CN110327343A - Application of the Rosuvastatin in preparation targeting PD-L1 treatment solid tumor drugs - Google Patents
Application of the Rosuvastatin in preparation targeting PD-L1 treatment solid tumor drugs Download PDFInfo
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- CN110327343A CN110327343A CN201910655056.3A CN201910655056A CN110327343A CN 110327343 A CN110327343 A CN 110327343A CN 201910655056 A CN201910655056 A CN 201910655056A CN 110327343 A CN110327343 A CN 110327343A
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- rosuvastatin
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- 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
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- 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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Abstract
The present invention provides a kind of application of Rosuvastatin in the drug of preparation targeting PD-L1 treatment solid tumor.Rosuvastatin makes intracellular cholesteryl synthesis reduce to play Regulation serum lipids as clinically used fat-reducing medicament by blocking intracellular mevalonic acid metabolic pathway.The present invention tests in vitro confirms that Rosuvastatin can lower PD-L1 protein level in kinds of tumor cells, and confirms that it can enhance the effect of T cell killing tumor cell in the system that T cell and tumour cell are incubated for altogether in vitro.Rosuvastatin may provide new medical usage for Rosuvastatin, can apply in solid tumor immunization therapy as the micromolecular inhibitor of potential target tumor immunologic test point PD-L1, the present invention.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to application of the Rosuvastatin in preparation targeting PD-L1 treatment solid tumor drugs.
Background technique
In the past few years, we achieve important breakthrough to the understanding of immunosuppressive therapy solid tumor.Cancer immunity is escaped
The key mechanism kept away is that a variety of inhibition ligands are expressed on cancer cell surfaces, especially Programmed death ligand-1 (PD-L1).
PD-L1 is combined with apoptosis albumen -1 (PD-1) as a kind of I type transmembrane protein and is generated inhibition signal, cause
Cancer cell escape immunosurveillance, and block the interaction of the two that can then restore T cell function and increase to treat curative effect.Immune inspection
Make an inventory for the treatment of it is significant in efficacy, clinical response is lasting, at present the multiple PD-1/PD-L1 monoclonal antibodies of FDA approved for treat it is black
Melanoma, non-small cell lung cancer, gastric cancer, kidney and head and neck cancer etc..
But in view of the antibody drug of targeting PD-1/PD-L1, reactivity is low in most treatment of solid tumors, is no more than 20%,
Have research think wherein reason first is that macromolecular antibody drug is difficult to effectively permeate tumor tissues, can not be reached with enough amounts
Caused by all areas of tumour.In addition, general immunity related reactions caused by antibody drug are the non-spies by immune system
Discrete toxicity caused by the opposite sex activates, can influence substantially any tract.Compared with macromolecular antibody drug, small molecule medicine
Object usually has many advantages, such as that good penetrability, toxic side effect are small, can take orally and at low cost, therefore, finds and is directed to PD-1/PD-L1
Small-molecule drug be considered as one of the alternative route for overcoming antibody drug defect.
The current small-molecule drug research and development for PD-1/PD-L1 are mainly unfolded by two kinds of thinkings: 1) according to PD-1/PD-L1
The crystal structure feature of compound, the brand new small-molecule drug that exploitation directly blocks the two to combine.2) based on the egg of PD-L1
White expression and regulation mechanism, design small molecule compound intervene key link, it is inhibited to express or promote its degradation.However
These compounds stay in the laboratory research stage more, and therefore, the research of the small-molecule drug of PD-1/PD-L1 is generally in progress
Slowly.
Rosuvastatin (Rosuvastatin) is that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibits
Agent is the rate-limiting step being catalyzed in Biosynthesis of cholesterol, is clinically widely used to treatment hypercholesterolemia.In recent years
Come, has a large amount of research shows that the use of statins is related to the reduction of the death rate of kinds cancer type, including prostate
Cancer, kidney, colorectal cancer, breast cancer and lung cancer.It is by inhibiting the isoprenoid (example in mevalonic acid (MVA) approach
Such as FPP, GGPP) and cholesterol biosynthesis, it played inhibition tumor cell proliferation, inducing cell cycle arrest, promoted tumour cell
Apoptosis inhibits tumor cell migration and transfer and blood vessel formation against function etc..
Summary of the invention
The object of the present invention is to provide a kind of Rosuvastatin answering in preparation targeting PD-L1 treatment solid tumor drugs
With, Rosuvastatin (Rosuvastatin), chemical name: double-[E-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyl -2- [methyl
(mesyl) amino]-pyrimidine -5- base] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acid], molecular weight 506.5, molecular formula is
C22H24D3FN3NaO6S, pharmaceutical dosage 5-10mg/d.
The drug is made of Rosuvastatin and pharmaceutically acceptable auxiliary material, and dosage form is gelling agent, soft capsule
Agent, oral preparation, injection, freeze drying powder injection or infusion solution type.Once a day.
It is verified by experiments, told Rosuvastatin (Rosuvastatin) lowers the work of PD-L1 in cell experiment in vitro
It is 10 μm of ol/L with concentration.It is non-small thin to find that it can significantly reduce by Western blotting and flow cytometry investigation
The expression of immunologic test point albumen PD-L1 and cell surface PD-L1 in born of the same parents' lung carcinoma cell.PD-L1 level T in vitro is lowered simultaneously
There is biological significance in the system that cell and tumour cell are incubated for altogether, the effect of T cell killing tumor cell can be enhanced.This hair
Bright meaning is a possibility that clear Rosuvastatin is for Clinic solid tumor treatment, to substitute or being combined the suppression of immunologic test point
Preparation, the generation for mitigating adverse drug reaction provide possibility.
The screening of system is carried out in inventor's early-stage study to the drug clinically used, discovery is clinically used extensively
It can significantly reduce the protein level of kinds of tumor cells PD-L1 in the Rosuvastatin of lipid-lowering therapy, it is thin to tumour to restore T cell
The lethal effect of born of the same parents.It is clinical at present that there has been no preferably listed micromolecular inhibitor to pass through the protein expression tune of intervention PD-L1
Control mechanism reaches antineoplastic action, while also having no the correlative study invention of Rosuvastatin regulation PD-L1 protein expression.This
Invention provides the listing micromolecular inhibitor of immunotherapy of tumors, and new medical usage is provided for Rosuvastatin.
Detailed description of the invention
Fig. 1 is that 10 μM of Rosuvastatin (Rosuvastatin) acts on non-small cell lung cancer NCI-H1299, NCI-H460
And NCI-H292 cell for 24 hours after protein immunoblotting figure.
Fig. 2 is after 10 μM of Rosuvastatin (Rosuvastatin) acts on non-small cell lung cancer NCI-H1299 cell for 24 hours
Flow cytometry histogram.
Fig. 3 is that 10 μM of Rosuvastatin (Rosuvastatin) acts on non-small cell lung cancer NCI-H1299, NCI-H460
Afterwards to the influence result of T cell killing tumor cell effect.
Specific embodiment
The present invention is further described in conjunction with the accompanying drawings and embodiments.
Embodiment 1:
Rosuvastatin is significant after acting on non-small cell lung cancer NCI-H1299, NCI-H460 and NCI-H292 cell for 24 hours to be lowered
PD-L1 protein level.Specific step is as follows:
After non-small cell lung cancer NCI-H1299, NCI-H460 and NCI-H292 cell dissociation, piping and druming is at unicellular outstanding
Liquid, is inoculated in 6 orifice plates, and 1.0 × 106Cells/well, the hole culture medium 2ml/, 37 DEG C, 5%CO2Overnight incubation in incubator；Secondary bu
Rosuvastatin (Rosuvastatin, 10 μM) is not given and gamma interferon (IFN-γ, 10ng/ml) is cultivated in the incubator
24h.2.5 × Loading of 150uL is added according to cell concentration and receives sample, 95 DEG C of metal baths heat 15min.Western Blotting
Detect the expression of PD-L1 albumen in cell.Specific Rosuvastatin is to non-small cell lung cancer NCI-H1299, NCI-H460
And the inhibitory effect of PD-L1 albumen is shown in Fig. 1 in NCI-H292 cell.
Embodiment 2:
Rosuvastatin is significant after acting on non-small cell lung cancer NCI-H1299 cell for 24 hours to lower cell membrane surface PD-L1 water
It is flat.Specific step is as follows:
After the non-small cell lung cancer NCI-H1299 cell dissociation of logarithmic growth phase, blows and beats into single cell suspension, be inoculated in
6 orifice plates；1.0×106Cells/well, the hole culture medium 2ml/, 37 DEG C, 5%CO2Overnight incubation in incubator；Next day is given auspicious respectively
It relaxes and cuts down statin (Rosuvastatin, 10 μM) and gamma interferon (IFN-γ, 10ng/ml) is cultivated for 24 hours in the incubator.Using
The expression of Flow cytometry cell surface PD-L1, specific Rosuvastatin are thin to non-small cell lung cancer NCI-H1299
The inhibitory effect of the PD-L1 albumen on after birth surface is shown in Fig. 2.
Embodiment 3
Rosuvastatin enhances T cell to the lethal effect of non-small cell lung cancer NCI-H1299, NCI-H460 cell.Specific step
It is rapid as follows:
Human peripheral blood monocyte is separated by Ficoll separation agent, is inoculated in 2ml capsule, 2 μ l are added
IL-2 (50U/ μ l) and 50 μ l T-Activator CD3/CD28,37 DEG C, 5%CO248h is cultivated in incubator.Logarithm is raw
After long-term non-small cell lung cancer NCI-H1299, NCI-H460 cell dissociation, blows and beats into single cell suspension, be inoculated in 96 orifice plates；
3000 cells/wells, 200 hole μ l/ of culture medium, 37 DEG C, 5%CO2Overnight incubation in incubator；Next day gives Rosuvastatin respectively
(Rosuvastatin, 10 μM) and gamma interferon (IFN-γ, 10ng/ml) are cultivated for 24 hours in the incubator.3rd day, to tumour
1.0 × 10 are added in cell6T cell/hole, while PD-L1 antibody drug is added as positive control, it co-cultures for 24 hours.Using knot
Crystalviolet decoration method investigates T cell to the killing situation of tumour cell.Fig. 3 is shown in specific effect.
Claims (3)
1. a kind of application of Rosuvastatin in preparation targeting PD-L1 treatment solid tumor drugs, the chemical name of Rosuvastatin:
Double-[E-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyl -2- [methyl (mesyl) amino]-pyrimidine -5- base] (3R, 5S) -3,
5- dihydroxy heptyl -6- olefin(e) acid], molecular weight 506.5, molecular formula C22H24D3FN3NaO6S.
2. application according to claim 1, which is characterized in that protein level of the solid tumor because of tumour cell PD-L1
Increasing causes.
3. application according to claim 1, which is characterized in that the drug by Rosuvastatin with it is pharmaceutically acceptable
Auxiliary material preparation, the pharmaceutical dosage form are gelling agent, soft capsule, oral preparation, injection, freeze drying powder injection or infusion solution
Type.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827607A (en) * | 2021-09-03 | 2021-12-24 | 山东大学 | Application of ubenioside in preparation of preparation for reducing tumor cell PD-L1 level |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190046514A1 (en) * | 2016-01-14 | 2019-02-14 | University-Industry Foundation, Yonsei University | Use of statin-based drug for treatment of eml4-alk-positive non-small cell lung cancer resistant to alk inhibitor |
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- 2019-07-19 CN CN201910655056.3A patent/CN110327343A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190046514A1 (en) * | 2016-01-14 | 2019-02-14 | University-Industry Foundation, Yonsei University | Use of statin-based drug for treatment of eml4-alk-positive non-small cell lung cancer resistant to alk inhibitor |
Non-Patent Citations (2)
| Title |
|---|
| D. FALCONE等: "Effects of simvastatin and rosuvastatin on RAS protein, matrix metalloproteinases and NF-kappa B in lung cancer and in normal pulmonary tissues", 《CELL PROLIFERATION》 * |
| IBRAHIM EL SAYED等: "Inhibition of SRC/FAK cue: A novel pathway for the synergistic effect of rosuvastatin on the anti-cancer effect of dasatinib in hepatocellular carcinoma", 《LIFE SCI.》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113827607A (en) * | 2021-09-03 | 2021-12-24 | 山东大学 | Application of ubenioside in preparation of preparation for reducing tumor cell PD-L1 level |
| CN113827607B (en) * | 2021-09-03 | 2024-05-03 | 山东大学 | Application of ouabain in preparation of preparations for down regulating tumor cell PD-L1 level |
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Application publication date: 20191015 |