CN115400106A - Application of natural compound and composition thereof in removing senescent cells - Google Patents
Application of natural compound and composition thereof in removing senescent cells Download PDFInfo
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Abstract
Application of natural compound and its composition in eliminating senescent cells is provided. The application provides application of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof in preparing a medicament for clearing aging cells or delaying aging or down-regulating an aging-related secretory phenotype. Also provided is the use of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof in combination with dasatinib or quercetin in the preparation of a medicament for the clearance of senescent cells or the retardation of senescence or the downregulation of senescence-associated secretory phenotype. Also provides a pharmaceutical composition comprising 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof, dasatinib or quercetin and optional pharmaceutically acceptable auxiliary materials and application thereof. The application or the pharmaceutical composition has good effect of eliminating senescent cells, has small lethality to normal cells, and thus shows lower toxicity.
Description
Technical Field
The present invention relates to a nutrient health-care medical technology, in particular, it relates to 4,4' -dimethoxy chalcone (DMC) and its composition for removing senescent cell and delaying senility.
Background
Aging is the first risk factor of various chronic diseases, and greatly influences human health and social development. With the continuous development of global science and technology and situation, the population is slowly increased, the aging problem is serious, and the relationship between aging and cell aging is always a focus of people. In recent years, a large number of researches show that the accumulation of senescent cells is an important mechanism for driving the aging and the occurrence and development of senile diseases, the senescent cells become a new target for preventing and treating the senile diseases, and the research and development of medicines with the effect of clearing the senescent cells also become a hotspot [1].
The phenomenon of cellular senescence was first reported in 1961, and the American biologist Leonard Hayflick found that when fibroblasts were cultured in vitro in normal humans, growth arrest occurred even when the cells were divided to a certain passage number, given the optimum growth conditions for the cells, and this limit of cell proliferation capacity was called the Hayflick limit [2]. Mechanistic studies have shown that this phenomenon is due to the shortening of telomeres and the decrease in telomerase activity as cells replicate more frequently. In addition, common in vitro stimulation, chemotherapy and radiotherapy, as well as inducing reprogramming of cells, can also induce senescence of cells. The classification is based on the causative factors of cellular senescence, which can be subdivided into: 1. telomere-induced cellular senescence; 2. oxidative stress-induced cellular senescence; 3. oncogene-induced senescence; 4. treatment-induced cellular senescence; 5. reprogramming-induced cell aging, and the like. The basic characteristics of senescent cells are permanent growth arrest (i.e., cell cycle arrest), altered cell morphology, telomere shortening, anti-apoptotic effects, changes in Senescence-associated molecules (molecular markers), and a Senescence-associated secreted phenotype (SASP). (1) permanent growth arrest of cells: the phenomenon of cell cycle arrest is one of the most fundamental and indispensable indicators for identifying cellular senescence in vitro. (2) cell morphology change: senescent cells usually become flat, the whole cell and the nucleus become large in volume, and the morphological change of the cell after senescence can only be used as auxiliary evidence for judging cell senescence. (3) telomere shortening: the detection of telomere shortening is one of the characteristics of cell senescence, but this phenomenon can only be used as an aid. (4) anti-apoptotic Effect: when cells are stressed, if the p53 level is lower, the capability of activating effector proteins of downstream apoptosis pathways is weaker, and the cells can have senescence instead of apoptosis. (5) changes in senescence-associated molecules: there are specific molecular marker expression changes during senescence, for example, senescence-associated β -galactosidase expression levels or activities increase, and cell cycle-associated molecules such as p14, p16, p21 increase. (6) SASP: cells senesce and secrete a range of cytokines that alter the senescing cells themselves or the surrounding microenvironment, such as insulin-like growth factor (IGF), transforming growth factor beta, interleukins, and plasminogen activator inhibitor type I (PAI-1).
The drug or drug combination for targeted elimination of senescent cells is called Senolytics, and currently, the Senolytics drug has made good progress in clinical trials, and the combination of Dasatinib (Dasatinib) + quercetin (quectetin) (D + Q) has entered the phase II clinical trial stage. In 2019, australian researchers screened 4,4 '-dimethyl chalcone (4,4' -dimethyloxychalcone, DMC) to have the function of prolonging the longevity of various species such as yeast, nematode and fruit fly [3]. Our laboratory performed multi-target identification of DMC by means of Thermoproteomics (TPP) technology and analyzed its anti-tumor cell proliferation effect [4] [5].
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
Currently, whether 4,4 '-dimethyl chalcone (4,4' -dimethyloxychalcone, DMC) extends species longevity by way of eliminating senescent cells has not been explored, and whether DMC in combination with the currently hottest D + Q combination results in a composition with Senolytics potential is unknown.
Although Senolytics can kill senescent cells, it also kills a small number of healthy cells. The main reason for this problem may be the dosage of the drug or the toxicity of the drug itself. Our experiments show that dasatinib (D) alone, quercetin (Q) alone and D + Q all have greater killing effects on normal cells, while DMC treatment alone can achieve the same effect on senescent cells as D, Q or D + Q, and simultaneously has less killing effects on normal cells, thereby showing lower toxicity.
Therefore, in order to solve the above problems, the present application provides a pharmaceutical composition for eliminating senescent cells, which can achieve the same effect of eliminating senescent cells as D, Q or D + Q, and at the same time, has less lethality to normal cells, thereby exhibiting lower toxicity.
In an embodiment of the present application, there is provided a use of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof in the manufacture of a medicament for clearing senescent cells or delaying senescence or down-regulating a senescence-associated secretory phenotype.
In an embodiment of the present application, there is provided a use of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in combination with dasatinib or quercetin in the manufacture of a medicament for the clearance of senescent cells or the delay of senescence or the downregulation of senescence-associated secretory phenotype.
In some embodiments of the present application, the molar ratio of 4,4' -dimethoxychalcone, or a pharmaceutically acceptable salt, hydrate, or prodrug thereof, to dasatinib is (500-50): 3, preferably 500, preferably 250, preferably 100, 3, preferably 50.
In some embodiments of the present application, the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to quercetin is in the range of (1-3): (1-4), preferably 1:1, preferably 1:2, preferably 2:3, preferably 3:4.
In an embodiment of the present application, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof, and dasatinib or quercetin and optionally a pharmaceutically acceptable adjuvant.
In some embodiments of the present application, the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to dasatinib is in the range of (500-50): 3, preferably 500, preferably 250, preferably 100.
In some embodiments of the present application, the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to quercetin is in the range of (1-3): (1-4), preferably 1:1, preferably 1:2, preferably 2:3, preferably 3:4.
In an embodiment of the application, the use of the above pharmaceutical composition for clearing senescent cells or delaying senescence or down-regulating a senescence-associated secretory phenotype.
The present application includes the following advantages compared to the related art.
DMC has lower toxicity to normal cells than Q, and has stronger cleaning ability to senescent cells; the toxicity of the D + DMC composition on normal cells is significantly lower than that of the D + Q composition; the combination of DMC and Q is better than that of DMC alone, so that the harm of possible anticancer drugs is reduced; and DMC and its combination with D or Q is significantly more potent in senescent cell clearance than the D + Q combination. And DMC can also reduce the level of SASP in senescent LO2 cells.
Additional features and advantages of the present application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the present application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.
Drawings
The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.
FIG. 1 shows the molecular structure of DMC.
FIG. 2 shows Etoposide-induced β -galactosidase staining of senescent LO2 cells.
FIG. 3 shows the expression of the SASP gene in Etoposide-induced senescent LO2 cells.
FIG. 4 is a CCK8 assay to examine the clearance of DMC and its compositions against senescent cells.
FIG. 5 shows that beta-galactosidase staining test detects the clearance of senescent cells by DMC and its composition.
Fig. 6 is a SASP phenotype of DMC-inhibited senescent LO2 cells.
FIG. 7 is a graph of the hair color of aging mice darkened by the promotion of DMC and its combination with Q.
FIG. 8 is a graph of DMC and its composition with Q reducing mouse liver tissue SASP phenotype.
FIG. 9 shows that DMC and its composition eliminate senescent mouse tail fibroblasts.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is obvious that the described embodiments are a part of the embodiments of the present invention, but not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
Currently, whether 4,4 '-dimethyl chalcone (4,4' -dimethyloxychalcone, DMC) extends species longevity by way of eliminating senescent cells has not been explored, and whether DMC in combination with the currently hottest D + Q combination results in a composition with Senolytics potential is unknown.
While Senolytics can kill senescent cells, they also kill a small number of healthy cells. The main reason for this problem may be the dosage of the drug or the toxicity of the drug itself. Our experiments show that dasatinib (D) alone, quercetin (Q) alone and D + Q all have greater killing effects on normal cells, while DMC treatment alone can achieve the same effect on senescent cells as D, Q or D + Q, and has less killing effects on normal cells, thereby showing lower toxicity.
4,4 '-dimethylchalcone (4,4' -dimethyloxychalcone, DMC) is a flavonoid compound that has been screened in recent years for its ability to extend the life of a variety of species [3]Molecular formula is C 17 H 16 O 3 The structure is shown in figure 1, two benzene rings form C through three carbons 6 -C 3 -C 6 In the structure (1), a double bond and a carbonyl group exist between three carbons. We have unexpectedly found that DMC has the ability to eliminate senescent cells and it is expected that a more effective composition with other Senolytics could be developed for the elimination of senescent cells.
Next, we used 10. Mu.M Etoposide (Etoposide, molecular formula C) 29 H 32 O 13 Cell senescence induction) was performed for 24 hours to successfully construct a senescent cell model (a model of senescent cells (SEN cells for short) in which Etoposide-induced LO2 cells were not found in literature research) in which normal LO2 cells were not induced, and accordingly, the normal LO2 cells were used as control cells. And detecting the morphological difference and the beta-galactosidase staining condition of the normal cell and the SEN cell and the SASP gene expression level of the normal cell and the SEN cell, thereby judging whether the senescent cell model is successfully constructed.
Dasatinib is abbreviated as D, quercetin is abbreviated as Q, and different concentrations of DMC (5 mu M, 10 mu M, 25 mu M and 50 mu M), different concentrations of DMC (5 mu M, 10 mu M, 25 mu M and 50 mu M) +300nM D composition, different concentrations of Q (5 mu M, 10 mu M, 25 mu M and 50 mu M) +300nM D composition and different concentrations of DMC + Q (10 mu M, 25 mu M and 50 mu M) are used for treating normal cells and SEN cells, and compared with the clearance effect of different compositions of DMC, D + Q and DMC + Q on senescent cells, the clearance effect and the phenotype inhibition effect of DMC and the composition thereof on the senescent cells are researched through experiments of CCK-8, beta-galactosidase staining experiment, SASP gene qPCR detection and the like.
The influence of the DMC or DMC + Q composition on the hair and motor ability of aging mice was examined by treating aging mice (20months, C57BL6) with the solvents DMSO, DMC (50 mg/kg), DMC (25 mg/kg) + Q (25 mg/kg) by intraperitoneal injection for 2 months (every 4-5 days). And (3) detecting whether DMC, DMC + Q can reduce SASP phenotype of the aged mice by using a mouse liver slice immunohistochemical experiment and a qPCR experiment.
Separating primary fibroblasts at the tail of a C57BL6 mouse of 6 months, culturing to the 8 th generation, and verifying the influence of DMC and a composition thereof on the senescence marker of the senescent fibroblasts of the mouse and whether the senescent fibroblasts of the mouse can be eliminated.
Compared with the existing senescent cell scavenger, the invention has the following advantages:
DMC and Q are both flavonoids, but DMC was found to be less toxic to normal cells than Q and more potent in scavenging senescent cells; secondly, it was found that the D +10 μ M DMC, D +25 μ MDMC composition had an effect comparable to the senescent cell clearance of D +10 μ M Q, D +25 μ M Q, but the D + DMC composition was significantly less toxic to normal cells than the D + Q composition; furthermore, the DMC and Q combination is found to be better than DMC alone, which indicates that the combination of two flavonoids also has good capacity of eliminating senescent cells, thus the anticancer drug D is not needed to be added, and the harm of the possible anticancer drug is reduced.
In addition, DMC can eliminate senescent LO2 cells and delay senescence in mice, reducing the mouse hepatic SASP phenotype, and DMC and its combination with D or Q also has senescent cell clearance effect, and several of these combinations have stronger senescent cell clearance than the D + Q combination.
The present invention will be described in further detail with reference to specific examples, but the present invention is not limited to the following examples.
The reagents used in the present application are as follows:
4,4' -dimethoxychalcone: (Alfa Aesar, USA Cat #. L10585)
Dasatinib: (TargetMol, USA, cat #. T1448)
Quercetin: (TargetMol, USA, cat #. T2174)
Etoposide：(Beyotime,China,Cat#.SC0173)
Mice: (Beijing Weitonglihua) C57BL6 variety
Immunohistochemical kit: (Wuhan Severer, cat #. GB11117, cat #. GB 11113)
Example 1:
DMC and pharmaceutical compositions thereof have the ability to eliminate Etoposide-induced senescent LO2 cells.
Etoposide, DMC, dasatinib and quercetin were dissolved in DMSO to prepare respective appropriate working solutions.
Etoposide (Etoposide) as an antitumor agent can exert a cancer-suppressing effect by suppressing the synthesis of DNA and protein in tumor cells. Studies have shown that Etoposide can induce apoptosis in tumor cells at high doses, whereas Etoposide can induce senescence in tumor cells at low doses. An aging LO2 cell model is constructed by Etoposide for the first time, the specific method is that 10 mu M Etoposide (Etoposide) is used for treating human normal liver cell line LO2 cells 24h, and most of cells treated by Etoposide are blue after being stained by beta-galactosidase, namely, the cells enter an aging state, namely, the construction success of the aging cell model induced by DNA damage is proved. SASP of the Etoposide-induced senescent cells IL-1 alpha, IL-1 beta, IL-6, IL-8, P21, P16 and the like was found to be significantly increased compared with normal cells after qPCR detection (Etoposide-induced senescent LO2 cell beta-galactosidase staining is shown in FIG. 2; etoposide-induced senescent LO2 cell SASP gene expression is shown in FIG. 3). Subsequently treating senescent LO2 cells with DMC and its pharmaceutical composition for 48h, detecting senescent markers by beta-galactosidase staining and SASP phenotype by qPCR found that DMC (5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M) can eliminate senescent LO2 cells with less effect on normal cells and DMC treatment alone is more effective than Q treatment alone (C of FIG. 4, D of FIG. 4); in addition, we also combined DMC and D and DMC and Q to observe the clearance effect of the pharmaceutical composition on senescent cells, and we found that the composition of 300nM D + DMC (5 μ M, 10 μ M, 25 μ M, 50 μ M) had comparable clearance ability to 300nM D + Q (5 μ M, 10 μ M, 25 μ M, 50 μ M) senescent cells, but the killing effect of DMC + Q on normal cells was less at the same concentration combination, indicating that the composition of D + DMC was better than the composition of D + Q (A of FIG. 4); furthermore, we also combined DMC with Q and found that DMC + Q compositions also have senescent cell clearance ability, whether both are 10 μ M, 25 μ M or 50 μ M, with 10 μ M DMC +10 μ M Q composition having no effect on normal cells (fig. 4B), suggesting that compositions between flavonoids also have the potential to be called Senolytics. In addition, we also tested mRNA levels of SASP such as IL-1 α, IL-1 β, TNF- α and CXCL10 by qPCR and found that DMC can also reduce SASP levels in senescent LO2 cells (FIG. 6). The above results demonstrate that DMC and compositions thereof can eliminate senescent cells and can reduce the level of SASP in senescent cells.
Example 2:
DMC and its pharmaceutical compositions eliminate mouse aged fibroblasts.
Primary fibroblasts from the tail of a C57BL6 mouse of 6 months old were isolated and cultured until the 8 th generation, and used as a replicative senescent cell model. The DMSO-treated group was used as a control group, senescent cells were treated with D + Q, DMC and its composition, and beta-galactosidase staining experiments were performed, and the results in FIG. 9 show that DMC (1. Mu.M, 5. Mu.M, 10. Mu.M, 25. Mu.M, 50. Mu.M), D + DMC (10. Mu.M, 25. Mu.M, 50. Mu.M), 50. Mu. M Q + DMC (25. Mu.M, 50. Mu.M) treatment for 48h can eliminate mouse senescent fibroblasts, and exhibit concentration dependence, with higher concentrations providing better effect of elimination; as can be seen from FIG. 9, the action of 300nM D +10 μ M DMC is equivalent to that of 300nM D +50 μ M Q, the action of 300nM D +25 μ M DMC and 300nM D +50 μ M DMC are superior to that of 300nM D +50 μ M Q, and the action of 300nM D +50 μ M DMC is significantly superior to that of 300nM D +50 μ M Q; 50 μ M Q +25 μ MDMC and 50 μ M Q +50 μ M DMC also have the effect of eliminating senescent cells. The above results demonstrate that DMC and compositions thereof are effective in eliminating senescent cells.
Example 3:
DMC and its pharmaceutical composition delay mice aging and reduce liver tissue SASP phenotype.
After 2 months of treatment (every 4-5 days) of 20-month-old male aged mice (C57 BL6 variety) with DMSO, DMC (50 mg/kg), DMC (25 mg/kg) + Q (25 mg/kg) by intraperitoneal injection, the hair color and the exercise capacity of the aged mice are observed by taking the DMSO-treated group as a control group, and the hair color of the aged mice is dense and black and the exercise capacity of the aged mice is enhanced by the DMC-treated group and the DMC + Q-treated group (figure 7); liver tissues of three groups of mice (4-6 mice per group) were subjected to immunohistochemistry, and it was found that the expression levels of SASP genes such as IL-6, IL-1. Beta. And the like in the livers of aging mice in DMC and DMC + Q-treated groups were lower than those in the control group (A in FIG. 8). Meanwhile, we extracted RNA from mouse liver tissue, and detected mRNA levels of SASPs such as IL-1 alpha, IL-1 beta, CXCL10 and MMP12 by qPCR, and found that the mRNA levels of SASPs in DMC and DMC + Q treated groups were lower than those in the control group (B in FIG. 8). The above results suggest that DMC and compositions thereof have the effects of delaying mouse aging and reducing the SASP phenotype.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Reference documents:
[1] su Lulu, bobo text, fan Feiyue, and the like. Senescent cell scavenger study progress [ J ] chinese pharmacological report 2019,35 (10): 5.
[2]Hayflick L,Moorhead P S.The serial cultivation of human diploid cell strains[J].Experimental Cell Research,1961,25(3):585-621.
[3]The flavonoid 4,4′-dimethoxychalcone promotes autophagy-dependent longevity across species[J].Nature Communications,2019,10(1).
[4]Yang C,Zhu S,Chen Y,Liu Z,Zhang W,Zhao C,Luo C,Deng H.Flavonoid 4,4'-dimethoxychalcone suppresses cell proliferation via dehydrogenase inhibition and oxidative stress aggravation.Free Radical Biology and Medicine.2021,175:206-215.
[5]Yang C,Wang T,Zhao Y,Meng X,Ding W,Wang Q,Liu C,Deng H.Flavonoid 4,4'-dimethoxychalcone induced ferroptosis in cancer cells by synergistically activating Keap1/Nrf2/HMOX1 pathway and inhibiting FECH.Free Radical Biology and Medicine.2022,188:14-23.
Claims (8)
1.4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof for use in the preparation of a medicament for clearing senescent cells or delaying senescence or downregulating senescence-associated secretory phenotype.
Use of 2.4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in combination with dasatinib or quercetin in the preparation of a medicament for the clearance of senescent cells or the retardation of senescence or the downregulation of senescence-associated secretory phenotype.
3. The use according to claim 2, wherein the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof to dasatinib is (500-50) to 3, preferably 500, preferably 250, preferably 100, 3, preferably 50.
4. The use according to claim 2, wherein the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof to quercetin is in the range of (1-3): (1-4), preferably 1:1, preferably 1:2, preferably 2:3, preferably 3:4.
5. A pharmaceutical composition comprising 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate, or prodrug thereof and dasatinib or quercetin and optionally a pharmaceutically acceptable adjuvant.
6. The pharmaceutical composition according to claim 5, wherein the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof to dasatinib is in the range of (500-50) 3, preferably 500.
7. The pharmaceutical composition according to claim 5, wherein the molar ratio of 4,4' -dimethoxychalcone or a pharmaceutically acceptable salt, hydrate or prodrug thereof to quercetin is in the range (1-3) to (1-4), preferably 1:1, preferably 1:2, preferably 2:3, preferably 3:4.
8. Use of a pharmaceutical composition according to any one of claims 5-7 for clearing senescent cells or delaying senescence or down-regulating a senescence-associated secretory phenotype.
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