CN114949223B - Application of PERK activator in preparing medicament for inhibiting development of brain glioma and medicament - Google Patents

Application of PERK activator in preparing medicament for inhibiting development of brain glioma and medicament Download PDF

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CN114949223B
CN114949223B CN202210508527.XA CN202210508527A CN114949223B CN 114949223 B CN114949223 B CN 114949223B CN 202210508527 A CN202210508527 A CN 202210508527A CN 114949223 B CN114949223 B CN 114949223B
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perk
activator
glioma
medicament
cells
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CN114949223A (en
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李宁宁
王涛
绍豪
周云侠
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Seventh Affiliated Hospital Of Sun Yat Sen University Shenzhen
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses an application of PERK activator in preparing a medicine for inhibiting brain glioma development and the medicine, and relates to the field of biological medicine. The inventor of the application proves that the PERK activator has the capacity of passing through the blood brain barrier, can activate a PERK channel to inhibit the activity of brain glioma cells, the cell activity is decreased along with the increase of the concentration of the PERK activator, the endoplasmic reticulum stress of tumor cells is increased to trigger death, the PERK in the tumor cells is induced to be phosphorylated, the biological function of the PERK is activated, the development of brain glioma is obviously inhibited, and the PERK activator is expected to be a new targeted preparation of a medicament for preventing and treating the brain glioma.

Description

Application of PERK activator in preparing medicament for inhibiting development of brain glioma and medicament
Technical Field
The invention relates to the field of biological medicine, in particular to application of a PERK (PERK) activator in preparing a medicine for inhibiting development of brain glioma and the medicine.
Background
With the development of socioeconomic performance and the change of dietary structure, the incidence of tumors has increased significantly. At present, the incidence and death of brain tumors are the first ten malignant tumors in China, and the global incidence rate is increased year by year. Gliomas are the most common intracranial tumors, and are rapid in growth, strong in invasiveness and extremely easy to relapse. Gliomas have been reported to be the second leading cause of cancer death in adults under 15 years of age and between 15 and 34 years of age. During the last 20 years, although clinical diagnosis is continuously advanced, gliomas still face serious challenges in terms of treatment, such as survival rate of less than 5% in 5 years, drug resistance, high recurrence rate and the like. Since glioma infiltration fronts are generally not significantly limited to normal brain tissue, surgery is difficult to completely ablate.
The only drugs currently used to treat gliomas are Temozolomide (TMZ) marketed in 2005 and bevacizumab approved by FDA in 2009, but the more serious fact is that TMZ is facing the dilemma of drug resistance, high recurrence rate and non-targeting. In recent years, the research on GBM treatment by CAR-T and PD-1 is very popular, but the clinical experiment effect is poor; whereas the treatment of IDH mutated gliomas by IDH mutated activators is not FDA approved. Therefore, searching for new molecular drug targets is obviously a leading-edge difficulty in effectively developing glioma-targeted drugs.
Disclosure of Invention
The invention provides an application of PERK activator in preparing a medicine for inhibiting development of brain glioma and the medicine, so as to provide a medicine for targeted treatment and high-efficiency inhibition of development of brain glioma.
In order to solve the technical problems, one of the purposes of the invention is to provide an application of PERK activator in preparing a medicine for inhibiting brain glioma development.
Preferably, the PERK activator is CCT020312 or MK-28.
Preferably, the PERK activator is CCT020312.
In order to solve the technical problems, the second object of the present invention is to provide a drug for inhibiting the development of glioma, which comprises a PERK activator.
Preferably, the PERK activator is CCT020312 or MK-28.
Preferably, the PERK activator is CCT020312.
Preferably, the medicament is for ex vivo or in vivo administration.
Preferably, the dosage of the medicine is 20mg/kg d, and the administration object is a mouse.
Preferably, the medicament further comprises an adjuvant, wherein the adjuvant is one or more of granules, a buffering agent and a surfactant.
Preferably, the drug is in a microinjection form or a form suitable for transfection.
Compared with the prior art, the embodiment of the invention has the following beneficial effects:
the inventor of the application proves that the PERK activator can obviously inhibit the development of brain glioma cells and has the capacity of passing through the blood brain barrier through a large amount of experimental data ， Can raise the endoplasmic reticulum stress of tumor cells to induce death, and the cell activity decreases with the increase of the concentration of PERK activator, so as to induce PERK in the tumor cells to be phosphorylated, activate the biological function of PERK, and be expected to be a new targeted preparation of the medicine for preventing and treating glioma.
Drawings
FIG. 1-molecular structural formula of PERK activator CTT020312 in the present application;
FIG. 2-in vitro culture of 3 patient-derived glioma tissues for 2-3 passages to obtain in vitro cultured and passaged glioma organoids;
FIG. 3-shows the results of the glioma cell activity assay in example one of the present application (note: A-U87 glioma cell activity versus CCT020312 versus CCT020312 versus CCT020312 versus CCT020312 versus C-SF295 glioma cell activity versus CCT 5234 versus CCT020312 versus);
FIG. 4-shows Western blot detection results of glioma cells treated with different concentrations of CCT020312 in example two of the present application;
FIG. 5-is a graph showing the results of fluorescence in vivo imaging of glioma cells in the brain of mice in example III of the present application;
fig. 6-image results (left) and 5 day dimension statistics (right) of in vitro glioma organoid volume inhibition for 72h for different concentrations of CCT020312 drug in example four of the present application.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The inventors found that IDH mutation promotes glioma cells to be exposed to a long-term Endoplasmic Reticulum Stress (ERS) environment to obtain vulnerability to apoptosis, whereas ERS molecular switch miR-183 can enhance sensitivity of glioma initiating cells (glioma-initiating cells) to TMZ.
Cell stress is a series of adaptive changes that occur when cells are subjected to environmental changes or drug stimulation resulting in damage to biological macromolecules, which in turn results in changes in gene expression, either in an attempt to restore cellular homeostasis or in an irreparable state, to induce cell death to clear unrepaired cells. The cellular stress response process involves a number of organelles such as the endoplasmic reticulum, mitochondria, etc. Tumor cells are stimulated during crazy proliferation attack by insufficient nutrients such as glucose or amino acids, blocked folding of peptide chains, overload of secreted proteins, viral infection, gene mutation, metabolic disorders, and calcium ion imbalance, which breaks the intrinsic balance of sugar, lipid, protein homeostasis, causes endoplasmic reticulum stress (Endoplasmic Reticulum Stress, ERS), and activates unfolded protein responses (Unfolded Protein Response, UPR). The ERS/UPR mechanism is just an effective means of rapidly initiating, attempting to reverse the crisis, restoring cellular homeostasis when the cell is challenged with a deleterious stimulus. ERS/UPR is both a natural molecular marker "place of origin" and an important research direction for tumor targeted therapies. The key genes involved in ERS are significantly altered in many cancers, such as up-regulated levels of IRE1 alpha and XBP1 in more than 10 cancers, such as colorectal cancer, glioma and primary hepatoma. The endoplasmic reticulum stress response system ERS can determine the death fate of tumor cells to a considerable extent, and participate in modeling immune microenvironment phenotypes, ultimately regulating tumor malignancy. We found that ERS is abnormal and PERK level is abnormally increased in brain glial cells, which suggests that PERK can play an oncogene role, but the relation between PERK and brain glioma is not reported yet.
CCT020312 is a selective EIF2AK3/PERK activator, CCT020312 can induce EIF2A phosphorylation in cells, and CCT020312 treatment can effectively inhibit cell proliferation, and its molecular structural formula is shown in fig. 1. The application further successfully screens the small-molecule PERK activator CTT020312 with the capacity of passing through the blood brain barrier, and proves that the small-molecule PERK activator CTT020312 has glioma targeting killing capacity in vivo and in vitro, and meanwhile, the PERK activator MK-28 is found to have the functions of inducing PERK phosphorylation and activating PERK biological functions, and the PERK small-molecule activator is expected to become a new small-molecule drug for brain glioma.
The drug for inhibiting the development of the glioma comprises PERK activator, and can be added with one or more pharmaceutically acceptable adjuvants, including but not limited to granules, buffering agents, surfactants and other well-known drug adjuvants, and the drug can be prepared into the drugs including but not limited to microinjection agents, transfection-suitable types and the like according to the conventional methods in the pharmaceutical field.
Collecting a clinical cancer sample: brain gliomas (non-tumor cell lines) and paracancerous normal tissues of 3 patients are provided by a seventh hospital affiliated to the university of Zhongshan, and the whole acquisition and subsequent experimental process accords with the ethical requirements of medicine and strictly follows the confidentiality principle of case data. After the tissue sample is taken out through operation, the tissue sample is quickly cut into small blocks, the small blocks are placed in a freezing tube and stored in liquid nitrogen for standby, a part of glioma tissues are used for in vitro culture and long-term passage of glioma organoids, and a glioma organoid cell line obtained by in vitro culture of 3 patient-derived glioma tissues is shown in figure 2.
The specific culture mode of in vitro culture is as follows: cutting into 1mm pieces 3 Patient-derived glioma tissue of size suspended in a suspension containing GlutaMax (1X), NEAA (1X), N2 (1X), B27 (1X), 2-mercaptoethanol (1X) and 2.5 μg/ml pancreasThe islanding DMEM/F12 and Neurobasal (volume ratio: 1:1) mixed culture medium is placed in a 37 ℃ incubator and 5% CO 2 Long term culture was performed under conditions, specific culture mode references: jacob et al 2020, cell (https:// doi.org/10.1016/j.cell.2019.11.036).
Example 1
The influence of PERK activator CTT020312 on glioma cell activity is verified, and the specific steps are as follows:
1) After inoculating equal amounts of U87, A172 and SF295 cell suspensions in 96-well plates, respectively, the culture was carried out in an incubator for 24 hours (37 ℃,5% CO) 2 )；
2) After adding CCT020312 incubators with different concentrations into each well of the culture plate for 48 hours, 10 μl of CCK-8 solution is added into each well, and incubated for 1 hour in a culture environment;
3) The absorbance (OD) at 450nm was measured with a microplate reader, and the relative cell numbers were calculated by a standard curve, and the detection results are shown in FIG. 3.
As shown in FIG. 3, the cell activities (CCK-8) of in vitro cultured U87, A172 and SF295 cells decreased with increasing concentrations of CCTC 020312.
Example two
Verification that the PERK activator CTT020312 is effective in inhibiting glioma cell proliferation, comprising the steps of:
1. cell culture:
human brain glioma cell line SF295 was cultured in DMEM medium (Thermo, USA) containing 10% fetal bovine serum (Gibco, USA), penicillin (100U/mL) and streptomycin (100U/mL), all cells were placed in a 37℃incubator, 5% CO 2 Culturing under conditions until the cells reach 70-80% confluency or glioma organoids reach 1mm 3 At this time, CTT020312 was added at a concentration specified in the experiment, and human brain glioma cells were set up as a plurality of samples with concentration gradients of 0 μm, 1.25 μm, 2.5 μm, 5 μm.
2. Detection of intracellular ERS-related gene expression levels:
A. culturing the human brain glioma cells SF295 in the step 1 for 48 hours, then digesting and centrifuging to collect cells, adding 100 mu L of cell lysate to lyse the cells, centrifuging at 13400g and 4 ℃ for 15 minutes, and extracting total cell proteins;
B. after detecting the protein concentration, 20 mug of each sample is mixed with 4X SDS-PAGE loading buffer, and the mixture is heated at 95 ℃ for 5min, and then 10% SDS-PAGE gel is used for separating the protein, so that gel electrophoresis test is carried out;
C. after electrophoresis, the blotting membrane is blocked by 5% skimmed milk for 1 hour in a Transfer Buffer for 60 minutes, diluted primary antibody is added after TBST is washed 3 times, incubation is carried out at 4 ℃ overnight, proper secondary antibody diluent is added after TBST is washed 3 times, and incubation is carried out at room temperature for 1 hour;
D. the TBST was washed 3 times again, and after development and fixation treatment, the gel imaging system photographed, and the band was subjected to gray-scale analysis treatment using Image J software, and the result is shown in FIG. 3.
The results show that: as shown in fig. 4, after the activation of the PERK small molecule activator, the endoplasmic reticulum stress related proteins PERK and ATF4 of the tumor cells are raised, and the phosphorylated PERK and ATF4 in the glioma cells are obviously enhanced along with the increase of the concentration of CCTC020312, which indicates that the PERK activator CCTC020312 can effectively activate the PERK pathway to inhibit the cell activity of glioma cells, thereby inhibiting the growth of tumor organoids.
Example III
Construction of xenograft brain glioma in-brain from primary cells of human brain glioma to nude mice (NOD) a mouse model verifies the effect of PERK activator CCT020312 on tumor growth, comprising the steps of:
(1) And (3) molding: obtaining fresh tumor tissue from patient diagnosed with glioma, removing tissue and blood vessel, collecting tumor tissue block, cutting tumor tissue into 1mm pieces by ophthalmic scissors 3 Washing the small pieces of the strain with serum-free culture solution for 2-3 times, adding pancreatin to digest for 30min, filtering with a 100-mesh steel mesh to prepare tumor cell suspension, centrifuging at 1500rpm/min for 10min, discarding supernatant, adding complete culture medium to resuspend cells, and performing primary culture; 50 mu L of the mixture was concentrated to 2X10 7 The cells/ml of luciferase marked human glioma cells are injected into the brain of a nude mouse (NOD) to construct an in-situ transplantation tumor model of the human glioma mouse.
(2) Grouping and administration: the following two sets of experiments were started 2 weeks after the implantation of the above mouse model into cells: 1. a no drug control group; 2. CCT020312 dosing treatment group; the administration mode is intraperitoneal injection, the dosage is 20mg/kg, and the administration is carried out every two days for one month.
(3) And (3) observation: in the drug treatment, the living body analysis is carried out on the tumor size through luciferase, and the living body analysis and detection result after CCT020312 is administrated for one month is shown in fig. 5, which shows that CCT020312 can inhibit the growth of brain glioma and reduce the tumor volume.
Example IV
CCT020312 in vitro tumor killing experiments:
in the drug test, the pieces were sheared to 1mm 3 Patient-derived glioma tissue of size was suspended in a mixed medium of DMEM/F12 and Neurobasal (volume ratio: 1:1) containing GlutaMax (1X), NEAA (1X), N2 (1X), B27 (1X), 2-mercaptoethanol (1X), 2.5 μg/ml insulin, placed in a 37℃incubator, 5% CO 2 The brain glioma organoids were obtained by culture growth for two months under the conditions, and then treated with CCT020312 (multiple samples with concentration gradients of 0 μm, 2.5 μm, 10 μm, 40 μm) for 5 days (up to 30 days), with no small molecule drug treatment as a control, and the size of organoids grown between the two groups and cell survival were compared, and the results are shown in fig. 6.
The foregoing embodiments have been provided for the purpose of illustrating the general principles of the present invention, and are not to be construed as limiting the scope of the invention. It should be noted that any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art without departing from the spirit and principles of the present invention are intended to be included in the scope of the present invention.

Claims (1)

1. An application of PERK activator in preparing a medicine for inhibiting brain glioma development, which is characterized in that the PERK activator is CCT020312, and the medicine is used for in vivo administration.
CN202210508527.XA 2022-05-11 2022-05-11 Application of PERK activator in preparing medicament for inhibiting development of brain glioma and medicament Active CN114949223B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111419844A (en) * 2020-05-09 2020-07-17 重庆医科大学 Application of cct020312 as medicine for treating breast cancer or prostate cancer

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WO2016024010A1 (en) * 2014-08-14 2016-02-18 Deutsches Zentrum Für Neurodegenerative Erkrankungen E.V. (Dzne) Perk activator for the treatment of neurodegenerative diseases

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111419844A (en) * 2020-05-09 2020-07-17 重庆医科大学 Application of cct020312 as medicine for treating breast cancer or prostate cancer

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Himanshu Soni et al..PERK-mediated expression of peptidylglycine α-amidating monooxygenase supports angiogenesis in glioblastoma.《Oncogenesis》.2020,第1-16页. *
Javier Ganz et al..A novel specific PERK activator reduces toxicity and extends survival in Huntington's disease models.《Scientific Reports》.2020,第1-15页. *
Mariam Markouli et al..Targeting of endoplasmic reticulum (ER) stress in gliomas.《Pharmacological Research》.2020,第157卷第1-11页. *

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