CN110327353B - Application of toosendanin in tumor treatment - Google Patents
Application of toosendanin in tumor treatment Download PDFInfo
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- CN110327353B CN110327353B CN201910622457.9A CN201910622457A CN110327353B CN 110327353 B CN110327353 B CN 110327353B CN 201910622457 A CN201910622457 A CN 201910622457A CN 110327353 B CN110327353 B CN 110327353B
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- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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Abstract
The invention discloses an application of toosendanin in tumor treatment, and relates to the technical field of tumor treatment. The invention discloses an application of toosendanin as a tumor drug resistance reversal agent. The research of the invention discovers for the first time that the toosendanin is a V-shaped hydrogen ATPase inhibitor and an autophagy inhibitor, and the toosendanin can be combined with other anti-cancer drugs which are easy to cause the tumor to generate drug resistance, so that the toosendanin can inhibit or prevent the tumor cells induced by the anti-cancer drugs from generating autophagy, and the tumor treatment effect of the anti-cancer drugs is improved. The toosendanin can be used in combination with other anticancer drugs such as drugs inducing tumor cells to generate protective autophagy, is used for treating tumors, improves the effect of tumor treatment, and provides a new medication strategy and treatment idea for the current tumor treatment. Toosendanin can also be developed into a tool (commercial biological reagent) for inhibiting the activity and autophagy function of V-type hydrogen ATPase, and is also suitable for treating diseases treated by the V-type hydrogen ATPase inhibitor, such as osteoporosis.
Description
Technical Field
The invention relates to the technical field of tumor treatment, in particular to application of toosendanin in tumor treatment.
Background
Research has found that some anticancer drugs can induce tumor cells to generate protective autophagy. The protective autophagy is one of the main ways for tumor cells to generate multidrug resistance, and can protect cancer cells against the killing of chemotherapeutic drugs, such as DNA damage, and degrade damaged organelles, thereby maintaining the steady state of the tumor cells and preventing the death of the tumor cells.
Disclosure of Invention
The invention aims to provide a new application of toosendanin in tumor treatment, for example, the toosendanin is used as a tumor drug resistance reversal agent to improve the anti-tumor effect, and provides a new medication strategy and treatment idea for the current tumor treatment.
It is another object of the present invention to provide a pharmaceutical combination for the treatment of tumors. The medicine composition has good anti-tumor effect.
The invention also aims to provide the application of the toosendanin in preparing the inhibitor for inhibiting the protective autophagy of tumor cells.
Another object of the present invention is to provide a method for inhibiting autophagy.
The invention is realized in the following way:
in a first aspect, the present invention provides the use of toosendanin as a reversal agent of tumor resistance.
In a second aspect, the invention provides a pharmaceutical composition for treating tumor, which comprises a tumor drug resistance reversal agent and an anti-tumor drug, wherein the tumor drug resistance reversal agent is toosendanin;
preferably, the anti-tumor drug has the property of inducing protective autophagy of tumor cells;
preferably, the toosendanin has an inhibitory effect on protective autophagy of tumor cells.
Further, in some embodiments of the invention, the anti-tumor drug is camptothecin.
Further, in some embodiments of the invention, the mass ratio of the tumor resistance reversal agent to the anti-tumor drug is 1: 4.
further, in some embodiments of the invention, the therapeutically effective amount of the tumor resistance reversal agent is 0.06mg/kg and the therapeutically effective amount of the anti-tumor drug is 0.24 mg/kg.
Further, in some embodiments of the invention, the tumor is cervical cancer.
The existing part of anticancer drugs can induce tumor cells to generate protective autophagy, and the protective autophagy can cause the tumor cells to generate drug resistance, so that the tumor cells resist the killing effect of the drugs, and the anticancer effect of the drugs is reduced.
Toosendanin (TSN) is an azadirachne type tetracyclic triterpene compound extracted from bark and root bark of Melia azedarach, and has molecular formula of C 30 H 38 O 11 The molecular weight is 574.62, and the powder is light yellow or white powder, bitter in taste, odorless, easily soluble in organic solvent and water, and has anthelmintic, anti-botulinum, anticancer and analgesic effects.
The research of the invention firstly discovers that toosendanin can inhibit autophagy of cells, and the toosendanin can be used together with the anti-cancer drugs to inhibit or prevent autophagy of tumor cells induced by the anti-cancer drugs, so that the tumor cells are prevented from generating drug resistance, and the tumor treatment effect of the anti-cancer drugs is provided. Therefore, the toosendanin can be used as a tumor drug resistance reversal agent and combined with other anti-cancer drugs such as drugs for inducing tumor cells to generate protective autophagy, is used for treating tumors, improves the effect of treating the tumors, and provides a new medication strategy and a new treatment idea for the current tumor treatment.
In a third aspect, the invention provides an application of toosendanin in preparing an inhibitor for inhibiting tumor cell protective autophagy.
Further, in some embodiments of the invention, the azadirachtin acts to inhibit autophagy by disrupting lysosomal function to inhibit degradation by autophagosomes.
Further, in some embodiments of the present invention, the azadirachtin acts to disrupt lysosomal function by inhibiting the activity of V-type hydrogen atpase.
The further research of the invention also discovers the mechanism of the toosendanin for inhibiting the autophagy of cells for the first time, and the toosendanin inhibits V-type hydrogen ATP enzyme (vacuolar H) + -ATPase, V-ATPase) activity, disrupting the acidic environment required for the functioning of lysosomes, thereby inhibiting degradation of autophagososomes and, in turn, inhibiting autophagy of cells. Therefore, based on the above, the toosendanin can be used as an inhibitor for inhibiting autophagy and is used for inhibiting autophagy.
In a fourth aspect, the invention provides an application of toosendanin in preparing a V-type hydrogen ATPase inhibitor.
In a fifth aspect, the invention provides a use of toosendanin in preparing a medicament for treating related diseases caused by V-type H ATPase activity, wherein the diseases are osteoporosis.
In a sixth aspect, the present invention provides a kit for inhibiting V-shaped hydrogen atpase activity or inhibiting cytoprotective autophagy, the kit comprising toosendanin.
In a seventh aspect, the invention provides a method of treating a non-disease that inhibits autophagy, comprising: contacting toosendanin with the target cells.
Further, in some embodiments of the present invention, azadirachtin is used at a concentration equal to or higher than 0.01 μ M;
preferably, the azadirachtin is used at a concentration of 0.01-24 μ M.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1A shows the effect of TSN (0.01. mu.M, 0.1. mu.M, 1. mu.M, 10. mu.M) at various concentrations on the protein content of LC 3B-II and SQSTM1 on HeLa cell line for 24 hours as measured by Western Blotting (WB).
FIG. 1B shows the effect of 1. mu.M TSN on the protein content of LC 3B-II and SQSTM1 at different time points (4h, 8h, 12h and 24h) on the HeLa cell line by WB assay.
FIG. 1C shows the effect of different concentrations of TSN (0.01. mu.M, 0.1. mu.M, 1. mu.M, 10. mu.M) on the protein content of LC 3B-II and SQSTM1 on A549 cell line after 24 hours of treatment by WB method.
FIG. 1D shows the effect of 1. mu.M TSN on LC 3B-II and SQSTM1 protein levels at different time points (4h, 8h, 12h and 24h) on A549 cell line by WB assay.
FIG. 1E shows the effect of BAF (100nM), Torin1(200nM), TSN (1. mu.M) on the punctate aggregation of RFP and GFP in a HeLa RFP-GFP-LC3 cell line.
FIG. 2A is the mean fluorescence intensity per cell calculated on a HeLa cell line by treating with Torin1(200nM), BAF (100nM), TSN (1. mu.M) for 24 hours, staining with LysoTracker, and photographing using a laser scanning confocal fluorescence microscope.
FIG. 2B shows the mean fluorescence intensity of each cell calculated by treating A549 cell line with Torin1(200nM), BAF (100nM), and TSN (1. mu.M) for 24 hours, staining with LysoTracker, and photographing with a laser scanning confocal fluorescence microscope.
FIG. 2C shows the effect of 1. mu.M TSN treatment on HeLa cell line for 24 hours on CTSB and CTSD protein content as measured by WB method.
FIG. 2D shows the effect of 1. mu.M TSN treatment on A549 cell line for 24 hours on CTSB and CTSD protein content measured by WB method.
FIG. 3A is a graph of the effect of different concentrations of BAF on V-ATPase activity in an ATP/NADPH coupled enzymatic reaction.
FIG. 3B is a graph of the effect of different concentrations of TSN on V-ATPase activity in an ATP/NADPH-coupled enzymatic reaction.
FIG. 4A shows the effect of CPT (0.01. mu.M, 0.1. mu.M, 1. mu.M, 10. mu.M) on the protein content of LC 3B-II and SQSTM1 on the WB assay at various concentrations for 24 hours on the HeLa cell line.
FIG. 4B shows the effect of 10. mu.M CPT on the content of LC 3B-II and SQSTM1 proteins at different time points (4h, 8h, 12h and 24h) on a HeLa cell line by WB assay.
FIG. 4C shows the effect of CPT (1. mu.M), TSN (1. mu.M) and combinations thereof on the protein content of LC 3B-II and SQSTM1 on HeLa cell lines for 24 hours as measured by WB assay.
FIG. 4D is a graph showing the effect of CPT (1. mu.M), TSN (1. mu.M) and combinations thereof on the punctate aggregation of RFP and GFP on a HeLa RFP-GFP-LC3 cell line.
FIG. 5A shows MTT assay for cell viability in HeLa cell lines treated with different concentrations of TSN, CPT and combinations thereof for 24, 48 hours.
FIG. 5B is a plate cloning assay: on a HeLa cell line, TSN, CPT and combinations thereof with different concentrations are treated for 10 days, and the number of clones in each well is calculated by photographing after crystal violet staining.
FIG. 6A is a photograph showing the size and shape of tumor at the time of sacrifice in HeLa cell nude mouse tumor-bearing test, in which the drug-free group, TSN (0.5mg/kg), TSN (1mg/kg), CPT (2mg/kg), TSN (0.5mg/kg) and CPT (2mg/kg) were administered in combination, i.p..
FIG. 6B tumor volume sizes recorded during the HeLa cell nude mouse tumor-bearing test, with no drug group, TSN (0.5mg/kg), TSN (1mg/kg), CPT (2mg/kg), TSN (0.5mg/kg) in combination with CPT (2mg/kg), i.p..
FIG. 6C shows the tumor weight of the day of sacrifice after intraperitoneal injection once every two days after drug-free group, TSN (0.5mg/kg), TSN (1mg/kg), CPT (2mg/kg), TSN (0.5mg/kg) and CPT (2mg/kg) were administered in combination in HeLa cell nude mice tumor-bearing test.
FIG. 6D is the mouse body weight recorded in the HeLa cell nude mouse tumor-bearing test, i.e., the time after the drug-free group, TSN (0.5mg/kg), TSN (1mg/kg), CPT (2mg/kg), TSN (0.5mg/kg) and CPT (2mg/kg) were administered in combination, i.e., i.p., once every two days.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more apparent, the technical solutions of the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are conventional products which are not indicated by manufacturers and are commercially available.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
1. Toosendanin (TSN) inhibits autophagy tide
To determine whether azadirachtin could affect autophagy, we first examined the effect of azadirachtin on LC 3B-II and SQSTM1(p62) protein levels at different concentrations and at different time points on the HeLa, A549 cell line. The results showed (FIG. 1A, FIG. 1B, FIG. 1C, FIG. 1D) that azadirachtin increased LC 3B-II and SQSTM1(p62) protein levels in a concentration-dependent manner on both cell lines. Similarly, 1 micromolar (. mu.M) of azadirachtin also increased the levels of LC 3B-II and SQSTM1(p62) protein at different time points. In addition, we can judge the change of autophagic tide by observing the number of autophagosomes. The increase in the number of autophagosomes may be caused by an increase in their synthesis or by a hindrance to their degradation. At this time, we can observe the change of autophagosome under drug stimulation through LC3 with double fluorescent protein tandem. On a HeLa cell line stably expressing mRFP-GFP-LC3 (fig. 1E), we seen only minimal punctate aggregation of Green Fluorescent Protein (GFP) or Red Fluorescent Protein (RFP) in the Control (CTRL) as not stimulated by the drug. Under the stimulation of the autophagy inducer Torin1(200nM), we can see that there are many punctate aggregates of GFP and RFP. At this time, autophagic tide smoothly proceeds, and autophagosome and lysosome fuse to form autophagososome, and the substrate is degraded. GFP can be quenched in autophagosomes compared to RFP, which is not easily quenched. So on the merged image (Merge) we see more red punctate clusters. Under the stimulation of an autophagy inhibitor Bafilomycin A1 (BAF; 100nM), a lot of punctate aggregation of GFP and RFP can be seen, but the BAF can increase the pH value of a lysosome in an acidic environment, the degradation capability of the lysosome is damaged, and the quenching and degradation of GFP and RFP are blocked. So on the merged image (Merge) we see more yellow punctate aggregations (formed after green and red overlap). Similar results to the autophagy inhibitor BAF were seen after 24 hours of 1 μm azadirachtin treatment. From this, it was determined that toosendanin is an autophagy inhibitor.
Example 2
Toosendanin inhibits autophagy substrate degradation by destroying lysosome acidic environment
Lysosome functions normally, autophagosomes and lysosomes are fused to form autophagosomes, autophagy substrates are degraded, and autophagy tides normally proceed. If the lysosome acidic environment is destroyed, the pH value is increased, the maturation of the hydrolase is hindered, the autophagy substrate cannot be degraded, and the autophagy tide is hindered. LysoTracker is a dye that stains lysosomes in an acidic environment red. Autophagy inducer, Torin1, can promote translocation of nuclear transcription factor eb (tffb) into the nucleus to up-regulate autophagy and lysosome-related gene expression. On the HeLa, a549 cell line, we can see that the number of lysosomes is increased after the Torin1 treatment compared with the control group, and the average red fluorescence intensity of each cell is obviously enhanced. The autophagy inhibitor BAF mainly destroys lysosome acidic environment, the pH value is increased, and the average red fluorescence intensity of each cell is obviously weakened. Similar results to the autophagy inhibitor BAF were seen after 24 hours of 1 μm azadirachtin treatment (fig. 2A, 2B). In addition, Cathepsins (Cathepsins) are converted to mature forms in normal lysosomes and exert hydrolytic and digestive functions. After 1 μm toosendanin treatment for 24 hours on HeLa, a549 cell line, the protein level of mature cathepsin B, D (mate-CTSB, mate-CTSD) was significantly reduced (fig. 2C, fig. 2D). From this, it was determined that toosendanin inhibits autophagy substrate degradation by destroying lysosomal function.
Example 3
Toosendanin is used for inhibiting V-type hydrogen ATPase (vacuolar H) + -ATPase, V-ATPase) activity disrupts the lysosomal acidic environment
V-ATPases on the lysosomal membrane transport hydrogen ions (H) from the cytoplasm under ATP supply + ) To the lysosome to maintain its acidic environment. Therefore, we tested whether toosendanin destroys the lysosomal acidic environment by inhibiting V-ATPase activity. We extracted lysosomes from sd (sprague dawley) rat livers, followed by establishment of ATP/NADPH coupled enzymatic reactions, initiation of enzymatic reactions by addition of ATP after 30 min pretreatment with different drugs, and dynamic detection of absorbance (OD) at 340 nm. The results showed (fig. 3A, fig. 3B) that the lysosome in the control group functioned normally, NADPH was continuously consumed in the enzymatic reaction, and the OD value was gradually decreased. The positive control drug BAF can inhibit the activity of V-ATPase, and the higher the drug concentration is, the greater the inhibition degree is, the more the degradation of NADPH is blocked, and the reduction of OD value is slowed down. OD values after different concentrations of azadirachtin pre-treatment showed similar results to BAF. It was thus determined that toosendanin inhibits V-ATPase activity.
Example 4
The toosendanin can inhibit autophagy induced by chemotherapeutic drugs (such as camptothecin, CPT)
Similarly, to determine whether the chemotherapeutic drug (camptothecin) affected autophagic tides, we examined the effect of camptothecin on LC 3B-ii and SQSTM1(p62) protein levels at different concentrations and at different time points on the HeLa cell line. The results show (fig. 4A, fig. 4B) that camptothecin increased LC 3B-ii, decreased SQSTM1(p62) protein levels in a concentration-dependent manner. Similarly, 10 micromoles of camptothecin also increased LC 3B-II, decreased SQSTM1(p62) protein levels at different time points. In addition, in the LC3 reversal test (LC3 turnover assay), significant increases in LC 3B-II and SQSTM1 protein levels were observed when camptothecin was combined with toosendanin, as compared to camptothecin alone (FIG. 4C). We also judged the changes in autophagic tides by observing autophagosome numbers on HeLa cell lines stably expressing mRFP-GFP-LC3 (FIG. 4D). We can see a lot of punctate aggregation of both GFP and RFP under stimulation of 1 μm camptothecin, but on the merged image (Merge) we see more red punctate aggregation, suggesting that most of the punctate aggregated GFP is quenched in lysosomes, suggesting that camptothecin can induce autophagic tide. However, after 1 μm of azadirachtin was used in combination, we hardly seen punctate aggregates of RFP on the combined images. It is determined that toosendanin can inhibit camptothecin-induced autophagy.
Example 5
Toosendanin enhances anticancer effects by inhibiting protective autophagy of chemotherapeutic drugs (camptothecin). first, we examined the effect of camptothecin, toosendanin and combination on cell viability of HeLa cell line (MTT assay). The results (fig. 5A) show that both groups of combination significantly reduced cell viability compared to 0.1, 1, 10 μmol camptothecin and 0.1 μmol toosendanin used alone. Furthermore, in the HeLa cell line plate cloning assay (Colony format assay), we can see that the combination significantly reduces Colony formation compared to 10 nanomolar camptothecin alone and 1 nanomolar toosendanin alone (FIG. 5B). In order to observe the anticancer effect of the drug in vivo, HeLa cells were planted in the right axilla of nude mice, camptothecin, toosendanin and the combination drug (intraperitoneal injection, once every two days) were used after 1 week, the tumor volume and the weight of the nude mice were recorded periodically, and the mice were sacrificed after 21 days of drug administration. The results show that 2mg/kg (weight of nude mice) (mg/kg) of camptothecin, 1mg/kg and 0.5mg/kg of toosendanin can significantly inhibit Tumor growth (fig. 6A), including Tumor volume (Tumor size) (fig. 6B) and Tumor weight (Tumor weight) (fig. 6C), while the combination (2mg/kg of camptothecin and 0.5mg/kg of toosendanin) can more significantly inhibit Tumor growth. In addition, each drug group had no significant effect on the body weight of nude mice (fig. 6D).
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (5)
1. The application of a medicine composition comprising a tumor drug resistance reversal agent and an anti-tumor medicine in preparing a medicine for treating tumors is characterized in that the tumor drug resistance reversal agent is toosendanin;
the anti-tumor drug is camptothecin;
the tumor is cervical cancer;
the mass ratio of the tumor drug resistance reversal agent to the anti-tumor drug is 1: 1. 1: 4. 1: 10 or 1: 100.
2. the use according to claim 1, wherein the therapeutically effective amount of the tumor resistance-reversing agent is 0.06mg/kg and the therapeutically effective amount of the antitumor drug is 0.24 mg/kg.
3. Use of toosendanin for non-disease treatment for inhibiting autophagy in a cell, comprising: contacting toosendanin with the target cells.
4. The use according to claim 3, wherein the azadirachtin is used at a concentration of 0.01 μ M or higher.
5. The use according to claim 3, wherein the azadirachtin is used at a concentration of 0.01 to 24 μ M.
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| CN108432820A (en) * | 2018-03-27 | 2018-08-24 | 靖西市秀美边城农业科技有限公司 | A kind of shatian pomelo special-purpose insecticide and the preparation method and application thereof |
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