CN115364111B - Application of glycerophospholipids compound in treatment of tumor - Google Patents
Application of glycerophospholipids compound in treatment of tumor Download PDFInfo
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- CN115364111B CN115364111B CN202110534893.8A CN202110534893A CN115364111B CN 115364111 B CN115364111 B CN 115364111B CN 202110534893 A CN202110534893 A CN 202110534893A CN 115364111 B CN115364111 B CN 115364111B
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- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
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- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
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Classifications
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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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
- A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to application of glycerophospholipids in treating tumors. In particular to the application of glycerophospholipids compound containing a structure shown in a formula (I) in preparing medicines for treating tumors, especially malignant tumors. The compound can induce tumor cells to generate iron death, thereby having excellent anti-tumor effect.
Description
Technical Field
The invention relates to the field of tumor treatment, in particular to application of glycerophospholipids in preparing a medicament for treating tumors, especially malignant tumors.
Background
Malignant tumor is one of the main diseases that threatens human health and affects life span. The first ten cancers of global incidence were in turn: breast cancer, lung cancer, colorectal cancer, prostate cancer, stomach cancer, liver cancer, cervical cancer, esophageal cancer, thyroid cancer, bladder cancer. The first ten cancers in death were in turn: lung cancer, colorectal cancer, liver cancer, gastric cancer, breast cancer, esophageal cancer, pancreatic cancer, prostate cancer, cervical cancer, leukemia. Therefore, the research and development of more and better antitumor drugs has great market value and important social significance.
At present, malignant tumors still lack effective treatment means, and many treatment means aim at killing malignant tumor cells in the past, but the effect is not ideal. The traditional radiotherapy and chemotherapy have poor specificity, and can kill malignant tumor cells and simultaneously generate serious damage to other various tissue cells such as immune cells, thereby weakening the anti-tumor immunity. Apoptosis is a special way of early-discovered cell death, and is generally a mechanism for removing infected or damaged cells and maintaining normal functions of an organism, but malignant tumor cells have special mechanisms for avoiding apoptosis [1] . In addition, malignant tumors also have multiple immune escape abilities to attack immune cells [2] . Therefore, lack of a method for specifically and effectively killing malignant cells has been one of the important reasons for impeding the therapeutic effect of malignant tumors.
In recent years, cells have been found to have multiple ways of death, of which iron death (ferroptosis) has attracted considerable attention. Iron death is iron ion dependent, cell death due to membrane lipid peroxidation [3] . More and more researches find that iron death can be used as a new target for inhibiting tumor, and various genes related to iron death mechanism are found [4] Targeting these genes to induce tumor cell death becomes a new strategy for developing therapeutic agents for malignant tumors. Existing iron death activators such as Erastin, RSL3 and the like are mostly small molecular compounds [5] The function of inhibiting the cell antioxidant mechanism is suitable for some specific tumor cells, and the application range, side effect and the like of the tumor cells need to be further researched and evaluated. Therefore, there is a need to develop more iron-like death activators with different targets and different application ranges.
In recent years, the role of lipid metabolism abnormality in the occurrence and development of malignant tumors has been increasingly emphasized. Mammal fineThe cell lipids are of various types and functions, and glycerophospholipids are the most abundant lipids, are the main components of biological membranes and are also important signal pathway molecules. Abnormal glycerophospholipid metabolism is associated with various tumors [6] . The inventor researches and discovers that glycerophospholipids can induce malignant tumor cells to generate iron death, and have no effect on various normal cells. The mechanism of inducing malignant tumor cells to generate pig death is different from that of common iron death activator for inhibiting cell antioxidant mechanism, and the glycerophospholipids are new iron death activator and are hopeful to develop new medicine for treating malignant tumor.
Disclosure of Invention
The invention aims to provide an application of glycerophospholipids in preparing medicines for treating tumors, in particular malignant tumors.
Therefore, the invention provides the application of the compound with the structure shown in the formula (I) or the pharmaceutically acceptable salt thereof or the pharmaceutical composition containing the compound in preparing the drugs for treating tumors,
in a specific embodiment, the use according to the invention, wherein the compound comprising the structure of formula (I) is represented by formula (II) below:
wherein:
-OR is selected from-OH, choline, L-serine;
M + selected from Na + 、K + ;
Wherein when-OR is a choline group, M + Is not present.
In another specific embodiment, the use according to the invention, wherein the compound comprising the structure of formula (I) is selected from the following compounds:
in another specific embodiment, the use according to the invention, wherein the tumor is a malignant solid tumor, preferably osteosarcoma, colon cancer, rectal cancer, melanoma, prostate cancer, cervical cancer.
In another specific embodiment, the use according to the invention, wherein the tumor is a hematological malignancy, preferably leukemia.
In another specific embodiment, the use according to the invention is characterized in that the compound treats the tumor by inducing tumor cell death, preferably by inducing tumor cell iron death.
In another specific embodiment, the use according to the invention is characterized in that the compound treats the malignant solid tumor by alleviating pathological symptoms and signs, preferably by slowing the growth rate of the tumor, and/or reducing the volume of the tumor, and/or enhancing the efficacy of other treatments, and/or reducing the proportion of tumor recurrence after other treatments, and/or prolonging the time of tumor recurrence after other treatments.
In another specific embodiment, the use according to the invention is characterized in that the compound treats the hematological malignancy by alleviating pathological symptoms and signs, preferably by reducing the number of tumor cells, and/or enhancing the efficacy of other treatments, and/or reducing the proportion of tumor recurrence after other treatments, and/or prolonging the time of tumor recurrence after other treatments.
In another specific embodiment, the use according to the invention, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound having the structure according to formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and a pharmaceutically acceptable carrier or excipient.
In another specific embodiment, the use according to the invention, wherein the compound comprising the structure of formula (I) is used in combination with another therapeutic method or methods of treatment, preferably radiation therapy, chemotherapy, immunotherapy, targeted therapy, or a therapeutic agent, preferably another agent for the treatment of tumors.
The compound containing the structure shown in the formula (I) is structurally characterized in that: the fatty acyl side chain in the phospholipid is double-chain octadecadienoic acid, and the phosphate group of the fatty acyl side chain bonding part can be connected with different polar heads to form different glycerophospholipids, preferably 1, 2-dioleoyl-sn-glycero-3-phosphatidylcholine (1, 2-dioleoyl-sn-glycero-3-phosphaline) (18:2 PC, DLPC), 1, 2-dioleoyl-sn-glycero-3-phosphatidic acid sodium ester (sodium 1, 2-dioleoyl-sn-glycero-3-phosphate) (18:2 PA), 1, 2-dioleoyl-sn-glycero-3-phosphate-L-serine (18:2 PS).
The choline base isA group; the L-serine radical is +.>A group.
The term "pharmaceutically acceptable salts" as used herein refers to pharmaceutically non-toxic acid addition salts and base addition salts. The acid addition salt is a salt formed by a compound and a proper inorganic acid or organic acid, and comprises hydrochloride, phosphate, hydrogen phosphate, sulfate, bisulfate, sulfite, acetate, oxalate, malonate, valerate, glutamate, oleate, palmitate, stearate, laurate, borate and p-toluene Sulfonate, methanesulfonate, malate, tartrate, benzoate, pamoate, salicylate, vanillate, mandelate, succinate, gluconate, lactobionate, laurylsulfonate, and the like. The base addition salts are salts of the compounds with suitable inorganic or organic bases, including, for example, salts with alkali metals, amines or quaternary ammonium compounds, such as sodium, lithium, potassium, calcium, magnesium, amine, tetramethyl quaternary ammonium, tetraethyl quaternary ammonium, choline salts, in particular sodium and choline salts; amine salts, including with ammonia (NH) 3 ) Salts of primary, secondary or tertiary amines, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, ethanolamine, serine, lysine and arginine, in particular serine.
Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of: sweeteners, flavoring agents, coloring agents and preservatives to provide a pleasing and palatable pharmaceutical preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example microcrystalline cellulose, croscarmellose sodium, corn starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone or acacia; and lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, water-soluble taste masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethylcellulose, cellulose acetate butyrate may be used.
Oral formulations may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with a water-soluble carrier, for example polyethylene glycol or an oil vehicle, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and acacia; the dispersing or wetting agent may be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol such as heptadecaethyleneoxy cetyl alcohol, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol such as polyethylene oxide sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride such as polyethylene oxide sorbitan monooleate. The aqueous suspension may also contain one or more preservatives such as ethyl or Jin Zhengbing esters of nipagin, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oil suspension may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above-described sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
Dispersible powders and granules suitable for use in the preparation of an aqueous suspension by the addition of water provide the active ingredient in combination with a dispersing or wetting agent, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients, for example sweetening, flavoring and coloring agents, may also be added. These compositions are preserved by the addition of an antioxidant such as ascorbic acid.
The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, such as polyethylene oxide sorbitol monooleate. The emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous solutions. Acceptable vehicles and solvents that may be used are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then treated to form a microemulsion by adding it to a mixture of water and glycerol. The injection or microemulsion may be injected into the patient's blood stream by local bolus injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present invention. To maintain this constant concentration, a continuous intravenous delivery device may be used.
The pharmaceutical compositions of the present invention may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend stock oil may be used, including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.
The compounds of the present invention may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, glycerogelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycols.
It is well known to those skilled in the art that the amount of drug administered depends on a variety of factors, including but not limited to the following: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the patient's integument, the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of the drugs, etc. In addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.
The invention can contain a compound with a structure shown in a formula (I) or pharmaceutically acceptable salt thereof as an active ingredient, and is mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition and a clinically acceptable dosage form.
The compounds of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions and the like. The compounds of the present invention may be used as the sole active ingredient, or in combination with other drugs. Combination therapy is achieved by simultaneous, separate or sequential administration of the individual therapeutic components.
The compounds of the present invention or pharmaceutically acceptable salts thereof may be used alone or in combination with another therapeutic method or methods of treatment or agents conventionally used in clinic, such as radiation therapy, chemotherapy, immunotherapy, targeted therapy, etc., including but not limited to the following antitumor drugs and therapeutic methods:
1) Alkylating agents such as cisplatin, oxaliplatin, chlorambucil, cyclophosphamide, mechlorethamine, melphalan, temozolomide, busulfan, nitrosoureas;
2) Antitumor antibiotics such as doxorubicin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin C, actinomycin, mithramycin; antimitotics such as vincristine, vinblastine, vindesine, vinorelbine, paclitaxel, taxotere, and Polo kinase inhibitors;
3) Antimetabolites and antifolates such as fluoropyrimidine, methotrexate, cytarabine, azacytidine, decitabine, tetroxide, hydroxyurea, IDH1/IDH2 mutant inhibitors;
4) Topoisomerase inhibitors such as epipodophyllotoxin, camptothecine, irinotecan;
5) Cytostatic agents such as antiestrogens/antiandrogens, such as tamoxifen, fulvestrant, toremifene, raynaxifene, qu Nuoxi, iodoxifene, bicalutamide, flutamide, nilutamide, cyproterone acetate;
LHRH antagonists or LHRH agonists such as goserelin, leuprorelin, and buserelin, progestins such as megestrol acetate;
aromatase inhibitors such as anastrozole, letrozole, vorozole, exemestane, 5 a-reductase inhibitors such as finasteride;
6) An anti-invasive agent such as a c-Src kinase family inhibitor, a metalloprotease inhibitor, an inhibitor of urokinase plasminogen activator receptor function, or an antibody to a heparanase;
7) Cytostatic agents include inhibitors of tyrosine kinases such as inhibitors of Ras/Raf signaling, inhibitors of MEK and/or AKT kinase cell signaling, inhibitors of c-Kit, inhibitors of c-Met, PDGFR, ABL kinase, PI3 kinase, CSF-1R kinase, inhibitors of EGFR family kinase, inhibitors of FGFR family kinase, inhibitors of IGF receptor kinase, inhibitors of aurora kinase, inhibitors of cyclin dependent kinases such as CDK2 and/or CDK4, CDK6, inhibitors of nuclear transport protein CRM1, wnt/beta-catenin;
8) Inhibitors of anti-apoptotic proteins such as BCL2 inhibitors (Venetoclax) and MCL1 inhibitors;
9) PARP inhibitors such as Olaparib and Rucaparib, etc.;
10 Anti-angiogenic inhibitors such as VEGFR inhibitors;
11 Epigenetic inhibitors such as Histone Deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors;
12 Tumor immunotherapy includes any in vitro and in vivo method that increases the immunogenicity of a patient's tumor cells, such as transfection with the cytokines IL-2, IL-4 or GM-CSF; methods for reducing T cell inefficiency such as anti-PD-1/PD-L mab; methods of using transfected immune cells such as cytokine-transfected dendritic cells; methods of using cytokine-transfected tumor cell lines; methods of reducing the function of immunosuppressive cells, such as regulatory T cells, myeloid-derived suppressor cells, or dendritic cells expressing indoleamine 2, 3-deoxyenzymes; a method for preparing a cancer vaccine comprising tumor-associated antigen proteins or peptides;
13 Chimeric antigen receptor T cell immunotherapy (CAR T);
14 Tumor gene therapies such as CRISPR-Cas 9, rnai and gene transduction.
The invention relates to a method for reducing pathological symptoms and signs, which mainly refers to tumor mass reduction or growth speed reduction, pain reduction, ulcer area reduction, bleeding reduction, anemia reduction, obstruction reduction, tumor infiltration and tumor metastasis reduction.
The invention relates to a method for slowing down the growth rate of a tumor or reducing the volume of the tumor, which mainly aims at slowing down the growth rate of a solid tumor with rapid growth rate and obvious volume increase in a short period or reducing the volume of the tumor. Or decrease the abnormal cell number of the blood system tumor.
The term "enhancing the therapeutic effect of other treatments" as used herein refers mainly to enhancing the therapeutic effect of other methods of treating tumors, such as surgical treatments, chemotherapies, radiotherapy, immunotherapy, etc.
The invention mainly refers to reducing the ratio of tumor recurrence after other treatments and/or prolonging the time of tumor recurrence after other treatments, which means that the patient number ratio of tumor and corresponding symptom reappearance (tumor recurrence) after a period of time after the tumor is reduced or disappeared by adopting treatment means such as surgical treatment, chemotherapy, radiotherapy, immunotherapy and the like; or the time interval between the tumor reduction or disappearance and the reappearance of the tumor and the corresponding symptom sign (tumor recurrence) is prolonged after the treatment means such as surgical treatment, chemotherapy, radiotherapy, immunotherapy and the like are adopted.
The specific experiment proves that the compound containing glycerophospholipid structure can effectively induce the death of cell iron of tumor, thereby achieving the effect of killing tumor cells.
Drawings
FIG. 1 is a graph of cell clone formation numbers after 6 days of 0.1mM 18:2 PC (DLPC) with solvent BSA Negative Control (NC) on a mouse colon carcinoma MC38 cell line; wherein a is a photograph of clones of solvent BSA-treated MC38 cells, B is a photograph of clones of 0.1mm 18:2 PC (DLPC) -treated MC38 cells, C is a histogram of clone numbers of 0.1mm 18:2 PC (DLPC) and solvent BSA Negative Control (NC), and the values of the two histograms are statistically t-tested, wherein p-value <0.001 is represented, representing a very significant statistical difference between the two sets of data.
Fig. 2 is a graph of cell survival ratio of 18:2 PC (DLPC) versus solvent BSA Negative Control (NC) after 24 hours on a mouse colon cancer MC38 cell line, for several sets of histogram values, where p-value <0.05 represents a statistical difference between the data in this set and NC data, and p-value <0.001 represents a very significant statistical difference between the data in this set and NC data.
FIG. 3 is a photograph of cell morphology observed under an optical microscope 24 hours after 18:2 PC (DLPC) and solvent BSA Negative Control (NC) were applied to a mouse colon cancer MC38 cell line.
FIG. 4 is a chart of PI staining of cells after 24 hours of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on a mouse colon carcinoma MC38 cell line.
Fig. 5 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on a mouse melanoma B16F10 cell line, for several sets of histogram values statistically tested by t-test, where p-value <0.05 is indicated, representing statistical differences between the data in this set and NC sets.
Fig. 6 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on a human colorectal adenocarcinoma HT-29 cell line, for several sets of histogram values statistically t-tested, where p-value <0.001 is indicated, representing a very significant statistical difference between the data in this set and the NC set.
Fig. 7 is a graph of cell survival ratio after 24 hours of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on human colon carcinoma RKO cell lines, and statistical t-test was performed on the values of several sets of histograms, where p-value <0.001 is indicated, representing a very significant statistical difference between this set of data and NC set of data.
Fig. 8 is a graph of cell survival ratio after 24 hours of the application of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) to a human colon cancer SW480 cell line, for several sets of bar graph values, where p-value <0.05 represents a statistical difference between the data of the set and NC data, and p-value <0.001 represents a very significant statistical difference between the data of the set and NC data.
Fig. 9 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human osteosarcoma MG63 cell line, for several sets of bar graph values statistically t-tested, where p-value <0.05 represents a statistical difference between the data of the set and NC-set data, and p-value <0.001 represents a very significant statistical difference between the data of the set and NC-set data.
Fig. 10 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human osteosarcoma U2OS cell line, for several sets of bar graph values statistically t-tested, where p-value <0.01 represents a significant statistical difference between the data of the set and NC-set data, and p-value <0.001 represents a very significant statistical difference between the data of the set and NC-set data.
Fig. 11 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on a human prostate cancer LNCap cell line, for several sets of histogram values statistically t-tested, where p-value <0.01 represents a significant statistical difference between the data in this set and NC-set data, and p-value <0.001 represents a very significant statistical difference between the data in this set and NC-set data.
Fig. 12 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human cervical cancer Hela cell line, and statistical t-test was performed on the values of several sets of histograms, where p-value <0.001 is indicated, representing a very significant statistical difference between this set of data and NC set of data.
Fig. 13 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human chronic myeloid leukemia K562 cell line, for several sets of histogram values statistically t-tested, where p-value <0.05 represents a statistical difference between the data in this set and NC data, and p-value <0.001 represents a very significant statistical difference between the data in this set and NC data.
Fig. 14 is a graph of cell survival ratio of 18:2 PA to solvent BSA Negative Control (NC) after 24 hours on a mouse colon cancer MC38 cell line, for several sets of bar graph values statistically t-tested, where p-value <0.01 represents a significant statistical difference for the set of data compared to NC data, and p-value <0.001 represents a very significant statistical difference for the set of data compared to NC data.
Fig. 15 is a graph of cell survival ratio of 18:2 PS versus solvent BSA Negative Control (NC) after 24 hours on a mouse colon cancer MC38 cell line, for several sets of bar graph values statistically t-tested, where p-value <0.01 represents a significant statistical difference for the set of data compared to NC data, and p-value <0.001 represents a very significant statistical difference for the set of data compared to NC data.
FIG. 16 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) on primary spleen cells of normal mice with solvent BSA Negative Control (NC).
Fig. 17 shows graphs of cell survival ratios of solvent BSA Negative Control (NC), 18:2 PC (DLPC) +iron death inhibitor Ferrostatin-1 (dlpc+fer-1), 18:2 PC (DLPC) +iron death inhibitor Liproxstatin-1 (dlpc+lip-1) after 24 hours on the mouse colon cancer MC38 cell line, respectively, for several sets of bar graph values statistically t-examined, where x represents p-value <0.001, representing extremely significant statistical differences between this set of data and NC set of data.
Fig. 18 is a graph of the ratio of cell survival after 24 hours of solvent BSA Negative Control (NC), 18:2 PC (DLPC) +ferric ion chelator, desferrioxamine mesylate (DFO), on a mouse colon cancer MC38 cell line, for several sets of bar graph values statistically t-tested, where p-value <0.05 represents a statistical difference between the data in this set and NC data, and p-value <0.001 represents a very significant statistical difference between the data in this set and NC data.
FIG. 19 is a flow cytometer detection plot of BODIPY 581/591C 11 staining after 4 hours of solvent BSA Negative Control (NC), 18:2 PC (DLPC) +iron death inhibitor Liproxstatin-1 (Lip-1) on a mouse colon cancer MC38 cell line.
FIG. 20 is an electron micrograph of cell morphology of a 18:2 PC (DLPC) and solvent BSA Negative Control (NC) after 4 hours on a mouse colon carcinoma MC38 cell line.
Detailed Description
The invention is further described below by means of specific examples, which are to be understood as merely illustrative of the invention and are not to be construed as limiting the scope of the invention in any way.
Experimental materials
The structures of 18:2 PC (DLPC), 18:2 PA and 18:2 PS are shown below:
18:2 PC (DLPC) was purchased from Beijing Shikang Synthesis pharmaceutical technologies Co., ltd, 18:2 PA and 18:2 PS were purchased from Avanti corporation.
Cells used in the experiments:
example 1: effect test of 18:2 PC (DLPC), 18:2 PA and 18:2 PS on mouse and human tumor cells
(1) Cell clone formation assay
The experimental procedure was as follows:
an appropriate amount of 18:2 PC (DLPC) powder was weighed with a balance, dissolved in 0.5% BSA (BSA, known as bovine serum albumin from Biotoped Inc.) in an ultra clean bench, and prepared as a 0.1M 18:2 PC (DLPC) stock solution and stored at-20 ℃. MC38 cells in logarithmic growth phase were digested with Trypsin 0.25% (available from GE Healthcare) for 5-15 min, centrifuged at 1000rpm for 5 min to collect the cells, resuspended in medium to a single cell suspension, and added to 1/1000 volume of 0.1M 18:2 PC (DLPC) stock solution in one group to give a final concentration of 0.1mM 18:2 PC (DLPC), and added to the same volume of 0.5% BSA as a negative control group. 2000 cells were seeded into one well of a 6-well plate with 2ml of medium per well. 37 ℃,5% CO 2 Culturing in a cell culture box, and growing the cells for 6 days, wherein fresh culture medium can be replaced during the culture period to ensure that the cells obtain sufficient nutrition. After 6 days, the medium was decanted and 1ml of 3.7% formaldehyde was added to fix the cells. After pouring off the formaldehyde, the mixture was washed twice with 1 XPBS for 5 minutes each. 1 XPBS was decanted, stained with 1ml of crystal violet (available from Severe corporation) for 7 minutes, the crystal violet was blotted off and washed twice with 1 XPBS. After photographing with a normal camera, the number of clones was counted with Image J software.
Results:
FIG. 1 is a graph of the number of cell clone formations after 6 days of 0.1mM 18:2 PC (DLPC) and solvent 0.5% BSA Negative Control (NC) on a mouse colon carcinoma MC38 cell line. Cell clone formation experiments single cell viability was tested and it was seen from A, B and C of FIG. 1 that the number of cell clones formed by the 18:2 PC (DLPC) group was significantly less than that of the NC group after 6 days of single cell suspension planting in the medium.
(2) CCK-8 experiment
The experimental procedure was as follows:
taking MC38 cells in logarithmic growth phase, digesting the adherent growth cells with Trypsin 0.25% (purchased from GE Healthcare company) for 5-15 minutes, centrifuging at 1000rpm for 5 minutes to collect cells, re-suspending the cells with a cell culture medium, and adjusting the cell density to be proper. The cell suspension was seeded into 96-well plates, 2000 cells/well, and 100uL of medium was added to each well. When the cells grew to a density of 60% -70%, the medium was carefully discarded, the cells were washed one time with 1 XPBS, fresh medium containing 0.1mM, 0.2mM or 0.5mM 18:2 PC (DLPC) or 0.5% BSA (added in the same volume as the 0.5mM (DLPC) group), 100 uL/well, 37℃and 5% CO was added 2 After 24 hours incubation in the cell incubator, the medium was carefully discarded, the cells were washed once with 1 XPBS, fresh medium without the active agent was added, 100 uL/well, 10uL of a solution of Cell Counting Kit-8 (available from Dojindo Co.) in CCK8, 37℃and 5% CO per well 2 The cells were incubated in a cell incubator for 45 minutes, and absorbance at 450nm was measured using a multifunctional microplate reader FlexStation3, molecular Devices.
Results:
FIG. 2 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on a mouse colon carcinoma MC38 cell line. The CCK-8 experiment examined the ratio of surviving cells, which, as seen in the figure, was significantly less in the 18:2 PC (DLPC) group than in the NC group, decreased with increasing 18:2 PC (DLPC) concentration.
(3) Cell morphology observations
The experimental procedure was as follows:
18:2 the procedure for PC (DLPC) treatment of cells was the same as described above for the CCK-8 experiment. Fresh medium containing 0.1mM, 0.2mM or 0.5mM18:2 PC (DLPC) or 0.5% BSA, 100 uL/well, 37℃and 5% CO was added 2 After 24 hours of incubation in the cell incubator, the cell morphology was observed under an OLYMPUS optical microscope (model TH 4-200) and photographed.
Results:
FIG. 3 is a photograph of cell morphology observed under an optical microscope 24 hours after 18:2 PC (DLPC) and solvent BSA Negative Control (NC) were applied to a mouse colon cancer MC38 cell line. From this figure, NC group cell health, 18:2 PC (DLPC) group increased with 18:2 PC (DLPC) concentration, dead cells increased, 0.1mM18:2 PC (DLPC) group cell health, 0.2mM 18:2 PC (DLPC) group cell died slightly, 0.5mM18:2 PC (DLPC) group majority cell died.
(4) PI staining
The experimental procedure was as follows:
the procedure for 18:2 PC (DLPC) treatment of cells was the same as that described above for the CCK-8 experiment. Cells were cultured on 96-well cell culture dishes and when the density of cells reached 60% to 70%, the cells were treated with fresh medium containing 0.5% BSA or 0.1mM, 0.2mM or 0.5mM 18:2 PC (DLPC). After 24 hours, the medium was discarded and the cells were washed once with 1 XPBS. 100uL of fresh medium was added. PI dye (from Biolegend Corp.) was added to the medium at a concentration of 0.5mg/mL at a dilution of 1:500, 37℃and 5% CO 2 The cells are incubated for 15-30 minutes in the incubator in the absence of light, and observed under the green excitation light of an OLYMPUS optical microscope (model TH 4-200).
Results:
FIG. 4 is a chart of PI staining of cells after 24 hours of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on a mouse colon carcinoma MC38 cell line. PI staining detects the cellular rate of cell membrane damage, and PI staining positivity indicates that cell membrane is damaged, which is characteristic of dead cells. As can be seen from fig. 4, the NC group had few PI-staining positive cells, the 18:2 PC (DLPC) group had an increasing PI-staining positive cell ratio with increasing concentration of 18:2 PC (DLPC), the 0.1mm 18:2 PC (DLPC) group and the 0.2mm 18:2 PC (DLPC) group had slightly more PI-staining positive cells than the NC group, and the 0.5mm 18:2 PC (DLPC) group had a significantly increasing PI-staining positive cell ratio than the NC group.
Further, by the same experimental method as described above, except that 18:2 PC (DLPC) was replaced with compound 18:2PA or 18:2PS, and MC38 cells were replaced with other types of tumor cells, the inhibitory activity of 18:2 PC (DLPC) on other tumor cells, and the inhibitory activity of compounds 18:2PA and 18:2PS on tumor cells were examined.
The surviving cell fraction was examined by CCK-8 assay as described above, with the following results:
FIG. 5 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on the mouse colon cancer B16F10 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 6 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on the human colorectal adenocarcinoma HT-29 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 7 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human colon carcinoma RKO cell line. From this figure, the 0.5mM 18:2 PC (DLPC) group survived significantly less than the NC group.
FIG. 8 is a graph of cell survival ratio of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on human colon carcinoma SW480 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 9 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on human osteosarcoma MG63 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 10 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on human osteosarcoma U2OS cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 11 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) on a human prostate cancer LNCap cell line with solvent BSA Negative Control (NC). From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 12 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) and solvent BSA Negative Control (NC) on human cervical cancer Hela cell lines. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 13 is a graph showing the ratio of cell survival of 18:2 PC (DLPC) to solvent BSA Negative Control (NC) after 24 hours on the human chronic myelogenous leukemia K562 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2 PC (DLPC) group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2 PC (DLPC) concentration.
FIG. 14 is a graph showing the ratio of cell survival of the 18:2PA to solvent BSA Negative Control (NC) 24 hours after acting on the mouse colon carcinoma MC38 cell line. From this figure, the ratio of cells surviving in the 18:2PA group was significantly less than in the NC group, and the ratio of surviving cells decreased with increasing 18:2PA concentration.
FIG. 15 is a graph showing the ratio of cell survival after 24 hours of the application of 18:2PS to solvent BSA Negative Control (NC) to a mouse colon carcinoma MC38 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2PS group than in the NC group, and the ratio of surviving cells decreased with increasing 18:2PS concentration.
Example 2: survival of normal cells by 18:2 PC (DLPC)
The experimental procedure was as follows:
the surgical instruments which are needed to be used are sterilized under high pressure in advance, and the whole process of material drawing is paid attention to aseptic operation. C57BL/6 mice (purchased from Jackson lab) were sacrificed by cervical removal and sterilized with alcohol, the abdominal cavity of the mice was cut off with surgical scissors, the spleens were isolated, the spleens were washed 2-3 times with 1 XPBS, and other tissues around the spleens were removed. Grinding spleen of mouse with inner core of syringe on 200 mesh metal screen After the end of the milling, the mill was rinsed with RPMI-1640 medium (available from Hyclone) and the cell suspension was collected and centrifuged at 800rpm for 3 minutes to collect the cells. To the collected cells, 3 volumes of red blood cell lysate (from Solarbio corporation) was added. Placed on ice for 15 minutes during which time the red blood cells were lysed by gentle vortexing twice. The white blood cells were pelleted by centrifugation at 450 Xg for 10 minutes, the supernatant was carefully aspirated, and the cells were collected by washing them 3 times with RPMI-1640 medium and centrifugation at 800rpm for 3 minutes. Adding RPMI-1640 medium containing 10% foetal calf serum into cell sediment, and re-suspending cells to obtain cell density of 1×10 7 Individual cells/mL, placed at 37℃with 5% CO 2 Is cultured in a cell culture incubator.
The procedure for 18:2 PC (DLPC) treatment of cells and the CCK-8 experiment were the same as described in example 1.
Results:
FIG. 16 is a graph showing the ratio of cell survival after 24 hours of the action of 18:2 PC (DLPC) on primary spleen cells of normal mice with solvent BSA Negative Control (NC). From this figure, the ratio of surviving cells in the 18:2 PC (DLPC) group was the same as that in the NC group. It was shown that 18:2 PC (DLPC) had no effect on normal cell survival.
Example 3:18:2 PC (DLPC) test for pig death of tumor cells
(1) Iron death inhibitors block tumor cell death by 18:2 PC (DLPC)
There are various types of cell death, for example: iron death, pyro-death, apoptosis, and the like. Ferro-1 (Ferrosistatin-1) and Lip-1 (Liproxstatin-1) are specific inhibitors of iron death, and Ferro-1 can inhibit oxidized, iron-dependent cell death by blocking cystine transport and glutathione production. Lip-1 blocks lipid peroxidation. The foregoing experimental results indicate that 18:2PC (DLPC) caused tumor cell death, and that the addition of iron death inhibitor Fer-1 or Lip-1 while treating cells with 18:2PC (DLPC) prevented 18:2PC (DLPC) from causing tumor cell death, indicated that the type of tumor cell death caused by 18:2PC (DLPC) was iron death.
The experimental procedure was as follows:
preparation of 18:2PC (DLPC) and 0.5% BSA phases described in example 1 above were preparedAnd the same is true. MC38 cells in logarithmic growth phase were taken, digested with Trypsin 0.25% (available from GE Healthcare) for 5-15 min, centrifuged at 1000rpm for 5 min to collect cells, and the cells were resuspended in cell culture medium to adjust the cell density to appropriate. The cell suspension was seeded into 96-well plates, 2000 cells/well, and 100uL of medium was added to each well. When the cells grew to a density of 60% -70%, the medium was carefully discarded, the cells were washed once with 1 XPBS, medium containing 0.5mM 18:2PC (DLPC) or 0.5mM 18:2 PC+10uM Fer-1 or 0.5mM 18:2PC+200nM Lip-1 or 0.5% BSA (added in the same volume as the 0.5mM DLPC group), 100 uL/well, 37℃and 5% CO was added 2 After 24 hours incubation in the cell incubator, the medium was carefully discarded, the cells were washed once with 1 XPBS, fresh medium without the active agent was added, 100 uL/well, 10uL of a solution of Cell Counting Kit-8 (available from Dojindo Co.) in CCK8, 37℃and 5% CO per well 2 The cells were incubated in a cell incubator for 45 minutes, and absorbance at 450nm was measured using a multifunctional microplate reader FlexStation3, molecular Devices.
Results:
FIG. 17 is a graph showing the ratio of cell survival of solvent BSA Negative Control (NC), 18:2PC (DLPC) +iron death inhibitor Ferrostatin-1 (DLPC+Fer-1), 18:2PC (DLPC) +iron death inhibitor Liproxstatin-1 (DLPC+lip-1) after 24 hours on the mouse colon carcinoma MC38 cell line. From this figure, the ratio of surviving cells was significantly less in the 18:2PC (DLPC) group than in the solvent BSA Negative Control (NC) group, while the ratio of surviving cells in the DLPC+Fer-1 group and the DLPC+lip-1 group was the same as in the NC group. This result shows that iron death inhibitors Fer-1 and Lip-1 can prevent 18:2PC (DLPC) from causing tumor cell death, indicating that the type of tumor cell death caused by 18:2PC (DLPC) is iron death.
(2) Iron chelators reduce tumor cell death by 18:2PC (DLPC)
There are various types of cell death, of which iron death is a type of cell necrosis mediated by iron catalysis, excessive oxidation of polyunsaturated fatty acids. The iron chelator, desferrioxamine mesylate (deferoxamine mesylate, DFO), can form complexes with iron ions by chemical bonding, reducing the content of iron ions in the cell, thereby preventing or reducing the growth of iron death in the cell. While treating cells with 18:2PC (DLPC), the addition of the iron chelator DFO, if it prevents 18:2PC (DLPC) from causing tumor cell death, indicates that the type of tumor cell death caused by 18:2PC (DLPC) is iron death.
The experimental procedure was as follows:
the preparation method of 18:2 PC (DLPC) and 0.5% BSA was the same as that described in example 1. MC38 cells in logarithmic growth phase were taken, digested with Trypsin 0.25% (available from GE Healthcare) for 5-15 min, centrifuged at 1000rpm for 5 min to collect cells, and the cells were resuspended in cell culture medium to adjust the cell density to appropriate. The cell suspension was seeded into 96-well plates, 2000 cells/well, and 100uL of medium was added to each well. When the cells grew to a density of 60% to 70%, the medium was carefully discarded, the cells were washed once with 1 XPBS, and medium containing 0.2mM or 0.5mM 18:2 PC (DLPC) or 0.2mM/0.5mM 18:2 PC+50uM DFO (available from Selleck Corp.) or 0.5% BSA (added in the same volume as the 0.5mM DLPC group) was added at 100 uL/well, 37℃and 5% CO 2 After 24 hours incubation in the cell incubator, the medium was carefully discarded, the cells were washed once with 1 XPBS, fresh medium without the active agent was added, 100 uL/well, 10uL of a solution of Cell Counting Kit-8 (available from Dojindo Co.) in CCK8, 37℃and 5% CO per well 2 The cells were incubated in a cell incubator for 45 minutes, and absorbance at 450nm was measured using a multifunctional microplate reader FlexStation3, molecular Devices.
Results:
FIG. 18 is a graph showing the ratio of cell survival after 24 hours of solvent BSA Negative Control (NC), 18:2 PC (DLPC) +iron ion chelator deferoxamine mesylate (deferoxamine mesylate, DFO) on a mouse colon carcinoma MC38 cell line. From this figure, the 18:2 PC (DLPC) group survived significantly less than the solvent BSA Negative Control (NC) group, and the DLPC+DFO group survived significantly more than the 18:2 PC (DLPC) group. This result shows that the iron chelator DFO completely prevented 0.2mM 18:2 PC (DLPC) from causing tumor cell death, and partially prevented 0.5mM 18:2 PC (DLPC) from causing tumor cell death, indicating that the type of tumor cell death caused by 18:2 PC (DLPC) is iron death.
(3) 18:2 PC (DLPC) lipid peroxidation of tumor cells
One of the characteristics of cellular iron death is the occurrence of lipid peroxidation. BODIPY581/591C11 is a lipid peroxidation fluorescent probe useful for detecting Reactive Oxygen Species (ROS) in cells and in cell membranes. The oxidation of polyunsaturated butadiene groups of the dye leads to a shift in the fluorescence emission peak from 590nm to 510nm, and a shift in the fluorescence peak to the right is visible when detected by flow cytometry. After treatment of the cells with 18:2 PC (DLPC), the cells were stained with BODIPY581/591C11 and then examined by flow cytometry, if the fluorescence peak shifted to the right, indicating that 18:2 PC (DLPC) lipid peroxidation of the cells occurred, suggesting that the type of tumor cell death caused by 18:2 PC (DLPC) is iron death.
The experimental procedure was as follows:
the preparation method of 18:2 PC (DLPC) and 0.5% BSA was the same as that described in example 1. MC38 cells in logarithmic growth phase were taken, digested with Trypsin 0.25% (available from GE Healthcare) for 5-15 min, centrifuged at 1000rpm for 5 min to collect cells, and the cells were resuspended in cell culture medium to adjust the cell density to appropriate. The cell suspension was seeded into 96-well plates, 2000 cells/well, and 100uL of medium was added to each well. When the cells grew to a density of 60% to 70%, the medium was carefully discarded, the cells were washed once with 1 XPBS, medium containing 0.5mM 18:2 PC (DLPC) or 0.5mM 18:2 PC+1uM Lip-1 or 0.5% BSA (added in the same volume as 0.5mM DLPC), 100 uL/well, 37℃and 5% CO was added 2 After 4 hours of incubation in the cell incubator, the medium was carefully discarded, the cells were washed once with 1 XPBS, fresh medium without the active agent was added, 100 uL/well, 10uL of a solution of Cell Counting Kit-8 (available from Dojindo Co.) in CCK8, 37℃and 5% CO per well 2 The cells were incubated in a cell incubator for 45 minutes, and absorbance at 450nm was measured using a multifunctional microplate reader FlexStation3, molecular Devices. After staining with BODIPY581/591C11 (from Invitrogen) for 30 minutes, flow cytometry was performed with an Accuri C6 flow sorter (from BD).
Results:
FIG. 19 is a lipid peroxidation flow cytometer detection graph after solvent BSA Negative Control (NC), 18:2PC (DLPC) +iron death inhibitor Liproxstatin-1 (Lip-1) was applied to the mouse colon cancer MC38 cell line for 4 hours. From this figure, the fluorescence peak was significantly shifted to the right in the 18:2PC (DLPC) group compared to NC group cells, indicating that significant lipid peroxidation occurred, and the fluorescence peak was significantly shifted to the left in the DLPC+lip-1 group and the 18:2PC (DLPC) group, indicating that the degree of lipid peroxidation in the cells was significantly reduced compared to the 18:2PC (DLPC) group. It was demonstrated that 18:2PC (DLPC) caused lipid peroxidation in cells, while iron death inhibitor Fer-1 could partially prevent 18:2PC (DLPC) from causing lipid peroxidation in cells, which demonstrated that the type of tumor cell death caused by 18:2PC (DLPC) was iron death.
(4) 18:2PC (DLPC) causes damage to the mitochondrial membrane of tumor cells
Another common feature of iron death in cells is the damage of the mitochondrial membrane in cells, which can be seen under electron microscopy as a decrease in mitochondrial size, a blurry or missing mitochondrial ridge, and a darkened mitochondrial color. The cells treated with 18:2PC (DLPC) were observed by electron microscopy for changes in mitochondrial morphology common to iron-dead cells.
The experimental procedure was as follows:
The MC38 cells of the colon cancer of the mice are cultivated on a 6-well plate, when the cell density reaches 60 to 70 percent, fresh culture medium containing 0.5 percent BSA or 0.5mM 18:2 PC (DLPC) is replaced, the temperature is 37 ℃ and the CO is 5 percent 2 After 12 hours of incubation in the cell incubator, the original medium was discarded, and a mixed solution (1:1 mixture) of a fixing solution (2.5% glutaraldehyde (available from Sigma Co.) preheated at 37 ℃) and the cell medium was added and fixed at room temperature for 10 minutes. The mixed solution of the fixing solution and the culture medium is discarded. Fixing solution is added and the mixture is fixed at room temperature for 1 hour. After staining with uranyl acetate for 25 minutes and staining with lead nitrate for 5 minutes, photographs were observed with an H7650B electron transmission microscope (purchased from hitachi).
Results:
FIG. 20 is an electron micrograph of cell morphology of a 18:2 PC (DLPC) and solvent BSA Negative Control (NC) after 4 hours on a mouse colon carcinoma MC38 cell line. From this figure, the 18:2 PC (DLPC) group showed significantly smaller mitochondria, blurred or absent mitochondrial cristae, and significantly darker mitochondrial color compared to NC group cells, suggesting that the mitochondrial membrane was damaged. These morphological changes of mitochondria are consistent with mitochondrial morphological changes common to iron-dead cells, suggesting that the type of tumor cell death caused by 18:2 PC (DLPC) is iron death.
Reference to the literature
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[2] Activation of the VEGFC/VEGFR3 Pathway Induces Tumor Immune Escape in Colorectal Cancer Tacconi, federica Ungaro, carmen Correale, et al Cancer Res.2019;79 (16):4196-4210.
[3] Ferrotopsis a regulated cell death nexus linking metabolism, redox biology, and disease. Brent R.Stockwell, jose Pedro Friedmann Angeli, huly a Bayir, et al cell.2017;171 (2):273-285.
[4] MDM2 and MDMX promote ferroptosis by PPARalpha-mediated lipid remodelling. Venkatesh D, O' Brien NA, zandkarimi F, et al Genes Dev.2020;34 (7-8):526-543.
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Claims (4)
1. Use of a compound as the sole active ingredient in the manufacture of a medicament for the treatment of osteosarcoma, said compound being:
2. use of a pharmaceutical composition comprising a therapeutically effective amount of a compound as the sole active ingredient and a pharmaceutically acceptable carrier or excipient for the manufacture of a medicament for the treatment of osteosarcoma, said compound being:
3. Use of a compound selected from one of the following compounds as the sole active ingredient in the manufacture of a medicament for the treatment of colon cancer:
4. use of a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from one of the following compounds as the sole active ingredient and a pharmaceutically acceptable carrier or excipient in the manufacture of a medicament for the treatment of colon cancer:
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