CN111110826B - Medicine composition for preventing cancer by targeting mitochondria and application thereof - Google Patents
Medicine composition for preventing cancer by targeting mitochondria and application thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition for preventing cancer occurrence by targeting mitochondria, which comprises pregnenolone, melatonin, selenium, lipoic acid, reduced glutathione, coenzyme Q10, bifidobacteria and a pharmaceutically acceptable carrier. The pharmaceutical composition of the invention is used as a mitochondrial energy drug, and ensures multi-target repair of mitochondrial function through comprehensive construction of mitochondria of organisms, thereby realizing intervention before or simultaneously on cancer cells, inhibiting growth of the cancer cells and preventing cancer.
Description
Technical Field
The invention relates to a pharmaceutical composition, which can improve the function of mitochondria of an organism, inhibit the generation of cancer cells caused by the reduction of the activity of the mitochondria of the organism and prevent the occurrence of cancers.
Background
Mitochondria, one of the organelles essential to the body, are ancient and important, complex and delicate organelles in eukaryotic cells. The ancient symbiotic origin, the unique double-layer membrane ridge structure and the semi-autonomous self-replication capacity of mitochondria endow the mitochondria with important and diverse functions. For the body, mitochondria are the ultimate site for biological oxidation and energy synthesis of eukaryotic cells, and are the fundamental source of energy consumption for human activities.
With further intensive research on mitochondria, it was found that mitochondria are not only "energy-driven factories" of cells, but also involved in many pathophysiological processes such as cell signal transduction, redox balance, calcium level regulation, cell differentiation aging and death. Thus, the development of a variety of body diseases, including neuromuscular diseases, cardiovascular diseases, diabetes, cancer, etc., involves impairment of mitochondrial function.
The modern society develops rapidly, brings convenience and brings a plurality of problems. Natural environment pollution, various stress events, bad work and rest modes, unhealthy diet and no regularity, various external and self factors such as excessive living and working pressure and the like cause various system functional disorders to be damaged, mitochondria in human cells can not be prevented from being damaged, and the nervous system, the cardiovascular system, the immune system and the like which need energy supply most for an organism are most remarkable, so various system symptoms such as insomnia and dreaminess, hypomnesis, chest distress and shortness of breath, arrhythmia, hypodynamia, physical decline, cold and the like of the organism are often caused, and further the occurrence and development of cancers are further caused. Therefore, restoration of impaired mitochondrial function is an important research topic.
The human body is a complete systemic individual, the transformation of medical concepts is imperative, and the proposal of the overall medical view is a necessary and necessary fact. Based on the overall medical view and the wide and important functions of mitochondria, focus on the reconstruction and recovery of the functions of the mitochondria, can recover the whole homeostasis of a human body, improve the immune function and the whole endocrine regulation of the body, and treat, prevent and even reverse the occurrence and development of diseases.
Many reports on related drugs for repairing mitochondrial functions currently exist, and studies show that drugs such as Pregnenolone (PRE), Dehydroepiandrosterone (DHEA), Thyroid Hormone (TH), Melatonin (MLT), selenium (Se), Lipoic Acid (LA), reduced Glutathione (GSH), coenzyme Q10, tyrosine (Tyr), cortisol (cortisol), epinephrine (a) and the like are closely related to mitochondrial functions and play an important role in recovering mitochondrial functions. However, the specific effects reported for these drugs are also mainly limited to antioxidant effects or to compensate for mitochondrial respiratory chain function, and their deeper mechanisms of action are not yet clear. Meanwhile, the research on the synergistic effect among the medicines is less, and no evidence proves that the medicines can be used in combination, and whether the combination of the medicines can improve the fusion efficiency of mitochondria, improve the anti-mutation capability of the mitochondria and improve the activity of the mitochondria is needed to be further researched.
Restoration of mitochondrial function is also known as mitochondrial construction, and includes the construction of the intracellular and extracellular environments. The extracellular environment construction includes large internal environment of the body, heavy metal removal and environmental pollution, namely the elimination of evil factors for strengthening body resistance and eliminating evil in the theory of traditional Chinese medicine; the construction of the intracellular environment is based on the construction of the external environment, and various nutrients required by the energy production of mitochondria are provided, so that the functions of the mitochondria are recovered, and the self-healing of cells and human bodies is promoted, namely the strengthening of body resistance and elimination of pathogenic factors in the theory of traditional Chinese medicine.
The overall construction of mitochondria is never achieved by a single nutrient, nor is it simple to restore mitochondrial function with any combination of several nutrients. Just like the monarch, minister, assistant and guide in traditional Chinese medicine, proper mitochondrial function repairing drugs are correctly screened out for combination, and the synergic action and complementary action between the drugs are fully utilized, so that the drugs are combined and matched with each other, and the effect of restoring the mitochondrial function can be better realized.
Disclosure of Invention
The invention aims to provide a pharmaceutical composition for preventing cancer by targeting mitochondria, which has good effects of recovering and improving mitochondrial function as a mitochondrial energy medicament, is safe and reliable and is convenient to apply and popularize.
The invention also provides the application of the pharmaceutical composition in the aspects of improving the body immunity, inhibiting the generation of cancer cells and preventing the occurrence of cancers.
The present inventors have found that even the same mitochondrial function repairing drug may cause different results when used in the pre-, mid-and post-tumorigenic stages of cancer cells, thereby revealing that the mitochondrial function repairing drug exerts different effects in different stages of cancer. Based on the above findings, the inventors finally screened a pharmaceutical composition suitable for use before tumorigenesis, which significantly inhibits the production of cancer cells through the construction of mitochondria in the body, through a large number of studies and experiments.
The invention firstly provides a pharmaceutical composition for preventing cancer occurrence by targeting mitochondria, which comprises active ingredients of Dehydroepiandrosterone (DHEA), Melatonin (MLT), selenium (Se), Lipoic Acid (LA), reduced Glutathione (GSH), coenzyme Q10, bifidobacteria and pharmaceutically acceptable carriers.
Further studies have found that Pregnenolone (PRE) acts as a precursor hormone to Dehydroepiandrosterone (DHEA) and that the hormone converted in vivo is more potent than DHEA. Therefore, the invention also provides another mitochondria-targeted pharmaceutical composition for preventing cancer occurrence, which comprises the active ingredients of Pregnenolone (PRE), Melatonin (MLT), selenium (Se), Lipoic Acid (LA), reduced Glutathione (GSH), coenzyme Q10 and bifidobacteria, and pharmaceutically acceptable carriers.
In the present invention, the "pharmaceutically acceptable carrier" refers to a substance suitable for use in humans and mammals without adverse side effects such as toxicity, irritation and allergy, and includes, but is not limited to, various common excipients, diluents, binders, dissolution aids, antioxidants, disintegrants, lubricants, stabilizers, absorption enhancers, colorants and the like.
Furthermore, the pharmaceutical composition of the present invention may be at least one of any pharmaceutically acceptable dosage forms, including but not limited to tablets, capsules, powders, granules, syrups, and the like.
In the pharmaceutical composition of the present invention, there is no particular limitation on the weight ratio of the various active ingredients.
Preferably, however, the pharmaceutical composition may be obtained, for example, in parts by weight of the following active ingredients: 25-50 parts of pregnenolone or dehydroepiandrosterone, 3-5 parts of melatonin, 0.2-0.4 part of selenium, 150-300 parts of lipoic acid, 450-600 parts of reduced glutathione, 50-300 parts of coenzyme Q10150, and 0.5 multiplied by 10 of bifidobacterium4～1.5×104CFU per weight part of active ingredient.
The pharmaceutical composition can improve the immunity of the organism by recovering the function of mitochondria and improving the energy of mitochondria, and is used for preventing low physiological function caused by the injury of mitochondria and various diseases caused by abnormal function of mitochondria.
Furthermore, the pharmaceutical composition can be used for inhibiting the generation of various non-gonadal solid tumor cancer cells and preventing cancers such as lung cancer, thyroid cancer, bladder cancer, gastric cancer, renal cancer, intestinal cancer and the like by improving mitochondrial energy.
Furthermore, the pharmaceutical composition provided by the invention has a better and remarkable effect in preventing the occurrence of lung cancer.
It should be specifically noted that the effect of the pharmaceutical composition of the present invention is limited to inhibiting the generation of cancer cells, and does not include middle and advanced cancers.
Therefore, the pharmaceutical composition provided by the invention realizes the effects of obviously inhibiting the growth of cancer cells and preventing the occurrence of cancers through the intervention effect before or simultaneously with the generation of the cancer cells.
Animal level verification proves that the pharmaceutical composition has the effects of restoring mitochondrial function, improving mitochondrial energy, inhibiting cancer cell growth and preventing cancer.
The present invention emphasizes that mitochondria need to be constructed in advance to prevent disease. As an important organelle for providing energy in eukaryotic cells, mitochondria are related to the occurrence and development of various chronic diseases, and the whole network of the mitochondria is regulated and controlled, so that the health of the mitochondrial network is ensured, the metabolic capability of cells is improved, and the health is promoted and the diseases are prevented.
According to the experimental result, the mitochondrial energy pharmaceutical composition can better inhibit the growth of cancer cells of mice after being administered in advance, and is obviously higher than the administration after the formation of tumor and the administration at the same time of the formation of tumor. The importance of the administration time node on the disease development is illustrated, and the mitochondrial energy pharmaceutical composition is administered in advance, so that the mitochondrial overall network can be better built, and the disease can be healthily prevented.
The construction of mitochondria involves the construction of the intracellular and extracellular environment (the internal environment of the body). The homeostasis of the intracellular and extracellular environments is equally important for life as an organic whole, and the importance of intestinal micro-ecological regulation is becoming more and more certain. According to the experimental result, the bifidobacterium is added into the pharmaceutical composition, so that the growth of the cancer cells of the mice can be better prevented and controlled. The intestinal health not only protects the intestinal homeostasis, but also regulates and mobilizes the immunity of the organism.
The health of the body needs to be coordinated and coordinated by multiple systems and multiple organs, and the mitochondrial energy pharmaceutical composition also needs to be combined in multiple ways to exert the optimal benefit. According to the experimental results, the combination of a plurality of mitochondria function repairing drugs screened by experiments can obtain the pharmaceutical composition with the optimal effect of inhibiting the growth of cancer cells, which is superior to other combination schemes. Like traditional Chinese medicine wisdom accumulated in thousands of years, the monarch, minister, assistant and guide matched formula can exert the characteristics of all medicines, and the improvement of mitochondrial energy also needs the reasonable combination of multiple mitochondrial function repairing medicines (monarch, minister, assistant and guide). The mitochondrial energy medicinal composition obtained by combining the appropriate mitochondrial function repairing medicaments can best ensure the multi-target repairing of the mitochondrial function and realize the effect of finally inhibiting the growth of cancer cells.
Hormones are also important for mitochondrial repair. Hormones are used as messengers in vivo to transmit information, play an important role in regulating physiological processes of organisms and are important substances in life. Recent studies have found that hormones play a crucial role in the development of cancer. Hormone supplementation or reduction is also known as cancer endocrine therapy, and the hormone is used for building the level of mitochondria so as to better play the anticancer role.
Therefore, the pharmaceutical composition of the present invention performs mitochondrial construction through three levels to recover and increase mitochondrial energy.
First, the pharmaceutical composition of the present invention has Se, MLT and pre (dhea) as the inner ring of the composition, which is the main active ingredient of the pharmaceutical composition of the present invention.
Se is an indispensable trace element for human bodies. Se can synthesize thyroxine, thereby regulating metabolism and maintaining relatively stable internal environment. Se can also prevent the formation of peroxides and free radicals, block the metabolism of cancer cells, and inhibit the division and growth of cancer cells. The trace element Se has obvious prevention and treatment effects on various cancers such as liver cancer, breast cancer, ovarian cancer, gastric cancer, colon cancer, rectal cancer, prostate cancer, lung cancer and the like, and the occurrence and development of the cancers are related to the insufficient intake of Se. On one hand, Se has antioxidant activity, and the Se compound can relieve ROS-mediated mitochondrial dysfunction through an Nrf2 signal channel, improve the mitochondrial function of normal cells and has certain effect of preventing cancers. Se can also limit the effects of hypoxia on mitochondrial complexes by normalizing I and IV complex levels and significantly increasing the activity of II and III complexes. These effects may be associated with the modulation of binding of Akt and cAMP response elements. It is also found that Se compound can induce the MGC-803 cell of gastric cancer cell to stop in the cell cycle of G2/M phase, so as to show obvious inhibition effect on the proliferation of cancer cell. On the other hand, Se has a direct killing effect on cancer cells, and recent researches show that Se gradually destroys the mitochondrial membrane potential of liver cancer HepG2 cells, and finally leads to cancer cell apoptosis by triggering Bax-and Bcl-2-mediated mitochondrial apoptosis pathways.
MLT is an amine hormone mainly secreted by pineal body, and has multiple physiological functions of regulating day and night regularity, resisting aging, resisting oxidation, resisting inflammation, regulating immunity and the like. MLT is also an effective natural antioxidant and anti-inflammatory agent that can protect against the toxic side effects of radiation and chemotherapy. MLT increases mitochondrial function and autophagy by increasing the expression of SIRT1 and LC3 and ATP content, reduces ROS levels and TAC increases in damaged cells, can rescue mitochondria from oxidative stress-induced mitochondrial dysfunction, and prevents subsequent cell death, thereby ensuring normal cell function. Meanwhile, MLT increases the membrane potential and membrane fluidity of mitochondria, reduces the permeability of mitochondria and maintains the stability of mitochondrial membranes by increasing the generation activity of an electron transfer system and ATP. In cancer cells, MLT promotes cancer cell apoptosis by modulating several apoptotic mediators, such as Bax, Bcl-2, endogenous ROS, and apoptotic receptors. By increasing the activity of mitochondrial complex I, the generation of ROS and the expression of cyt-c in cell nucleus are increased, and cancer cell apoptosis is caused by triggering Bax and Bcl-2 mediated mitochondrial apoptosis pathways.
PRE is an important intermediate for the synthesis of steroids such as progesterone, finasteride and DHEA. Mitochondria are important sites of steroid hormone biosynthesis. Cholesterol is metabolized into steroid steroids such as PRE and the like which are necessary for human bodies in mitochondria, the stability of membranes is maintained, and a material basis is provided for the growth and development of organisms. Likewise, mitochondrial cholesterol levels can affect mitochondrial function. Decreased mitochondrial PRE synthesis in cancer cells leads to physiological upregulation of steroidogenic enzymes, resulting in decreased mitochondrial cholesterol levels and a concomitant decrease in mitochondrial membrane stability.
There is literature emphasizing that a variety of nutrients are critical to mitochondrial function, including Se, MLT, and optimizing their availability is expected to improve clinical outcome in critically ill diseases. These nutrients together with mitochondria form a complex network. The bioenergetic function of the mitochondria will be optimal when the substrates and cofactors in the network are present in the optimal combination. Due to the synergistic effect of many nutrients in the metabolic pathway, supplementation of only one nutrient may not improve downstream effects in the absence of another micronutrient. Therefore, the invention combines Se, MLT and PRE (DHEA) for application, can more effectively improve the whole mitochondrial network, increase the antioxidant effect from different approaches, increase the stability of mitochondrial membranes and inhibit the generation of cancer cells. These active ingredients are important nutrients for the mitochondria to support and protect against oxidative stress.
Secondly, the pharmaceutical composition takes Q10, LA and GSH as intermediate links of the composition to play a further strengthening role.
Q10 has two main functions in vivo, one is important in the process of converting nutrients into energy in mitochondria, and the other is obvious in lipid peroxidation resistance. It is an energy converter in the mitochondria of cells, and participates in the "tricarboxylic acid cycle" by transferring and transferring electrons to produce ATP (adenosine triphosphate), an energy factor, for use in cellular metabolism.
LA is a coenzyme present in mitochondria, like vitamins, and eliminates free radicals that accelerate aging and cause disease. LA enters cells after being absorbed by intestinal tracts in vivo, has the characteristics of fat solubility and water solubility, can pass through the whole body without hindrance and reaches any cell part, provides comprehensive efficacy for a human body, and is a universal antioxidant. As a coenzyme, LA has an important role in the metabolism of glucose in energy-producing cells. It plays a major role in activating cells, also known as antioxidant substances. Unlike other antioxidants, LA has a special task in vivo, but is a free radical, which can replace the work in time when other antioxidants are in shortage, has 400 times of antioxidant effect of vitamin C and E, and can enhance the action of other antioxidants if being compounded with other antioxidant factors in vivo such as CoQ10 and vitamin C, E, and the acting force of LA is longer than that of other antioxidants, and is water-soluble and fat-soluble, so that the LA can operate in vivo more efficiently.
GSH is a specific substance for detoxification, is a small molecular peptide consisting of three amino acids, is used as an important antioxidant and a free radical scavenger in vivo, and is combined with free radicals, heavy metals and the like, so that harmful toxicants in the body are converted into harmless substances to be excreted out of the body. GSH plays an important role in the biochemical defense system of the human body and has various physiological functions. Its main physiological action is to scavenge free radicals in human body, and it is used as an important antioxidant in human body to protect mercapto-SH in molecules of many proteins and enzymes. GSH combined with LA can maintain-SH in reduced state and maintain enzyme activity, and can convert oxidized GSH into reduced GSH to generate hydrogen peroxide (H) by metabolism2O2) And (4) reducing. Therefore, the combination of GSH and LA and Q10 can improve the efficacy and enhance the protection effect on mitochondria. The combination of the three components can continuously strengthen the effect of resisting external toxin and oxidation pressure, and simultaneously can mobilize autoimmunity to resistThe oxidation pressure.
Finally, the present invention adds bifidobacteria to the pharmaceutical composition as an external adjunct.
Bifidobacterium is a probiotic bacterium existing in human bodies, changes in quantity with the increase of human ages, and has been reported to have the following therapeutic effects: 1. maintain the balance of the growth and high flora, inhibit the growth of pathogenic bacteria and prevent and treat gastrointestinal diseases; 2. the intestinal tract is assisted to synthesize amino acid and vitamin, and the absorption of calcium ions is improved; 3. enhancing immunity and activating immunocyte function. The immunoregulation effect is closely related to the regulation of the mitochondrial function, and researches report that bifidobacterium can activate macrophages by improving the membrane potential of mitochondria so as to exert the phagocytic activity of the macrophages.
Drawings
Figure 1 is the results of the effect of each single drug group on tumor volume.
Fig. 2 is a result of the influence of each drug composition group on tumor volume.
Figure 3 is the effect of different dosing times of a single drug on tumor volume.
Figure 4 is the results of the effect of each single drug group on ATP levels in tumor tissues.
Fig. 5 shows the effect of each drug composition group on ATP levels in tumor tissues.
Figure 6 is the results of the effect of each single drug group on mitochondrial complex activity in tumor tissues.
FIG. 7 is a graph of the variation of immune cells in tumor tissue for each single drug group.
FIG. 8 shows the variation of immune cells in tumor tissues for each of the pharmaceutical composition groups.
Detailed Description
The following examples further describe embodiments of the present invention. The following examples are only for illustrating the technical solutions of the present invention more clearly, and do not limit the scope of the present invention. Various changes, modifications, substitutions and alterations to these embodiments will be apparent to those skilled in the art without departing from the principles and spirit of this invention.
Example 1.
Weighing raw materials including PRE 12.5g, MLT 1.5g, Se 0.1g, LA 75g, GSH 300g, Q1075 g, and Bacillus bifidus 5 × 109And CFU, adding the balance of corn starch, crystalline cellulose, lactose, magnesium stearate and polyvinylpyrrolidone as carriers according to a conventional capsule production process, mixing and granulating, and filling into gelatin hard capsules to obtain 2000 capsules, wherein the content of each capsule is 0.5 g.
Example 2.
Taking 12.5g of PRE, 1.25g of MLT, 0.05g of Se, 75g of LA, 112.5g of GSH, 7.5g of Q1037 and 2.5 multiplied by 10 of bifidobacterium as raw materials based on 2000 tablets9And (3) mixing the CFU with the balance of corn starch, crystalline cellulose, lactose, carboxymethyl cellulose and magnesium stearate according to a conventional tablet production process, adding a polyvinylpyrrolidone aqueous solution as an adhesive for granulation, finally adding talcum powder as a lubricant, and tabletting to obtain 2000 tablets, wherein each tablet is 0.25 g.
Example 3: effect of pharmaceutical composition on tumor volume.
The experimental animals were C57BL/6J mice, 4 week old males, randomized into tumor-bearing control, DDP and several drug groups, 3 per group. The experimental period was 4 weeks.
The drug groups are further specifically divided into single drug groups and drug composition groups.
Wherein the single drug components are PRE group, MLT group, LA group, GSH group and Q10 group 5.
The medicine composition group comprises 9 groups including a Se + PRE group, a Se + MLT group, a PRE + MLT group, a Q10+ GSH group, a Q10+ LA group, a GSH + LA group, a Se + PRE + MLT group, a Q10+ LA + GSH group and a medicine composition group (7 Drugs) of the invention.
The experiment was performed 10 days earlier, and each drug group was fed to mice by blending each single drug or drug combination in the feed until the end of the 4-week experiment.
The administration dose of each drug group was calculated according to the conversion formula of the administration dose of mice and humans, wherein PRE was 7.6mg/kg and MLT was 076mg/kg, 91mg/kg LA, 273mg/kg GSH, 45.5mg/kg Q10, 30.3 mug/kg Se, 1.5 x 10 bifidobacteria6CFU/kg. The dosage of each pharmaceutical composition group is the cumulative amount of each single dosage.
After mice in the tumor-bearing control group, DDP group and each drug group are fed with the respective feed for 10 days continuously, LLC cells (lung cancer cells of mice) are used for making Lewis lung cancer model, 3 multiplied by 105cells/mouse, injected subcutaneously.
After modeling, the DDP group was subjected to drug intervention with cisplatin (DDP), 1mg/ml, i.p. injection, 1 week for 3 times, until the end of the experiment.
After the experiment is finished, mice in each experimental group are killed by dislocation of spinal cords, subcutaneous tumor tissues of the mice are peeled, the tumor volume is measured, and the data are sorted and analyzed.
The results of comparing the tumor volumes of the mice of the experimental groups are shown in FIGS. 1 and 2. In the figure, x:p＜0.01；****：p＜0.0001。
as can be seen from fig. 1, the tumor volumes of the 5 single-drug groups were smaller than those of the tumor-bearing control group, with the PRE group having the most significant effect. Except for group Q10, the tumor volume of each single drug group was smaller than that of the DDP group. Proves that each single drug has the inhibiting effect on the growth of cancer cells.
As can be seen from fig. 2, the tumor volume inhibition effect of the drug composition group of the present invention is most significant compared to the tumor-bearing control group (p< 0.0001), and significantly better than the DDP group. The inhibition effect of the Se + MLT group, the PRE + MLT group and the GSH + LA group is better than that of the DDP group, the inhibition effect of the Se + PRE group, the Q10+ GSH group and the Q10+ LA group is basically equivalent to that of the DDP group, and the inhibition effect of the Se + PRE + MLT group and the Q10+ LA + GSH group is not as good as that of the DDP group.
From the inhibition effect of the drug combination groups on the growth of cancer cells, the drug combination groups have different degrees of inhibition effect on the growth of cancer cells, and the drug combination groups have the best tumor inhibition effect. The tumor inhibition effect of the two-drug combination group is good or bad, even slightly superior to that of the three-drug combination group, which indicates that the drug combination selection aiming at the recovery of the mitochondrial function is not simple superposition. Since mitochondria are an indispensable link for various vital activities, mitochondria have different targets in terms of oxidative stress resistance, hormone application, and biosynthetic metabolism. Mitochondrial repair at a single or very distinct target may not be able to reverse mitochondrial damage and may even be antagonistic. Therefore, the treatment for mitochondria must be a comprehensive integrated treatment, and simultaneously meet the energy production requirement, the anti-oxidation requirement, the positive hormone output and the biosynthesis requirement, reconstruct the energy metabolism environment of the organism and improve the micro-ecology of the whole body, thereby playing the role of achieving twice the result with half the effort.
Example 4: effect of different administration times of a single drug on tumor volume.
The experimental animals were C57BL/6J mice, 4-week-old males, randomly divided into tumor-bearing control group, PRE group, MLT group, GSH group and Q10 group, 4 single drug groups, and 3 animals per group. The experimental period was 3 weeks.
The experiment adopts a drug administration mode after tumor formation. The LLC cells (mouse lung cancer cells) are used for producing Lewis lung cancer models of mice of each experimental group, namely 3 multiplied by 105cells/mouse, injected subcutaneously.
One week after molding, the single drug groups were fed to mice with each single drug in the feed until the end of the experiment. The dose of each single drug group was the same as in example 3.
After the experiment is finished, mice in each experimental group are killed by dislocation of spinal cords, subcutaneous tumor tissues of the mice are peeled, the tumor volume is measured, and the data are sorted and analyzed.
The results of comparing the tumor volumes of the mice in the experimental groups are shown in FIG. 3. In the figure, x:pless than 0.05; ns: no statistical differences occurred.
As can be seen from fig. 3, GSH, MLT and PRE contributed to the inhibition of cancer cell growth and decreased tumor volume in each drug group given a single drug 1 week after tumorigenesis compared to the tumor-bearing control group, but tumor volume was significantly increased after Q10 was administered. The above experimental results show that the same drug used in different stages of tumorigenesis leads to different results, and it is clear that the mitochondrial function-restoring drug exerts different effects in different stages of cancer cells.
Example 5: effect of pharmaceutical composition on ATP level of tumor tissue.
The specific experimental procedure was the same as in example 3.
After the experiment is finished, the subcutaneous tumor tissue of the mouse is stripped, necrotic tissue is removed, and the tumor tissue is homogenized to prepare single cell suspension of cancer cells. And respectively using an ATP detection kit and mitochondrial complex I, II, III and IV activity detection kits to detect the mitochondrial productivity and 4 mitochondrial complex activities in the mouse cancer cells, and sorting and analyzing the collected data.
The results of comparison of ATP levels in tumor tissues of mice in each experimental group are shown in FIGS. 4 and 5. In the figure, x:p＜0.05；**：p＜0.01；****：p＜0.0001。
as can be seen from fig. 4, the ATP levels of tumor tissues of the 5 single-drug groups were higher than those of the tumor-bearing control group, while the ATP levels of tumor tissues of the DDP group were lower than those of the tumor-bearing control group. The above conclusion shows that the mechanism of tumor volume inhibition by each single mitochondrial function recovery drug is different from that of DDP, which can inhibit tumor volume but kill all rapidly proliferating cells (including mucosa and sperm cells) in a destructive manner, so that the immunity level of the organism is also reduced; the single mitochondrial function restoring drug achieves the purposes of inhibiting the occurrence and development of tumors by restoring mitochondrial functions, and simultaneously rebuilds the internal environment of an organism so as to eliminate the microenvironment suitable for the growth of the tumors and prevent cancers.
Fig. 5 also shows that the tumor tissue ATP level of each pharmaceutical composition group is higher than that of DDP group, further demonstrating the mitochondrial repair effect of the mitochondrial function restoration drug. However, the difference was observed in comparison with the tumor-bearing control group, wherein only the PRE + MLT group, GSH + LA group and the pharmaceutical composition group of the present invention were higher than the tumor-bearing control group, the Se + PRE group and Q10+ LA group were slightly lower, and the other combinations including the Se + MLT group, Q10+ GSH group, Se + PRE + MLT group and Q10+ LA + GSH group were significantly lower than the tumor-bearing control group.
From the above conclusions, it is demonstrated that not any combination of the individual drugs can increase ATP levels, possibly even producing antagonism, in comparison to the effect of the individual drugs on ATP level increase in fig. 4. For example, the increased ATP levels of MLT in fig. 4 were most significant, but their ATP levels were significantly lower for the two-drug combination with Se, and for the three-drug combination of Se and PRE than for the tumor-bearing control group. Similarly, the ATP levels of other combinations are lower than those of the tumor-bearing control group, and the ATP improvement levels of the single drugs are higher than those of the tumor-bearing control group, so that the synergistic effect on the restoration of the mitochondrial function is proved by not any combination.
Furthermore, this example also examined the activity of mitochondrial complexes in tumor tissues. It should be noted that, since the tumor growth of the mice in the drug composition group is very slow and the tumor volume is very small, as can be seen from fig. 2, only 20-30% of the tumor-bearing control group has insufficient material for further study, and therefore, only the complex activity study of a single drug is performed.
The results in fig. 6 show that a single drug acts on different complexes of mitochondria. For example, MLT and Q10 can increase the activity of complex I, but PRE and LA decrease the activity of complex I instead. For complex II, LA had a significant enhancement, but PRE, MLT and Q10 reduced its activity. The target of action of GSH may be in complex III, while for complex IV, all single drugs have the effect of raising their levels. The results further verify that the treatment for repairing mitochondrial functions is not simple superposition of various mitochondrial function repairing drugs, and a single drug or a simple combination of two drugs is not enough to completely repair mitochondrial functions, so that a mitochondrial energy drug composition with a synergistic effect needs to be completely screened.
Example 6: effect of pharmaceutical composition on the proportion of tumor tissue immune cells.
The single cell suspensions of the cancer cells prepared in example 5 were analyzed by flow cytometry for changes in the proportions of the immune cells (M, T, B, DC, NK) in the tumor tissues of mice, and the data were sorted and analyzed. The specific results are shown in fig. 7 and 8.
Compared with a tumor-bearing control group, the modeling mouse given the pharmaceutical composition in advance has the advantages that the DC cell proportion in tumor tissues is obviously increased, and NK cells are also improved; in contrast, in the DDP group, although DC cells were increased, the NK cell ratio was decreased.
The DC cell is an important efficient professional antigen presenting cell for stimulating immune response mediated by B and T lymphocytes, and can actively take a series of different antigen substances; NK cells can recognize and kill target cells and are an important immune factor for resisting cancers and infection of the body. According to the experimental result, the chemotherapeutic drug kills cancer cells by directly acting on the cancer cells, but the conditioning immunity of the chemotherapeutic drug is weaker, the proliferation of NK cells is inhibited, and the capability of the body of killing the cancer cells by self is reduced. The medicine composition greatly improves the proportion of DC cells by an autoimmune regulation mode, and up-regulates the antigen presenting capacity to resist the immune escape capacity of cancer cells. Moreover, the NK cell ratio is moderately increased, and the effect of killing cancer cells is achieved. Therefore, the pharmaceutical composition of the invention achieves the effect of resisting cancer cells by regulating autoimmunity.
The experimental results of the above examples 3-6 show that, in the early administration experiment of the single drug group, pre (dhea), LA, GSH, MLT, and Q10 all can significantly reduce the tumor volume of mice and significantly increase the ATP level of mice, compared with the tumor-bearing control group, wherein the complex I level of MLT and Q10 is significantly increased, the complex II level of LA is significantly increased, the complex III level of GSH is significantly increased, and each single drug can significantly increase the complex IV level, which suggests that these drugs can reestablish mitochondrial function. Further analyzing the change of the proportion of the immune cells M, T, B, NK in the tumor tissues of the mice, the results show that PRE (DHEA), LA, GSH and Q10 can all improve the proportion of T, B, NK cells, and MLT can improve the proportion of T, B cells. The above results suggest that these drugs can significantly increase the proportion of immune cells in the cancer cell microenvironment, thereby exerting an effect against cancer cells.
Furthermore, in the experiment of early administration of the pharmaceutical composition, the tumor volume of mice in all the pharmaceutical composition groups is obviously reduced compared with the tumor-bearing control group, wherein PRE + MLT and the pharmaceutical composition of the invention are most obvious. From the ATP level, the ATP levels of PRE + MLT, GSH + LA and the pharmaceutical composition of the present invention were higher than those of the tumor-bearing control group. From the flow cytometry results, the PRE + MLT and DC cell changes of the pharmaceutical compositions of the present invention were most pronounced.
Therefore, although there are two or three drugs combined individually to have similar tumor volume effect, from the viewpoint of immunoassay, the pharmaceutical composition of the present invention is most effective for the regulation of immune system function, especially for the improvement of DC cells, i.e. antigen presentation ability. Antigen presentation is the initiation of immune system activation and is the target against cancer cells.
Claims (3)
1. A pharmaceutical composition for preventing cancer occurrence by targeting mitochondria is prepared from pregnenolone 12.5g, melatonin 1.5g, selenium 0.1g, thioctic acid 75g, reduced glutathione 300g, coenzyme Q1075 g and Bacillus bifidus 5 × 109CFU is a raw material medicine, and is prepared by adding the balance of corn starch, crystalline cellulose, lactose, magnesium stearate and polyvinylpyrrolidone into the raw material medicine according to a conventional capsule production process, mixing and granulating the raw material medicine, and filling the mixture into a gelatin hard capsule, wherein the content of each capsule is 0.5 g.
2. A pharmaceutical composition for preventing cancer occurrence by targeting mitochondria comprises pregnenolone 12.5g, melatonin 1.25g, selenium 0.05g, thioctic acid 75g, reduced glutathione 112.5g, coenzyme Q1037.5 g and Bacillus bifidus 2.5 × 109And CFU is used as a raw material medicine, and is mixed with the balance of corn starch, crystalline cellulose, lactose, carboxymethyl cellulose and magnesium stearate according to a conventional tablet production process, a polyvinylpyrrolidone aqueous solution is added as an adhesive to granulate, and finally, talcum powder is added as a lubricant to perform tabletting to obtain 0.25g of the compound tablet.
3. Use of the pharmaceutical composition of claim 1 or 2 for the preparation of a medicament for preventing lung cancer caused by mitochondrial damage or mitochondrial dysfunction.
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