CN113786491B - An anti-tumor combined preparation containing tetrandrine, dihydroquercetin or quercetin - Google Patents
An anti-tumor combined preparation containing tetrandrine, dihydroquercetin or quercetin Download PDFInfo
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention relates to an anti-tumor combined preparation containing tetrandrine, dihydroquercetin or quercetin. The composition of tetrandrine and dihydroquercetin or quercetin and related salts thereof also comprise a targeting drug, wherein the targeting drug is oxitinib or a drug with similar action to the oxitinib. The tumor is preferably non-small cell lung cancer. The combined preparation of the invention has obvious functions of synergism and drug resistance reversion for the oxitinib.
Description
Technical Field
The invention belongs to the technical field of biological pharmacy, and particularly relates to an anti-tumor combined preparation containing tetrandrine, dihydroquercetin or quercetin.
Background
Tetrandrine (TET), also called tetrandrine, is derived from traditional Chinese medicines such as tetrandrine and has various pharmacological activities. In 1970 s, tetrandrine was marketed in China as an antihypertensive drug, and was found to have excellent silicosis-treating activity and to be widely used clinically. In 1992, he Qiyang and the like firstly found that tetrandrine can reverse the drug resistance of CHO cells to the antitumor drug doxorubicin, and later deeply researched and found that human leukemia HL-60 drug-resistant cells are more sensitive to tetrandrine. Researches of other scholars find that the tetrandrine can block tumor cells in the G1 stage and enhance the activity of the targeted drug sorafenib on liver cancer.
Dihydroquercetin (DHQ), also known as taxifolin (taxifolin), is a natural product of flavonoids, and is present in various vegetable and plant traditional Chinese medicines, such as: larch, onion, etc. Dihydroquercetin has low toxicity to human body and has various pharmacological activities, such as: has strong antioxidant activity and strong antitumor effect, and has stronger effect of resisting liver injury than quercetin (QUERetin, QUE) with similar structure. In 2019, the european union approved for food antioxidants. At the end of 4 months in 2021, the national Wei Jian Committee approved dihydroquercetin as a new resource food raw material, and the daily dosage is not more than 100mg.
Lung cancer is the most common tumor with the highest mortality in the world, as is the case in our country. Of these, 80-85% of lung cancers are non-small cell lung cancers, and of these, epidermal Growth Factor Receptor (EGFR) mutations in approximately 30-40% of patients are suitable targets for targeted drug tyrosine kinase inhibitors. Oxitinib (OSI) is a third generation targeted drug against mutant EGFR, developed and marketed by asixican, england. At present, the drug is approved by the FDA and the drug administration in China as a second-line therapy, a first-line therapy and a post-operative adjuvant therapy for EGFR T790M mutation patients for the treatment of 3 indications, and is a most excellent targeted drug in the field of lung cancer treatment. Ametinib (ALM) is a third-generation targeted drug which is developed by Hoisen Biotechnology corporation in China and has similar activity to Ochitinib, and is approved by the drug administration in China as second-line treatment aiming at EGFR T790M mutation. .
Disclosure of Invention
The invention firstly relates to an anti-tumor combined preparation, which comprises the following components:
(1) A therapeutically effective amount of tetrandrine (TET) or a salt thereof;
(2) A therapeutically effective amount of a flavonol or flavanonol compound; preferably, the flavonol compound is Quercetin (QUE) or its related salt; the flavanonol compound is Dihydroquercetin (DHQ) or its related salt;
(3) A therapeutically effective amount of a tyrosine kinase inhibitor; preferably, the tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor; more preferably, the tyrosine kinase inhibitor is Oxitinib (OSI) or Amitinib (ALM);
and (4) necessary pharmaceutical excipients;
the tumor is lung tumor; preferably, the tumor is non-small cell lung cancer; more preferably, the tumor is tyrosine kinase inhibitor drug-resistant non-small cell lung cancer caused by EGFR mutation.
The invention also relates to an anti-tumor combined preparation, which comprises the following components in part by weight:
(1) A therapeutically effective amount of tetrandrine (TET) or a salt thereof;
(2) A therapeutically effective amount of a tyrosine kinase inhibitor; preferably, the tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor; more preferably, the tyrosine kinase inhibitor is Oxitinib (OSI) or Amitinib (ALM);
and (3) necessary pharmaceutical excipients;
the tumor is lung tumor; preferably, the tumor is non-small cell lung cancer; more preferably, the tumor is tyrosine kinase inhibitor drug-resistant non-small cell lung cancer caused by EGFR mutation.
The invention also relates to an anti-tumor combined preparation, which comprises the following components in part by weight:
(1) A therapeutically effective amount of a flavonol or flavanonol compound; preferably, the flavonol compound is Quercetin (QUE) or its related salt; the flavanonol compound is Dihydroquercetin (DHQ) or its related salt;
(2) A therapeutically effective amount of a tyrosine kinase inhibitor; preferably, the tyrosine kinase inhibitor is a third generation tyrosine kinase inhibitor; more preferably, the tyrosine kinase inhibitor is Oxitinib (OSI) or Amitinib (ALM);
and (3) necessary pharmaceutical excipients;
the tumor is lung tumor; preferably, the tumor is non-small cell lung cancer; more preferably, the tumor is a tyrosine kinase inhibitor drug-resistant non-small cell lung cancer caused by EGFR mutation.
The invention also relates to the application of tetrandrine (TET), quercetin (QUE) or Dihydroquercetin (DHQ) in preparing an anti-tumor combined preparation, wherein the anti-tumor combined preparation at least comprises a tyrosine kinase inhibitor; preferably, the tumor is non-small cell lung cancer; more preferably, the tumor is tyrosine kinase inhibitor drug-resistant non-small cell lung cancer caused by EGFR mutation.
The invention also relates to an anti-tumor combined preparation, which comprises the following components in part by weight:
(1) 1-80% of tetrandrine;
(2) 1-80% of dihydroquercetin by mass ratio;
(3) A mass effective amount of oxitinib;
and (4) necessary pharmaceutic adjuvants.
Preferably, in the preparation, the content of tetrandrine: dihydroquercetin: the mass ratio of the oxitinib is 10:10:1.
the invention has the beneficial effects that:
1) The drug resistance of the lung cancer cells to the oxitinib is the most common problem in clinical treatment, and the drug resistance can be obviously reversed by applying the composition disclosed by the invention, so that the incidence rate of the drug resistance is reduced.
2) Although the clinical treatment effect of the oxitinib is good, part of patients are not sensitive to the oxitinib, the composition provided by the invention has the possibility of improving the curative effect of the oxitinib treatment, reducing the side effect, shortening the treatment period and prolonging the service life of the lung cancer patients.
3) The composition has a certain anti-tumor effect, and has a certain synergistic effect on other targeted drugs or cytotoxic chemotherapy drugs. Besides the oxitinib, the composition has the potential to be synergistic with more targeted drugs so as to improve the curative effect and survival rate of tumor patients.
4) The tetrandrine and the dihydroquercetin of the composition are both from natural products of traditional Chinese medicines, have low toxicity and high activity, are beneficial to the precise antitumor application of related traditional Chinese medicines, and expand the clinical application range.
Drawings
FIG. 1 the use of tetrandrine or dihydroquercetin alone to enhance the proliferation inhibitory effect of oxitinib on non-H1975 cells.
Figure 2 the combination of tetrandrine and dihydroquercetin enhances the proliferation inhibitory effect of oxitinib on non-H1975 cells.
FIG. 3 the combination of tetrandrine and dihydroquercetin reverses the proliferation inhibitory effect of HCC827/OR anti-Ottitinib cells.
FIG. 4 the composition of tetrandrine and dihydroquercetin enhances the proliferation inhibitory effect of Almetinib on H1975 cells.
FIG. 5 the combination of tetrandrine and quercetin enhances the proliferation inhibitory effect of oxitinib on H1975 cells.
FIG. 6 the combination of tetrandrine and dihydroquercetin enhances the proliferation inhibition effect of oxitinib on NCI-H460 cells.
Figure 7 the composition of tetrandrine and dihydroquercetin enhances the anti-tumor effect of oxitinib in nude mice.
Detailed Description
Experimental materials
Oxitinib (S7297), tetrandrine (S2403), quercetin (S2347) and dihydroquercetin (S2366) were purchased from SELLECK Chemical company.
Amatinib (S8817) was purchased from SELLECK Chemical company.
EGFR wild type non-small cell lung cancer NCI-H460 cell and non-small cell lung cancer H1975 cell were purchased from the cell center of the institute of basic medicine of Chinese academy of medical sciences.
Non-small cell lung carcinoma HCC827/OR cells resistant to oxizetinib were gifted by doctor of Western university of transportation Dan Puyu.
RPMI-1640 medium (C11875500 BT), fetal bovine serum (# 10099-141), HBSS balanced salt buffer (# 14025-092), and 0.25% trypsin (# 25200-072) were all purchased from Saehmer Feishel technologies, inc.
A60 mm dish (430166) and a 96-well plate (3599) for cell culture were purchased from Corning. CCK-8 reagent (B34302) was purchased from Bimake, USA.
Example 1 Sinomenine or Dihydroquercetin alone enhances proliferation inhibitory Effect of oxitinib on non-Small cell Lung cancer H1975 cells 1.1CCK-8 method for detecting cell proliferation Rate Change
1) H1975 cells in logarithmic growth phase were digested with 0.0625% trypsin at 3X 10% 3 Density of individual/well was inoculated into 96-well plates and placed at 5% CO 2 Culturing in a constant-temperature moisturizing incubator at 37 ℃ for 24 hours;
2) Adding different concentrations of drug to treat the cells, and setting 3 multiple wells for each concentration;
3) After the drug treatment is carried out for 72h, 20 mu L of CCK-8 reagent is directly added into the cell culture solution, after the mixture is fully mixed, the 96-well plate is put back into the cell culture box again, and the incubation is continued for 1h;
4) The 96-well plate was placed on an microplate oscillator and shaken for 30s for thorough mixing, and the absorbance value (OD) was measured at a wavelength of 450nm by means of a microplate reader.
The cell survival rate of each group was calculated by the following formula, in which the cell survival rate of the control group was set to 100%. The calculation formula is as follows: cell survival (%) = (OD value-blank OD value of administration group)/(OD value of control group-blank OD value) x 100%.
1.2 results of the experiment
The combination of hanfangchin A (TET) with concentration (1,2 mu M) without obvious inhibition on cell proliferation and Oxitinib (OSI) can detect that TET has obvious effect of enhancing oxitinib, and the inhibition effect of oxitinib is increased along with the increase of TET concentration (figure 1). Similarly, dihydroquercetin (DHQ) with concentration (50, 100 mu M) without obvious inhibition effect on cell proliferation is selected to be used together with oxitinib, so that the synergistic effect is obvious, and especially the synergistic effect of the high-concentration 100nM OSI effect group is the most obvious. The results of this example show that: the single use of TET or DHQ can obviously improve the antitumor activity of the oxitinib.
Example 2 the combination of tetrandrine and dihydroquercetin enhances the proliferation inhibitory effect of oxitinib on non-small cell lung carcinoma H1975 cells
2.1 Experimental methods
The cell proliferation inhibitory effect after the action of the drug was examined by the CCK-8 method, which was the same as in example 1.
2.2 results of the experiment
From the results of fig. 2, it can be seen that: the single TET and DHQ medicines have no obvious inhibition effect on cell proliferation, but can obviously enhance OSI effect after being used together, and have concentration correlation. For example: the combination of 2 mu M TET and 100 mu M DHQ can reduce the cell survival rate of 100nM OSI from 47% to 19.3%, and has obvious synergistic effect.
Example 3 composition of tetrandrine and Dihydroquercetin Reversate the proliferation inhibition of HCC827/OR Hicitinib cells 3.1 Experimental methods
The cell proliferation inhibitory effect after the action of the drug was examined by the CCK-8 method, which was the same as in example 1.
3.2 results of the experiment
HCC827/OR resistant cells were strongly resistant to oxitinib, therefore, OSI concentrations of 0.1, 1 μ M were selected, and the effect of the composition alone (2 μ M TET +100 μ M DHQ) had almost no effect on cell survival, but significantly enhanced the OSI proliferation inhibitory effect (fig. 3). The composition is proved to have the effect of reversing the drug resistance of the oxitinib.
Example 4 composition of tetrandrine and Dihydroquercetin enhances the proliferation inhibitory effect of Almetinib on H1975 cells
Ametinib (ALM) is a third generation tyrosine kinase inhibitor with similar effects to oxitinib, and this example observes whether the composition enhances the proliferation inhibitory effect of ALM.
4.1 Experimental methods
The cell proliferation inhibitory effect after the action of the drug was examined by the CCK-8 method, which was the same as in example 1.
4.2 results of the experiment
The single action of Ametitinib on H1975 cells has a stronger inhibiting effect than that of Oxititinib, so that the combination of 1nM or 5nM low concentration with the composition can obviously reduce the cell survival rate and has concentration dependence (figure 4). For example: the cell survival rate of 1nM ALM can be reduced from 64% to 21.9% by the combination concentration (2 muM TET +100 muM DHQ), and the synergistic effect is very obvious.
Example 5 composition of tetrandrine and Quercetin enhances proliferation inhibitory Effect of oxitinib on H1975 cells
Quercetin (QUE) is a compound with similar chemical structure and efficacy to dihydroquercetin, and this experimental example observes whether the composition of tetrandrine and quercetin can enhance the proliferation inhibition effect of oxitinib.
5.1 Experimental methods
The cell proliferation inhibitory effect after the action of the drug was examined by the CCK-8 method, which was the same as in example 1.
5.3 results of the experiment
The single-drug inhibitory effect of quercetin is significantly stronger than that of dihydroquercetin, and in this example, 10, 20 μ M and TET were selected for combined use. As shown in FIG. 5, the composition of TET and QUE at each concentration clearly showed the growth inhibitory effect of OSI, and had a certain concentration dependence. In particular, the combined concentration (2. Mu.M TET + 20. Mu.M QUE) can reduce the single-acting cell survival rate of 10nM OSI to 46% to 14.4%, and the synergistic effect is very obvious.
Example 6A composition of tetrandrine and Dihydroquercetin enhances the proliferation inhibitory effect of Oxecitinib on NCI-H460 cells
While oxitinib is primarily used for the treatment of EGFR-mutated non-small cell lung cancer, this example shows whether this composition enhances the proliferation inhibition of EGFR wild-type NCI-H460 cells by oxitinib.
6.1 Experimental methods
The cell proliferation inhibitory effect after the drug action was examined by the CCK-8 method, which was the same as in example 1.
6.3 results of the experiment
The NCI-H460 cells were not OSI-sensitive, so higher concentrations of OSI were selected for use with the compositions. The results show that the composition has obvious synergistic effect and has concentration dependence, and especially the combined concentration (4 mu M TET +200 mu M DHQ) can reduce the cell survival rate of 0.1 mu M OSI from 99% to 26.7%, and the synergistic effect is obvious (figure 6).
Example 7 composition of tetrandrine and Dihydroquercetin enhances the anti-tumor effects of Oxecitinib in nude mice
To better evaluate the results of the in vivo effect of the composition, H1975 cells were inoculated into nude mice for tumor formation at a dose of 10mg/kg TET and 10mg/kg DHQ, and the tumor-inhibiting effect of the composition in combination with oxitinib in vivo was examined by administering the same dose.
7.1 Experimental materials
Oxitinib (S7297) and tetrandrine (S2403) were obtained from SELLECK chemical, dihydroquercetin was obtained from Jianwei Natural Biotech, inc., jilin province, and the source of H1975 cells was the same as in example 1.
Experimental animals: 18-22g female BALB/c nude mice: purchased from si Bei Fu (beijing) biotechnology limited, certification number: 110324211103078355.
experimental equipment: scalpel, big forceps, flat head scissors, flat head forceps, trocar, 1ml syringe, normal saline, collodion cotton, alcohol cotton ball, etc.
Preparing experimental medicines: 5mg of OSI is weighed and dissolved in 100 mul of ethanol to prepare 50mg/ml mother liquor, 3.2 mul of the mother liquor is added with 1596.8 mul of physiological saline each time and mixed evenly, and the dosage is 1mg/kg. 1.6mg of TET was suspended in 1.6ml of physiological saline at a dose of 10mg/kg. 10mg of DHQ is weighed and dissolved in 100 mul of ethanol to prepare a mother solution of 100mg/ml, 16 mul of the mother solution is added with 1584 mul of physiological saline each time and mixed evenly, and the dosage is 10mg/kg.
7.2 Experimental methods
Feeding nude mice in specific germ-free environment, and making the volume reach 1000mm when the mice are adapted to environment and recovered 3 The H1975 tumor mass of (1) was taken out of the body of the mouse and cut into 1mm with a sterilized scalpel 3 The small blocks were inoculated to the right forelimb of mice and randomly grouped, and 5 were kept in one group.
When the tumor mass had grown to a palpable extent (approximately after one week), the mice were marked and randomly grouped on the average by body weight and tumor size, and the solvent control group, OSI, TET, DHQ single drug group, and three drug combination groups were set and administered at a frequency of once every two days while weighing, and the tumor volume was estimated by measuring the major and minor diameters of the tumor with a vernier caliper, the volume = (major diameter × minor diameter 2) ÷ 2. The administration mode is intragastric administration, and 200 mu l of the medicine is administered.
Seven times after administration, animals were sacrificed, tumor masses were taken and weighed, and the tumor inhibition rate of each group, tumor inhibition rate (%) = (average tumor weight of control group-average tumor weight of administration group)/average tumor weight of control group x 100%, was calculated.
7.3 results of the experiment
According to the results of periodic measurements of the change in tumor volume (FIG. 7A), 1mg/kg OSI, 10mg/kg TET and 10mg/kg DHQ, when administered alone, all had some inhibitory effect, with OSI being the most significant. The combination of the three medicines shows obvious in-vivo tumor inhibition effect, and the tumor volume is hardly increased obviously. The last dose gave tumor weight results (fig. 7C, D), similar to volume change, OSI single drug inhibition was 52.8%, stronger than TET (33.7%) and DHQ (6.1%); the combined composition has the tumor inhibition rate of 86.6 percent and obvious synergistic effect. During the dosing period, we monitored the body weight changes of the mice, and the body weight changes of the mice of each group were not significantly different (fig. 7B), indicating that the toxicity of the composition was low.
Finally, it should be noted that the above embodiments are only used to help those skilled in the art understand the essence of the present invention, and are not used to limit the protection scope of the present invention.
Claims (3)
1. An anti-tumor combined preparation, which comprises:
(1) A therapeutically effective amount of tetrandrine or its related salts;
(2) A therapeutically effective amount of dihydroquercetin or a related salt thereof;
(3) A therapeutically effective amount of a tyrosine kinase inhibitor which is oxitinib or amitinib;
and (4) necessary pharmaceutical excipients;
the tumor is the oxitinib drug-resistant non-small cell lung cancer.
2. The combined preparation for resisting tumors according to claim 1, wherein the content of tetrandrine: dihydroquercetin: the mass ratio of the oxitinib is 10:10:1.
3. the application of tetrandrine and dihydroquercetin in preparing an anti-tumor combined preparation, wherein the anti-tumor combined preparation at least comprises a tyrosine kinase inhibitor which is oxitinib or amitinib; the tumor is the oxitinib drug-resistant non-small cell lung cancer.
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