC1MJE 7Y.
Preferably, the medicine also comprises pharmaceutically acceptable auxiliary materials.
Preferably, the active ingredients of the medicine can reduce the expression of anti-apoptotic protein Bcl-2mRNA, and increase the content of the pro-apoptotic protein Caspase-3, 9 and the expression of Bax mRNA.
The invention provides an analogue AC1MJE7Y of a NAT10 inhibitor Remodelin, IUPAC Name: 4- (4-ethylphenyl) -N- [1- (4-ethylphenyl) ethyliden amine]-1,3-thiazol-2-amine), which can inhibit the proliferation of hepatoma cells, reduce the expression of anti-apoptotic protein Bcl-2mRNA, increase the content of Caspase-3, 9 and the expression of Bax mRNA. In the present example, the results of MTT assay evaluated for antitumor activity in vitro showed that the cell survival rate was significantly different (p) from the dose of 6. mu. mol/L compared to the drug-free group<0.05). With increasing doses of AC1MJE7Y, cell survival rates decreased gradually, in a dose-dependent relationship. Half inhibitory concentration IC at 48h50The value was 26.6. mu. mol/L. The apoptosis is further detected by a flow cytometer, and the result shows that compared with the group without the drug, the apoptosis rate is remarkably different from the dose of 6 mu mol/L (p)<0.05). The AC1MJE7Y can obviously increase the apoptosis rate. With the gradual increase of the dosage of the AC1MJE7Y, the apoptosis rate gradually increases in a dose-dependent relationship. The ELISA detects the activity of the Caspase-3, 9 in the cells, and the result shows that the activity of the Caspase-3, 9 in the cells is remarkably different from that in a drug-free group from 6 mu mol/L (p)<0.05). AC1MJE7Y can obviously increase Caspase-3, 9 activity. With the gradual increase of the dosage of the AC1MJE7Y, the Caspase-3, 9 activity is gradually increased in a dose-dependent relationship. The expression of Bcl-2 and Bax mRNA in the cells is detected by qPCR, and the result isIt was shown that cellular Bcl-2mRNA and Bax mRNA expression showed significant differences from the 6. mu. mol/L dose (p) compared to the drug-free group<0.05). AC1MJE7Y can obviously increase Bax mRNA expression and reduce Bcl-2mRNA expression. With the gradual increase of the dosage of AC1MJE7Y, the expression of Bax mRNA is gradually increased, and the expression of Bcl-2mRNA is gradually reduced in a dose-dependent relationship.
Drawings
FIG. 1 is a graph showing the growth inhibitory effect of AC1MJE7Y on human hepatoma cell lines, in which the bar graph represents the average of three experiments and the error bars represent the Standard Deviation (SD); 0.01< p <0.05 for each group compared to the non-dosed group; p <0.01 for each group compared to the non-administered group, the same applies below;
FIG. 2 the effect of AC1MJE7Y on intracellular Caspase-3 activity;
FIG. 3 the effect of AC1MJE7Y on intracellular Caspase-9 activity;
FIG. 4 expression of intracellular Bcl-2mRNA by AC1MJE 7Y;
FIG. 5 expression of Bax mRNA in cells by AC1MJE 7Y;
FIG. 6 effect of AC1MJE7Y on tumors in HepG2 tumor-bearing mice.
Detailed Description
The invention provides an analogue AC1MJE7Y of a NAT10 inhibitor Remodelin, wherein the structural formula of the AC1MJE7Y is shown as a formula I;
the Compound CID of the AC1MJE7Y is 3136076, and the chemical formula is C20H21N3S, molecular weight 335.469 g/mol; the chemical name is 4- (4-ethylphenyl) -N- [1- (4-ethylphenyl) ethylideneamine]。
The AC1MJE7Y has the capacity of inhibiting the proliferation of liver cancer cells and promoting the apoptosis of the liver cancer cells, can reduce the expression of anti-apoptosis protein Bcl-2mRNA, and increases the content of apoptosis-promoting protein Caspase-3, 9 and the expression of Bax mRNA, thereby showing the effect of treating liver cancer.
The invention also provides application of the AC1MJE7Y in preparing a medicament for inhibiting liver cancer cell proliferation and promoting liver cancer cell apoptosis.
The invention also provides application of the AC1MJE7Y in preparing a medicament for treating liver cancer.
The invention also provides a medicament for inhibiting the proliferation of the liver cancer cells and promoting the apoptosis of the liver cancer cells, and the effective component of the medicament comprises the AC1MJE 7Y. The dosage form of the drug is not particularly limited in the present invention, and conventional dosage forms in the art may be preferably used. The medicament of the invention preferably also comprises pharmaceutically acceptable auxiliary materials, and the corresponding auxiliary materials are selected according to different dosage forms. The effective components of the medicine can reduce the expression of anti-apoptosis protein Bcl-2mRNA, and increase the content of apoptosis-promoting protein Caspase-3, 9 and Bax mRNA expression.
The invention also provides a medicament for treating liver cancer, and the effective component of the medicament comprises the AC1MJE 7Y. The medicament of the present invention is preferably the same as the above-mentioned medicament, and will not be described herein again.
The analogue AC1MJE7Y of the NAT10 inhibitor Remodelin and the application thereof provided by the present invention will be described in detail with reference to the examples below, but they should not be construed as limiting the scope of the present invention.
Example 1
MTT method is adopted to evaluate the growth inhibition effect of AC1MJE7Y on human liver cancer cell line, the cell survival rate and IC50And (4) carrying out measurement. Liver cancer HepG2 cells at 2X 104Individual cells/well were seeded into 96-well plates and allowed to adhere overnight. The following day 0, 3, 6, 12, 24, 48. mu. mol/L AC1MJE7Y was added, and after 48h 100. mu.L of MTT solution (5mg/mL) (Sigma-Aldrich, St. Louis, MO, USA) was added to each well and incubated in the dark at 37 ℃ for 4 h. After removing the medium and adding 150. mu.L of dimethyl sulfoxide to dissolve the crystals of methoxyazepine, the absorbance was measured at 570nm using an enzyme reader (Thermo-electric Thermo full-automatic enzyme reader MK3, Saimer Feishel USA). Calculation of cell viability and half inhibitory concentration IC50The value is obtained. Cell survival rate (%) - (drug-treated OD-blank OD)/(non-administered control OD-blank OD)×100％。
As shown in FIG. 1, the cell survival rate was significantly different from that in the case of the drug-free group at a dose of 6umol/L (P)<0.05). With increasing doses of AC1MJE7Y, cell survival rates decreased gradually, in a dose-dependent relationship. Half inhibitory concentration IC at 48h50The value was 26.6. mu. mol/L.
Example 2
Apoptosis was detected after AC1MJE7Y action using flow cytometry. HepG2 cells were digested, resuspended, seeded in 6-well plates, 2mL of medium was added per well, and allowed to adhere overnight. Adding 0, 3, 6, 12, 24 and 48 mu mol/LAC1MJE7Y in the next day, collecting cells after 48 hours, directly transferring supernatant containing suspended cells to a centrifuge tube, digesting adherent cells with 0.25% pancreatin, transferring the cells to the centrifuge tube, combining the cells and the centrifuge tube, centrifuging for 6min at 5000r/min, collecting cells, strictly operating according to the instructions of an Annexin V-FITC/PI kit, and detecting the apoptosis condition by using a flow cytometer.
As shown in Table 1, the apoptosis rate was significantly different from the dose of 6. mu. mol/L (P <0.05) compared to the drug-free group. The AC1MJE7Y can obviously increase the apoptosis rate. With the gradual increase of the dosage of the AC1MJE7Y, the apoptosis rate gradually increases in a dose-dependent relationship.
TABLE 1 Effect of AC1MJE7Y on HepG2 apoptosis Rate
Note: p <0.05 compared to 0 umol/L; p <0.01 compared to 0 umol/L;
example 3
ELISA was performed to determine the effect of AC1MJE7Y on Caspase-3, 9-active cells in cells. Caspase-3, 9 activity detection kit (Beijing Baiolai Paclocktechnology, Ltd.) is used for detecting the intracellular Caspase-3, 9 activity. After the cells of each group are acted for 48h by 0, 3, 6, 12, 24 and 48 mu mol/LAC1MJE7Y, the supernatant culture solution is discarded, lysate is added, the cells are lysed in ice bath, 16,000g at 4 ℃ is carried out, and the centrifugation is carried out for 12 min. The supernatant was collected, and the protein concentration was measured by the Bradford method, whereby the protein concentration was adjusted to 1.5 mg/mL. Taking 50 mu L of a sample to be detected, adding 40 mu L of detection buffer solution, properly mixing, then adding 10 mu L of Caspase-3 chromogenic substrate Ac-DEVD-pNA (2mmol/L) in the detection of Caspase-3, adding 10 mu L of Caspase-9 chromogenic substrate Ac-LEHD-pNA (2mmol/L) in the detection of Caspase-9, and mixing uniformly again. After incubation at 37 ℃ for 100min, absorbance at 405nm was measured using a microplate reader (Thermo-electric Thermo full-automatic MK3, siemer feishel, usa). The absorbance values of the normal groups were taken as 100% with the normal groups as a reference, and the relative Caspase-3, 9 activities of the groups were expressed by the measured optical density values of the experimental group/optical density values of the normal group, respectively.
The results are shown in FIGS. 2-3, and compared with the group without the drug, the activity of the Caspase-3, 9 of the cells is significantly different from the dose of 6 mu mol/L (P < 0.05). AC1MJE7Y can obviously increase Caspase-3, 9 activity. With the gradual increase of the dosage of the AC1MJE7Y, the Caspase-3, 9 activity is gradually increased in a dose-dependent relationship.
Example 4
And real-time fluorescence quantitative detection is carried out on the expression of Bcl-2 and Bax mRNA in the cells by AC1MJE 7Y. After the cells of each group are acted for 48 hours by 0, 3, 6, 12, 24 and 48 mu mol/LAC1MJE7Y, total RNA in the cells is extracted by a Trizol method, and the concentration and the purity of the RNA are measured by an ultraviolet spectrophotometer. Total RNA was reverse transcribed into cDNA using a reverse transcription kit. Then, the cDNA after reverse transcription was used as a template and GAPDH was used as an internal reference, and fluorescent quantitative PCR amplification was carried out using a fluorescent quantitative kit GreenTMPremix Ex TaqTMII (Tli RNaseH Plus) (Dalianbao Biotech Co., Ltd.) in a LightCycler96 fluorescent quantitative PCR instrument. 20 μ L reaction: PCR Forward Primer (10. mu.M) 0.8. mu.L, PCR Reverse Primer (10. mu.M) 0.8. mu.L, TB GreenPremix Ex TaqII (2X) 10. mu.L, cDNA 2. mu.L, sterile deionized water 6.4. mu.L.
Wherein the primer sequence is as follows:
bcl-2 upstream (SEQ ID NO. 1): 5'-AGGATTGTGGCCTTCTTTGAG-3' the flow of the air in the air conditioner,
downstream (SEQ ID NO. 2): 5'-CCCACCGAACTCAAAGAAGG-3', respectively;
bax upstream (SEQ ID NO. 3): 5'-GGTTTCATCCAGGATCGAGCAGG-3' the flow of the air in the air conditioner,
downstream (SEQ ID NO. 4): 5'-ACAAAGATGGTCACGGTCTGCC-3', respectively;
GAPDH upstream (SEQ ID NO. 5): 5'-AGTGGGGTGATGCTGGTGCTG-3' the flow of the air in the air conditioner,
downstream (SEQ ID NO. 6): 5'-CGCCTGCTTCACCACCTTCTT-3' are provided.
Reaction conditions are as follows: pre-denaturation at 95 ℃ for 30 s; denaturation 95 ℃ for 5s, annealing extension 60 ℃ for 20s, 35 cycles were repeated. Relative expression amounts of the respective genes 2-ΔΔCtAnd (4) showing. The experiment was repeated 3 times in total.
The results are shown in FIGS. 4-5, and compared with the drug-free group, the expression of Bcl-2mRNA and Bax mRNA in the cells was significantly different from the dose of 6. mu. mol/L (P < 0.05). AC1MJE7Y can obviously increase Bax mRNA expression and reduce Bcl-2mRNA expression. With the gradual increase of the dosage of AC1MJE7Y, the expression of Bax mRNA is gradually increased, and the expression of Bcl-2mRNA is gradually reduced in a dose-dependent relationship.
Example 5
Effect of AC1MJE7Y on tumor volume and tumor suppression rate in HepG2 solid tumor mice. HepG2 cells were cultured at 37 ℃ with 5% CO2And (5) in a constant-temperature incubator, carrying out passage once for 2-3 d. When the cells were passed to the third generation, they were trypsinized and washed twice with PBS to give cells with a density of 1X 107Single cell suspension per ml. A cell suspension (0.2 ml) was injected into a mouse (weight (22-25) g, purchased from the center of Experimental animals of Henan province (license number SCXK 2015 0005)) after an approximately 5mm percutaneous injection into the right axillary region, the administration was started after 7 days of subcutaneous model replication, and the administration was started in the high and low dose groups of AC1MJE7Y by intraperitoneal injection at 20mg/kg and 10mg/kg, respectively. After 2 weeks of administration, the mice were sacrificed by dislocation of the cervical vertebrae, the tumors were completely detached and weighed. The tumor inhibition rate was calculated according to the following formula: tumor inhibition rate (average tumor weight of model group mice-average tumor weight of administration group mice)/average tumor weight of model group mice.
The results showed that 2 weeks after dosing, both the AC1MJE7Y high and low dose groups had less tumor weight than the model group (fig. 6). The differences are all statistically significant (P < 0.05-0.01). Both the high and low dose groups of AC1MJE7Y had higher tumor inhibition rates, with the high dose group being higher than the lower dose group (table 2).
TABLE 2 influence of AC1MJE7Y on tumor weight and tumor suppression rate of HepG2 tumor-bearing mice
(Note: P <0.05, P <0.01) compared to model group)
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. An analogue AC1MJE7Y of a NAT10 inhibitor Remodelin is characterized in that the structural formula of the AC1MJE7Y is shown as a formula I;
2. the AC1MJE7Y of claim 1, wherein the Compound CID of the AC1MJE7Y is 3136076, and the chemical formula is C20H21N3S, molecular weight 335.469 g/mol.
3. The use of the AC1MJE7Y of claim 1 or 2 in the preparation of a medicament for inhibiting proliferation and promoting apoptosis of liver cancer cells.
4. Use of the AC1MJE7Y of claim 1 or 2 in the manufacture of a medicament for the treatment of liver cancer.
5. A medicament for inhibiting proliferation of liver cancer cells and promoting apoptosis of liver cancer cells, wherein the effective component of the medicament comprises AC1MJE7Y according to claim 1 or 2.
6. A medicament for treating liver cancer, wherein the active ingredient of the medicament comprises AC1MJE7Y of claim 1 or 2.
7. The medicament of claim 5 or 6, wherein the medicament further comprises pharmaceutically acceptable auxiliary materials.
8. The drug of claim 5 or 6, wherein the active ingredient of the drug is capable of reducing the expression of anti-apoptotic protein Bcl-2mRNA, increasing the content of pro-apoptotic protein Caspase-3, 9 and increasing the expression of Bax mRNA.
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