CN116585293A - Use of phenolic compound-induced iron death in cell growth and tumor treatment - Google Patents
Use of phenolic compound-induced iron death in cell growth and tumor treatment Download PDFInfo
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- CN116585293A CN116585293A CN202310553561.3A CN202310553561A CN116585293A CN 116585293 A CN116585293 A CN 116585293A CN 202310553561 A CN202310553561 A CN 202310553561A CN 116585293 A CN116585293 A CN 116585293A
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- iron
- phenolic compound
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
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- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
- A01N31/08—Oxygen or sulfur directly attached to an aromatic ring system
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- A—HUMAN NECESSITIES
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- A01N31/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic oxygen or sulfur compounds
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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Abstract
The invention belongs to the technical field of microorganism and tumor treatment, and particularly relates to application of iron death induced by phenolic compounds in cell growth and tumor treatment. According to the invention, the iron death induced by the phenolic compound can inhibit the growth of bacteria, fungi and mammalian cells, and can inhibit the growth rate of tumor cells, reduce the final weight of the tumor cells and have remarkable anti-tumor effect by improving the iron death efficiency of cells. In addition, according to the known pharmacokinetics and safety, the repositioning effect of the phenolic compound can save the cost and time of drug development, and maximally utilize the existing resources, thus having good practical application value.
Description
Technical Field
The invention belongs to the technical field of microorganism and tumor treatment, and particularly relates to application of iron death induced by phenolic compounds in cell growth and tumor treatment.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Tumors are novel organisms formed by the fact that under the action of various cancerogenic factors, a certain cell of local tissues loses the normal regulation of the growth of the cells at the gene level, so that the cells are clonally abnormally proliferated. Along with the development of industry, the probability of human suffering from tumors is higher and higher in recent years due to pollution of living environment and change of diet life, especially the incidence of lung cancer is greatly increased, and the incidence of lung cancer can be improved by smoking or smoking second-hand smoke or working on cancerogenic substances for a long time. Lung cancer is now the first leading cause of cancer death worldwide.
Iron death is a novel mode of apoptosis, differing from other forms of cell death such as apoptosis, necrosis and autophagy, and is mainly characterized by ferrous ion accumulation and aggregation of peroxidized lipids on membranes. Currently, targeted therapeutic and immunotherapeutic drugs are currently two major drugs for lung cancer. The iron death inducer shows good treatment effect in cancer species such as liver cancer, intestinal cancer, kidney cancer and the like, but has poor treatment effect in lung cancer.
Disclosure of Invention
In view of the above-mentioned shortcomings of the prior art, the present invention provides the use of phenolic compound-induced iron death in cell growth and tumor therapy. According to the invention, research shows that the phenolic compound enhances the iron death effect by amplifying redox imbalance in cells, achieves the purpose of treating cancer, and has high efficiency. In addition, phenolic compounds can also cause bacterial iron death, fungal iron death, and mammalian cell iron death. Based on the above results, the present invention has been completed.
In order to achieve the technical purpose, the invention adopts the following technical scheme:
in a first aspect of the invention there is provided the use of phenolic compound induced iron death in any one or more of:
(a) Inhibit cell growth and/or promote cell death;
(b) Preparing a product that inhibits cell growth and/or promotes cell death;
depending on the object of action and purpose of application, the product may be any one or more of a medicine, an experimental reagent, a degerming (bactericide), a weed-killing (insecticide), a disinfectant, etc. The experimental reagent is used for basic research, so that a material basis is provided for related mechanism research of iron death induced by phenolic compounds.
In a second aspect of the invention there is provided a method of inhibiting cell growth and/or promoting cell death, the method comprising applying a phenolic compound to an environment in which the cells are present.
Wherein the cells may contain iron ions in the environment in which they are present, thereby further promoting inhibition of cell growth and/or promoting cell death.
The phenolic compound may be phenol or phloroglucinol.
In a third aspect of the invention there is provided the use of phenolic compound-induced iron death in the manufacture of a medicament for the treatment of a tumour.
Specifically, the phenolic compound may be phloroglucinol or an iron-phloroglucinol (Fe-PG) complex.
In a fourth aspect of the invention, there is provided a method of treatment of a disease, the method comprising administering to a subject a therapeutically effective dose of a phenolic compound or drug as described above.
The disease is preferably cancer, particularly preferably lung cancer.
The beneficial technical effects of one or more of the technical schemes are as follows:
the iron death induced by the phenolic compound provided by the technical scheme can inhibit the growth of bacteria, fungi and mammalian cells, can inhibit the growth rate of tumor cells by improving the iron death efficiency of cells, reduces the final weight of the tumor cells, and has remarkable anti-tumor effect. In addition, according to the known pharmacokinetics and safety, the repositioning effect of the phenolic compound can save the cost and time of drug development, and maximally utilize the existing resources, thus having good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 shows the toxic effect of phenolic compounds on E.coli with and without iron.
FIG. 2 shows the toxic effects of phenolic compounds on Klebsiella pneumoniae and Salmonella typhimurium in both iron and iron-free conditions.
FIG. 3 shows the toxic effect of phenolic compounds on Saccharomyces cerevisiae with and without iron.
Figure 4 is a graph showing the change in MDA levels of bacteria in the occurrence of phenolic-induced iron death.
Figure 5 is a graph showing the change in GSH levels in bacteria in the occurrence of phenolic-induced iron death.
Figure 6 is the effect of GSH on phenolic-induced bacterial iron death.
FIG. 7 is the effect of Fer-1 on phenolic-induced bacterial iron death.
FIG. 8 is a graph showing the effect of over-expression of btuE on phenolic-induced iron death on bacterial growth
FIG. 9 shows cytotoxicity of iron ions and PG on HeLa cells.
FIG. 10 shows the growth of H1299 tumors in mice treated with water, PG and Fe-PG complexes.
FIG. 11 is the weight of H1299 tumors on day 11 of water, PG and Fe-PG complex treated mice.
FIG. 12 is an iron ion staining image of H1299 tumors from mice treated with water, PG and Fe-PG complexes.
Figure 13 is a GPX4 and 4-HNE immunochemical image of water, PG and Fe-PG complex treated mice H1299 tumors.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. It is to be understood that the scope of the invention is not limited to the specific embodiments described below; it is also to be understood that the terminology used in the examples of the invention is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention.
Definitions and abbreviations
Coli (Escherichia coli): e.coli
Klebsiella pneumoniae (Klebsiella pneumoniae): kle
Salmonella typhimurium (Salmonella Typhimurium): sal (Sal)
Saccharomyces cerevisiae (Saccharomyces cerevisiae): s.cerevisiae ae
Phloroglucinol (Phloroglucinol): PG
Malondialdehyde (Malondialdehyde): MDA (MDA)
Reduced Glutathione (glutathone): GSH (GSH)
Iron death inhibitor Ferrostatin-1: fer-1
Thioredoxin/glutathione peroxidase encoding genes: btuE (BtuE)
Glutathione peroxidase 4 (Glutathione peroxidase): GPX4
4-hydroxynonenoic acid (4-hydroxynonenal): 4-HNE
Du's modified Eagle Medium (Dulbecco's Modified Eagle Medium): DMEM (DMEM)
By "pharmaceutically acceptable" is meant a material that, in view of the disease or condition to be treated and the corresponding route of administration, does not have properties that cause a reasonably cautious physician to avoid administration of the material to a patient, is theoretically non-toxic, irritating and allergic, and is capable of achieving or providing clinically acceptable pharmacokinetic, absorption, distribution and metabolic properties of the drug molecule, for its intended purpose.
"treating" refers to eradicating, removing, reversing, alleviating, altering or controlling the disease after its onset.
Thus, "treatment" as a whole refers to at least achieving inhibition or amelioration of symptoms associated with a painful condition in a subject, where inhibition or amelioration is broad, and refers to at least a decrease in the magnitude of a parameter, such as a symptom associated with a condition being treated, such that the method of the invention also includes cases where the condition is completely inhibited, such as prevention or cessation, such that the subject no longer experiences the condition.
In one exemplary embodiment of the invention, there is provided the use of phenolic compound-induced iron death in any one or more of:
(a) Inhibit cell growth and/or promote cell death;
(b) Products are prepared that inhibit cell growth and/or promote cell death.
Wherein the phenolic compound can be any one or more of monohydric phenol, dihydric phenol or ternary phenol, and in one specific embodiment of the invention, the phenolic compound is phenol or phloroglucinol.
The cell may be a cell of a prokaryote, eukaryote, or archaea.
Further, the cell may be any one or more of a bacterium, actinomycete, rickettsia, chlamydia, mycoplasma, cyanobacteria, archaebacteria, fungus, plant or animal cell,
specifically, the cells are any one or more of escherichia coli, klebsiella pneumoniae, salmonella typhimurium, saccharomyces cerevisiae and HeLa cells.
Depending on the object of action and purpose of application, the product may be any one or more of a medicine, an experimental reagent, a degerming (bactericide), a weed-killing (insecticide), a disinfectant, etc. Wherein, the experimental reagent is used for basic research, thereby providing a material basis for the related mechanism research of iron death induced by the phenolic compound, and therefore, the phenolic compound can be obviously used as (cell) iron death promoter.
In yet another embodiment of the invention, a method of inhibiting cell growth and/or promoting cell death is provided, the method comprising applying a phenolic compound to an environment in which the cell is present.
Wherein the cells may contain iron ions in the environment in which they are present, thereby further promoting inhibition of cell growth and/or promoting cell death.
The phenolic compound may be phenol or phloroglucinol.
In particular, it has been found through research that phenolic compounds are able to trigger cellular iron death pathways in bacteria, cause peroxidation of cell membrane lipids of bacteria and cause reduced expression of bacterial antioxidant systems.
In yet another embodiment of the invention, there is provided the use of phenolic compound-induced iron death in the manufacture of a medicament for the treatment of a tumor.
Specifically, the phenolic compound may be phloroglucinol or an iron-phloroglucinol (Fe-PG) complex.
Wherein, the specific preparation method of the iron-phloroglucinol complex is as follows: mixing ferric chloride and phloroglucinol, and standing. Wherein the ferric chloride can be FeCl 3 ·6H 2 The concentration ratio of O, ferric chloride and phloroglucinol is 5-15:11.04, preferably 10:11.04.
It is noted that tumors are used in the present invention as known to those skilled in the art, including benign tumors and/or malignant tumors. Benign tumors are defined as hyperproliferative cells that are unable to form aggressive, metastatic tumors in vivo. Conversely, a malignancy is defined as a cell with multiple cellular abnormalities and biochemical abnormalities that are capable of developing a systemic disease (e.g., tumor metastasis in a distant organ).
In yet another embodiment of the invention, the medicament of the invention is useful for the treatment of malignant tumors. Examples of malignant tumors that can be treated with the medicament of the invention include solid tumors and hematological tumors. Preferably a solid tumor, thereby more advantageously enabling intratumoral and/or peritumoral injection of the drug. The solid tumors may be tumors of bone, brain, bladder, breast, central and peripheral nervous system, colon, endocrine glands (including thyroid and adrenal cortex), esophagus, endometrium, germ cells, head, neck, liver, lung, larynx and hypopharynx, mesothelioma, ovary, pancreas, prostate, rectum, kidney, small intestine, soft tissue, skin, ureter, testis, stomach, vagina, and vulva. Preferably, the tumor is lung cancer.
According to the invention, the medicament may also comprise at least one other active ingredient for the same or a different treatment of the disease and/or at least one other pharmaceutically inactive ingredient.
The pharmaceutically inactive ingredients may be pharmaceutically acceptable carriers or excipients. The pharmaceutically acceptable carrier or auxiliary material is selected from at least one of solvent, disintegrating agent, diluent, surfactant, precipitation inhibitor, glidant, adhesive, dispersing agent, lubricant, suspending agent, thickening agent, isotonic agent, emulsifying agent, preservative, stabilizing agent, hydrating agent, emulsifying accelerator, buffering agent, coloring agent, absorbing agent, flavoring agent, sweetening agent, ion exchanger, release agent, coating agent, flavoring agent or antioxidant.
Moreover, the medicament may be formulated into a tablet (e.g., sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet, buccal tablet, etc.), pill, powder, granule, capsule (including soft capsule, microcapsule), lozenge, syrup, liquid, emulsion, suspension, controlled release preparation (e.g., instantaneous release preparation, sustained release microcapsule), aerosol, film (e.g., orally disintegrating film, oral mucosa-adhesive film), injection (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), intravenous drip, transdermal absorption preparation, ointment, lotion, adhesive preparation, suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop, etc., particularly in the form of a formulation of injection, according to a method usual in the art.
Furthermore, the medicament of the present invention may be administered to the body in a known manner. For example, by intravenous systemic delivery or local injection (e.g., intratumoral or intratumoral injection) into the tissue of interest. Such administration may be via single or multiple doses.
In yet another embodiment of the present invention, a method of treating a disease is provided, the method comprising administering to a subject a therapeutically effective dose of a phenolic compound or drug as described above.
The subject refers to an animal, preferably a mammal, e.g., a mouse, rabbit, cat, dog, monkey, cow, horse, sheep, pig, etc., most preferably a human, who has been the subject of treatment, observation or experiment. By "therapeutically effective amount" is meant that amount of active compound or pharmaceutical agent, including a compound of the present invention, which causes a biological or medical response in a tissue system, animal or human that is sought by a researcher, veterinarian, medical doctor or other medical personnel, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition or disorder being treated. It must be recognized that the optimal dosage and spacing of the active ingredients of the present invention is determined by its nature and external conditions such as the form, route and site of administration and the particular mammal being treated, and that such optimal dosage may be determined by conventional techniques. It must also be appreciated that the optimal course of treatment, i.e., daily dosage over the nominal time period, can be determined by methods well known in the art.
The disease is preferably cancer, particularly preferably lung cancer, in particular lung cancer treatment comprises amelioration of one or more of the following pathological conditions: cough, hemoptysis, chest pain, chest distress, short breath, hoarseness, fever, emaciation, cachexia, pulmonary osteoarthropathy caused by diseases, etc.
For a better description of the objects, technical solutions and advantages of the present invention, the present invention will be further described with reference to the following specific examples. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified. The kit for plasmid extraction, PCR product recovery and gel recovery is purchased from OMEGA company in the United states, and the operation steps are carried out according to the product specification; malondialdehyde (MDA) content detection kit was purchased from Beijing Soy Bao Corp, china; GSH and GSSG detection kits were purchased from Biyun Tian corporation;Non-Radioactive Cytotoxicity Assay kit was purchased from Promega corporation.
1) Seed liquid culture medium
LB medium: 5g/L yeast powder, 10g/L NaCl and 10g/L peptone.
2) Fermentation medium with iron
K 2 HPO 4 ·3H 2 O 9.8g/L，Citric acid·H 2 O2.1 g/L, ferric ammonium citrate 0.3g/L, (NH) 4 ) 2 SO 4 3.0g/L, glucose 20g/L, mgSO 4 ·7H 2 O0.4 g/L,1000 x trace element ((NH) 4 ) 6 Mo 7 O 24 ·4H 2 O 3.7g/L；ZnSO 4 ·7H 2 O 2.9g/L；H 3 BO 3 24.7g/L；CuSO 4 ·5H 2 O 2.5g/L；MnCl 2 ·4H 2 O 15.8g/L)。
3) Iron-free fermentation medium
K 2 HPO 4 ·3H 2 O 9.8g/L，Citric acid·H 2 O 2.1g/L，(NH 4 ) 2 SO 4 3.0g/L, glucose 20g/L, mgSO 4 ·7H 2 O0.4 g/L,1000 x trace element ((NH) 4 ) 6 Mo 7 O 24 ·4H 2 O 3.7g/L；ZnSO 4 ·7H 2 O 2.9g/L；H 3 BO 3 24.7g/L；CuSO 4 ·5H 2 O 2.5g/L；MnCl 2 ·4H 2 O 15.8g/L)。
Note that: k (K) 2 HPO 4 ·3H 2 O 9.8g/L，Citric acid·H 2 O2.1 g/L, (ferric ammonium citrate 0.3 g/L), (NH) 4 ) 2 SO 4 3.0g/L, adjusting to pH 7.0, sterilizing with high pressure steam at 121deg.C for 20 min. Glucose stock solution 500g/L,115 deg.C, 20min, independently sterilized, mgSO 4 ·7H 2 The O stock solution is 200g/L,121 ℃ and 20min, the 1000 times trace elements are filtered and sterilized by a 0.22 mu m strain film, and the glucose and MgSO which are independently sterilized are respectively added when the seed solution is transferred 4 ·7H 2 O, 1000 times trace element stock solution and antibiotics.
Example 1: use of phenolic compound-induced iron death in bacterial growth
First, the effect of iron death induced by phenolic compounds on the growth of E.coli, a prokaryote, was examined.
Experimental methods. The wild E.coli BL21 (DE 3) strain was inoculated into 4mL LB at 37℃and cultured overnight at 180rpm, followed by 20% inoculation into iron-and iron-free fermentation media at 37℃and cultured at 180rpm to OD 600 And (2) diluting the bacterial liquid step by 10 times according to the required concentration, respectively adding 1.3g/L PG or 2.5g/L phenol for continuous culture for 4 hours, diluting the bacterial liquid step by 10 times according to the required concentration, standing and culturing in a 37 ℃ incubator, counting viable bacteria after bacterial colonies grow out, and calculating the survival rate.
Experimental results. As can be seen from FIG. 1, E.coli BL21 (DE 3) strain grew normally in medium containing only 1.3g/L PG or only 2.5g/L phenol, but when the medium contained iron ions, the strain growth was severely inhibited, especially when iron ions and PG were present at the same time, the survival rate of E.coli BL21 (DE 3) was reduced by 3-4 orders of magnitude.
The effect of phenolic-induced iron death on klebsiella pneumoniae and salmonella typhimurium was subsequently examined.
Experimental methods. Klebsiella pneumoniae ATCC25955 and Salmonella typhimurium LT2 are inoculated into 4mL LB, cultured at 37 ℃ and 180rpm for overnight, then inoculated into an iron fermentation medium and a non-iron fermentation medium according to 20%, cultured at 37 ℃ and 180rpm for 6.5 hours, the bacterial liquid is taken to be diluted step by step according to the required concentration, 8g/L PG or 2.5g/L phenol is respectively added for continuous culture for 4 hours, the bacterial liquid is taken to be diluted step by step according to the required concentration by adopting 10 times, the bacterial liquid is subjected to stationary culture in a culture box at 37 ℃, and the viable count is calculated after bacterial colonies grow out, thus the survival rate is calculated.
Experimental results. As can be seen from fig. 2, the addition of iron ions significantly reduced the survival rate of klebsiella pneumoniae and salmonella typhimurium under PG and phenol conditions.
Example 2: use of phenolic compound-induced iron death in fungal growth
The effect of phenolic compound-induced iron death on the growth of the eukaryotic model organism Saccharomyces cerevisiae was examined.
Experimental methods. Saccharomyces cerevisiae s288c was inoculated into 4mL LB at 30℃and cultured overnight at 250rpm, followed by 20% inoculation into iron-and iron-free fermentation media at 30℃and 250rpm to OD 600 And (4) diluting the bacterial liquid step by 10 times according to the required concentration, respectively adding 8g/L PG or 4.2g/L phenol for continuous culture for 4 hours, diluting the bacterial liquid step by 10 times according to the required concentration, standing and culturing in a 30 ℃ incubator, counting the viable count after bacterial colonies grow out, and calculating the survival rate.
Experimental results. As can be seen from FIG. 3, the S.cerevisiae strain grew normally in a medium containing only 8g/L PG or only 4.2g/L phenol, but when the medium contained iron ions, the strain growth was severely inhibited.
Example 3: bacterial Malondialdehyde (MDA) level changes in iron death induced by phenolic compounds
Iron death is an iron-dependent oxidative cell death, and is distinguished from traditional apoptosis, necrosis and autophagy, and is characterized in that lipid peroxidation of cell membranes is catalyzed by iron or lipid oxidase, and the oxidation end product is malondialdehyde, which can cause cross-linking polymerization of living macromolecules such as protein, nucleic acid and the like, and has cytotoxicity. We examined the presence or absence of lipid peroxidation of cells by PG in the presence of iron.
Experimental methods. The wild E.coli BL21 (DE 3) strain was inoculated into 4mL LB, incubated at 37℃at 180rpm overnight, then 20% in iron fermentation medium, incubated at 37℃at 180rpm to OD 600 =2.5, with or without 1.3g/L PG, for 4h, 1 x 10 9 The cell detects the MDA content by using a Malondialdehyde (MDA) content detection kit (Soy pal, beijing, china),
experimental results. As can be seen from FIG. 4, the presence of PG in the iron-containing medium increased MDA levels in E.coli cells by more than 70-fold. The above results indicate that phenolic compounds are able to trigger cellular iron death pathways in bacteria, causing peroxidation of cell membrane lipids of bacteria.
Example 4: changes in intracellular reduced Glutathione (GSH) levels in bacteria in the occurrence of phenolic-induced iron death
Iron death in eukaryotic cells also appears as a decrease in the amount of glutathione GSH expressed, and we therefore further examined whether PG was present in the presence of iron on the GSH content in the cells.
Experimental methods. First, 20% of wild E.coli BL21 (DE 3) strain is inoculated in a fermentation medium with iron, and cultured at 37 ℃ and 180rpm until OD 600 =2.5, with or without 1.3g/L PG, treatment for 4h, followed by centrifugation of 1mL of bacterial liquid to obtain a pellet, and detection of absorbance of the sample at a412 according to the procedure of "GSH and GSSG detection kit" (bi yun, cat#s005), and calculation of GSH content according to the specification.
Experimental results. As can be seen from fig. 5, the co-presence of iron ions and PG leads to a dramatic decrease in reduced Glutathione (GSH) in the e.coli cells. The above results indicate that phenolic compounds are able to trigger cellular iron death pathways in bacteria, leading to reduced expression of bacterial antioxidant systems.
Example 5: influence of reduced Glutathione (GSH) on phenolic-induced bacterial iron death
GSH, an important antioxidant in the body, can scavenge free radicals in the body and iron death can deplete GSH. It was therefore sought to confirm whether supplementation with GSH would alleviate the phenomena of cell death caused by iron ions and PG.
Experimental methods. Firstly inoculating wild E.coli BL21 (DE 3) strain into iron fermentation medium at 20%, culturing at 37deg.C and 180rpm for 6 hr, adding 200 μm GSH or not, and continuously culturing to OD 600 And (2) diluting the bacterial liquid step by 10 times according to the required concentration, respectively adding 1.3g/L PG, treating for 4 hours, diluting the bacterial liquid by 10 times according to the required concentration, standing and culturing in a 37 ℃ incubator, counting the viable count after bacterial colonies grow out, and calculating the survival rate.
Experimental results. As can be seen from fig. 6, GSH restores the viability of the e.coli cells in the PG toxicity assay.
Example 6: effect of iron death inhibitors on phenolic-induced bacterial iron death
Ferrosistatin-1 (Fer-1) is a selective iron death inhibitor that inhibits oxidative, iron-dependent cancer cell death by blocking cystine transport and glutathione production. We therefore examined whether Fer-1 could inhibit bacterial iron death.
Experimental methods. Firstly, inoculating wild E.coli BL21 (DE 3) strain into iron fermentation medium according to 20% inoculum size, culturing at 37 deg.C and 180rpm for 6 hr, adding or not adding 5 μm Fer-1, continuously culturing until OD 600 =2.5, add 1.3g/L PG, treat 4h. And (3) taking bacterial liquid before and after PG addition, adopting 10-time progressive dilution spot plates according to the required concentration, standing and culturing in a 37 ℃ incubator, counting viable bacteria after bacterial colonies grow out, and calculating the survival rate.
Experimental results. As can be seen from FIG. 7, iron death inhibitor Fer-1 can inhibit iron death of Escherichia coli caused by PG.
Example 7: effect of BtuE on phenolic Compound-induced iron death on bacterial growth
Glutathione peroxidase 4 (GPX 4) is reported to be the main defense system for iron death in animals, detoxify lipid hydroperoxides and inhibit iron death, and the homologous protein BtuE of GPX4 is present in e.coli, encoded by BtuE. Glutathione peroxidase can catalyze reduced glutathione to oxidized glutathione, so that toxic peroxide is reduced to a nontoxic hydroxyl compound, and meanwhile, the decomposition of hydrogen peroxide is promoted, so that the structure and the function of a cell membrane are protected from being interfered and damaged by the peroxide. Therefore, we examined whether BtuE overexpression could alleviate phenolic-induced bacterial iron death.
Experimental methods.
1) Construction of the overexpression plasmid pTrc-btuE. The E.coli BL21 (DE 3) genome was used as a template, and guo-btueF (5'
gatccgagctcgagatctatgcaagattccattctgacg 3 ') and guo-btuER (5'
aattcccatatggtaccattattttgccaacgccag 3') as primers, the gene fragment was amplified and purified using Prime STAR. Using pTrcHis2B plasmid as a template, pTrc-F (5'tggtaccatatgggaattcgaag 3') and pTrc-R (5'agatctcgagctcggatccatg 3') were used, and the vector backbone was obtained by amplification and purification with Prime STAR. According to the in vitro multi-fragment recombination kit, the 2 fragments are recombined, and the reaction product is transformed into E.coli DH5 alpha and is subjected to plate culture by applying ampicillin. Colony PCR was performed using colonies as templates and pTrcyanF (5'tcgaccggaattatcgattaac 3') and pTrcyanR (5'tcaatgatgatgatgatgatggtc 3') as primers, rapid Taq Mix was used to verify that positive colonies were sequenced using the primers pTrcyanF and pTrcyanR and correct preservation was confirmed, thus obtaining pTrc-btuE plasmid for btuE gene overexpression.
2) Construction of control strain pvactor and overexpressing strain pbtuE. The plasmid pTrcHis2B, pTrc-btuE was transferred into E.coli BL21 (DE 3) strain by chemical transformation and spread on ampicillin plates for cultivation at 37℃respectively,
the positive clones were PCR-screened to obtain a negative control strain, pvactor, and a strain, pbtuE, over-expressing btuE.
3) Verification of the tolerance of bacteria to PG. We inoculated the pVector strain, the pbtuE strain in 4mL LB, cultured overnight at 37℃and then inoculated at 20% respectively in 100mL of iron-containing fermentation medium, cultured at 37℃at 180rpm to OD 600 =0.6, 0.5mM IPTG was added and incubated at 37℃to OD 600 =2.5, add 1.3g/L PG, process for 4h.
Taking bacterial liquid before and after PG addition, adopting 10-time progressive dilution spot plates according to the required concentration, standing and culturing in a 37 ℃ incubator,
and counting the number of viable bacteria after the bacterial colonies grow out, and calculating the survival rate.
Experimental results. As can be seen from fig. 8, overexpression of btuE significantly improved the tolerance of escherichia coli to PG and iron ions.
Example 8: use of phenolic compound-induced iron death in mammalian cell growth
Experimental methods. HeLa cells were cultured in DMEM supplemented with 10% fetal bovine serum using 12-well plates, and three plates were sub-packed together, 5% CO 2 Culturing at 37 ℃ for 16h. Discarding the old medium, replacing with new DMEM without fetal calf serum and adding 0.2g/L FeCl respectively 3 ·6H 2 O and 0.5g/L PG, 0.2g/L FeCl 3 ·6H 2 O, 0.5g/L PG, and nothing. The treatment is carried out at 37℃for 4h.250g is centrifuged for 5min, 50 mu L of supernatant is transferred to a 96-well plate in each well, a pure culture medium is added as a background control, and 50 mu L of reaction substrate is addedNon-Radioactive Cytotoxicity Assay kit, promega), mixing well, incubating at room temperature in the absence of light for 30min, adding 50 μl of stop reaction solution (& gt)>Non-Radioactive Cytotoxicity Assay kit, promega), mix well, absorbance at 490 nm. Cytotoxicity was calculated for different conditions.
Experimental results. As can be seen from fig. 9, the combination of PG and iron ions had significant cytotoxicity to HeLa cells, whereas the supplementation of either PG or iron alone did not kill HeLa cells. Phenolic compounds are shown to trigger iron death in mammalian cells.
Example 9: preparation method of Fe-PG complex for enhancing iron death effect
10g/L FeCl was added to the beaker 3 ·6H 2 O and 11.04g/L PG were mixed and left to stand overnight to give an aqueous complex solution, which was then poured into a bottle for sealed storage.
Example 10: phenolic compound-induced iron death can inhibit tumor growth
Researchers believe that iron death is a novel cancer treatment strategy with great application prospects, since it is still functional in tumor cells, and can escape other forms of cell death. We examined whether phenolic-induced iron death could inhibit tumor growth in vivo.
Experimental methods. H1299 cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum. 5-week-old male BALB/C nude mice were subcutaneously injected 5X 10 6 Mice were tumor-developed by 5 days of culture of H1299 cells. The tumor size is 73-172 mm 3 21 mice of (2) were randomly divided into 3 groups. Then, 0.4. Mu. Mol PG and Fe-PG complex were continuously injected in situ for 11 days, respectively, with ultrapure water as a control. Vernier calipers measure the maximum and minimum diameters of tumors. Tumor volume = minimum diameter 2 X maximum diameter/2. The nude mice are sacrificed by cervical dislocation, and the tumor tissues of the nude mice are peeled off and weighed.
Experimental results. As can be seen from fig. 10 and 11, PG itself has a certain inhibition effect on tumor growth, but the difference between the control group and the PG treated group is not statistically significant, however, compared with the Fe-PG complex treated mice, the growth rate and weight of tumor are both the lowest, indicating that the Fe-PG complex significantly reduced H1299 tumor growth.
Example 11: phenolic-induced iron death results in an increase in iron ion content in tumor cells
Experimental methods. Mice treated in example 10 were sacrificed by cervical dislocation and nude mouse tumor tissue was dissected. Fresh tumor tissue was fixed with 4% paraformaldehyde, washed with PBS and stored at 4 ℃. The tissue was dehydrated and embedded in paraffin and sectioned at a thickness of 4 μm. Cell morphology was then observed by Prussian blue and nuclear solid red staining.
Experimental results. As can be seen from fig. 12, iron ions accumulated in the Fe-PG complex treated tumors, whereas no iron ions accumulated in the two groups of tumors treated with water and PG, respectively.
Example 12: iron death induced by phenolic compounds increases GPX4 expression and 4-HNE accumulation in tumor cells
Lipid peroxidation is a marker for iron death, producing toxic products including 4-hydroxynonenoic acid (4-HNE), while glutathione peroxidase 4 (GPX 4) is an effective defense system to protect biofilms from peroxidative damage. We therefore examined the levels of GPX4 and 4-HNE in tumor cells under different treatment conditions.
Experimental methods. Immunohistochemical analysis was performed on the basis of the experiment of example 11 using anti-GPX 4 (Abcam, ab 125066) and anti-4-HNE antibodies (Abcam, ab 48506) and DAB horseradish peroxidase color-developing solution, while separating nuclei with hematoxylin, and detecting GPX4 and 4-HNE contents in cells.
Experimental results. As can be seen from FIG. 13, GPX4 expression and 4-HNE accumulation in PG-treated tumor cells were higher than in the control group, but significantly lower than in the Fe-PG complex. The results show that the capability of inducing tumor cell iron death after PG and iron ions form a complex is obviously improved. Fe-PG complex induced iron death can effectively inhibit tumor growth.
Finally, it should be noted that the above-mentioned embodiments are only preferred embodiments of the present invention, and the present invention is not limited to the above-mentioned embodiments, but may be modified or substituted for some of them by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention. While the foregoing describes the embodiments of the present invention, it should be understood that the present invention is not limited to the embodiments, and that various modifications and changes can be made by those skilled in the art without any inventive effort.
Claims (10)
1. Use of phenolic compound-induced iron death in any one or more of:
(a) Inhibit cell growth and/or promote cell death;
(b) Products are prepared that inhibit cell growth and/or promote cell death.
2. The use according to claim 1, wherein the phenolic compound is any one or more of a monohydric phenol, a dihydric phenol or a trihydric phenol; further, the phenolic compound is phenol or phloroglucinol.
3. The use according to claim 1, wherein the cell is a cell of a prokaryote, eukaryote or archaea;
further, the cell is any one or more of bacteria, actinomycetes, rickettsia, chlamydia, mycoplasma, cyanobacteria, archaebacteria, fungi, plants or animal cells,
further, the cells are any one or more of E.coli, klebsiella pneumoniae, salmonella typhimurium, saccharomyces cerevisiae and HeLa cells.
4. The use according to claim 1, wherein the product is any one or more of a medicament, an experimental agent, a degerming agent, a weed killer, an insect killer, a disinfectant.
5. A method of inhibiting cell growth and/or promoting cell death, comprising applying a phenolic compound to an environment in which the cell is present.
6. The method of claim 5, wherein the environment in which the cells are present comprises iron ions;
the phenolic compound is phenol or phloroglucinol.
7. Use of iron death induced by phenolic compounds in the preparation of a medicament for the treatment of tumors.
8. The use according to claim 7, wherein the phenolic compound is phloroglucinol or an iron-phloroglucinol complex;
further, the specific preparation method of the iron-phloroglucinol complex is as follows: mixing ferric chloride and phloroglucinol, and standing.
9. The use of claim 7, wherein the neoplasm comprises benign neoplasm and/or malignant neoplasm; the malignant tumor comprises solid tumor and blood tumor; preferably a solid tumor, more preferably a lung cancer.
10. The use according to claim 7, wherein the medicament may further comprise at least one other active ingredient for the same or a different disease treatment and/or at least one other pharmaceutically inactive ingredient.
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