CN113329745A - Pharmaceutical composition for effectively resisting malignant tumor and application thereof - Google Patents

Pharmaceutical composition for effectively resisting malignant tumor and application thereof Download PDF

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CN113329745A
CN113329745A CN201980089318.2A CN201980089318A CN113329745A CN 113329745 A CN113329745 A CN 113329745A CN 201980089318 A CN201980089318 A CN 201980089318A CN 113329745 A CN113329745 A CN 113329745A
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cancer
tumor
pharmaceutical composition
metformin
chlorpromazine
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宁志丰
李文静
刘复兴
吴基良
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Hubei University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract

The pharmaceutical composition comprises, by mole, 4-10 parts of metformin and 1-3 parts of chlorpromazine as active components, and has a synergistic anti-tumor effect. The metformin and chlorpromazine have good anti-tumor effect after combined application, the anti-tumor curative effect can be maximized through the drug synergistic effect of the metformin and chlorpromazine, and the metformin and chlorpromazine have high scientific research value and good application prospect.

Description

Pharmaceutical composition for effectively resisting malignant tumor and application thereof Technical Field
The invention relates to the technical field of cancer treatment methods, in particular to a pharmaceutical composition for effectively resisting malignant tumors and application thereof.
Background
Metformin is an oral hypoglycemic drug widely used clinically for treating type 2diabetes mellitus (T2 DM). Preclinical studies have shown that metformin can inhibit the proliferation and apoptosis of a variety of cancer cells in vitro and in vivo. Some retrospective studies and prospective trials have also demonstrated that metformin can reduce the morbidity and mortality of tumors. Clinical trials of metformin as an adjuvant anticancer agent are being widely conducted. The necessary summary of the existing research can provide a basis for developing more intensive research. Chlorpromazine belongs to the classical antipsychotic of the phenothiazines, the first phenothiazine antipsychotic discovered in 1950 when studying the structural modification of the phenothiazine antiallergic promethazine and opened the new era of psychiatric medication, in recent years phenothiazines were found to have a significant antimicrobial effect in addition to their antipsychotic activity, and phenothiazines have also been shown to destroy cancer cells and render them susceptible to chemotherapy, certainly phenothiazine being one of the most functional compounds from the biological activity point of view.
The potential anticancer mechanism of metformin is that metformin activates adenylate-activated protein kinase (AMPK) by liver kinase B1(liver kinase B1, LKB1), inhibits Protein Kinase B (PKB) and downstream rapamycin target protein (mTOR) pathway; the cell can also be blocked in G0/G1 phase by the down-regulation of cyclin D1 (cyclin D1) level by AMPK. Metformin reduces circulating levels of insulin and IGF-1, blocks the phosphatidylinositol-3 kinase (PI 3K)/Akt/mTOR and RAS/RAF/mitogen-activated protein kinase (MAPK) pathways associated with cell growth; induces apoptosis through the MAPK pathway and enhances the expression of growth inhibitory and DNA damage inducing gene 153 (GADD 153). In addition, the metformin can simultaneously regulate and control multiple miRNAs, and plays the biological functions of inhibiting the proliferation and invasion of cancer cells, promoting apoptosis and the like. Metformin also maintains cytotoxic T cell activity, degrading programmed cell death-ligand 1 (PD-L1). The potential anti-tumor mechanisms of chlorpromazine include apoptosis induction, efflux pump inhibition, angiogenesis inhibition and anti-cancer stem cell activity, the most important of which are the apoptosis induction process and the targeted tumor stem cell inhibition effect, such as DNA repair mechanism inhibition and signal transduction pathway inhibition, and the phenothiazine drugs inhibit the combination of calcium and calcium-dependent enzymes such as calmodulin. Many calcium-mediated signal transduction pathways may be disturbed, may lead to apoptosis and inhibition of proliferation, in addition to the direct DNA damage and cell membrane destabilization of phenothiazines, which may also target inhibition of the dominant gene PELP 1. The main mechanism of the metformin for inhibiting the tumor is to inhibit the tumor proliferation and invasion, and the chlorpromazine mainly induces the cell apoptosis and the tumor stem cells, so that the theory of the combined application of the two medicines has a synergistic effect.
Disclosure of Invention
In order to solve the problems in the background art, the present invention aims to provide a pharmaceutical composition effective against malignant tumors and an application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides a pharmaceutical composition for effectively resisting malignant tumors, which comprises the effective components of 100-400 parts of metformin and 1-10 parts of chlorpromazine in parts by mole.
Furthermore, the pharmaceutical composition is prepared by mixing the effective components and pharmaceutic adjuvants, and the dosage form of the pharmaceutical composition is oral preparation, injection or sustained-release preparation.
The invention also provides application of the pharmaceutical composition for effectively resisting malignant tumors in preparation of antitumor drugs.
Furthermore, the anti-tumor drug is a drug for treating lung adenocarcinoma, stomach cancer, lung squamous cancer, liver cancer, cervical cancer, breast cancer, esophageal cancer, colon cancer, pancreatic cancer, nasopharyngeal cancer, peritoneal cancer, mesothelioma, kidney cancer, bladder cancer, prostate cancer, urethral cancer, endometrial cancer, ovarian cancer, glioblastoma, bone tumor, fibrosarcoma, retinoblastoma, leukemia and lymphoma.
Furthermore, the anti-tumor drug is a drug capable of inhibiting tumor cell proliferation.
Furthermore, the anti-tumor drug is a drug capable of inhibiting proliferation and metastasis of tumor cell lines such As lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520, liver cancer cells HepG2, cervical cancer Hela, breast cancer MCF-7, esophageal cancer EC109, colon cancer LOVO, pancreatic cancer As-PC1, nasopharyngeal cancer CNE2, bladder cancer T24, renal cancer OS-RC-2, prostate cancer PC3, endometrial cancer KLE, ovarian cancer Hey, glioblastoma U87, bone tumor U2-OS, fibrosarcoma Ag104, retinoblastoma y79, leukemia NOMO-1, lymphoma Daudi and the like.
Furthermore, the anti-tumor drug is a drug capable of reducing the volume and weight of the tumor.
Compared with the prior art, the invention has the beneficial effects that:
the active components of the pharmaceutical composition with the synergistic anti-tumor effect provided by the invention consist of metformin and chlorpromazine, and can be used for preparing anti-tumor drugs. The invention discovers that the metformin and the chlorpromazine have good anti-tumor effect after combined application, can maximize the anti-tumor curative effect through the drug synergistic effect of the metformin and the chlorpromazine, and has high scientific research value and good application prospect.
The invention researches the inhibition effects of metformin and chlorpromazine on lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520, liver carcinoma cells HepG2, cervical carcinoma Hela, breast carcinoma MCF-7, esophageal carcinoma EC109, colon carcinoma LOVO, pancreatic carcinoma As-PC1, nasopharyngeal carcinoma CNE2, bladder carcinoma T24, renal carcinoma OS-RC-2, prostate carcinoma PC3, endometrial carcinoma KLE, ovarian carcinoma Hey, glioblastoma U87, bone tumor U2-OS, fibrosarcoma Ag104, retinoblastoma y79, leukemia NOMO-1 and lymphoma Daudi by respectively adopting an MTT method and a drug combined action index, and obtains the suitable mixing ratio and concentration of the metformin and the chlorpromazine. The result proves that the pharmaceutical composition provided by the invention has the obvious effects of inhibiting the proliferation of malignant tumor cells such as lung adenocarcinoma, gastric adenocarcinoma, lung squamous carcinoma, liver cancer and the like, and subcutaneous tumor formation of nude mice, and can be used for treating malignant tumors such as lung adenocarcinoma, gastric adenocarcinoma, lung squamous carcinoma, liver cancer and the like.
Drawings
FIG. 1 shows the inhibition of the proliferation of lung adenocarcinoma cells A549 by metformin alone, chlorpromazine alone, and a combination of metformin and chlorpromazine;
FIG. 2 shows the inhibition of AGS proliferation of gastric adenocarcinoma cells by metformin alone, chlorpromazine alone, and metformin and chlorpromazine in combination;
FIG. 3 shows the inhibition of proliferation of H520 squamous cell lung carcinoma cells by metformin alone, chlorpromazine alone, and metformin and chlorpromazine in combination;
FIG. 4 shows the inhibition of the proliferation of hepatoma cells HepG2 by metformin alone, chlorpromazine alone and metformin and chlorpromazine in combination.
FIG. 5 shows the inhibition of migration of A549 cells of lung adenocarcinoma cells by metformin alone, chlorpromazine alone, and metformin and chlorpromazine in combination
FIG. 6 shows the inhibition of the invasion capacity of lung adenocarcinoma cells A549 caused by the single administration of metformin, the single administration of chlorpromazine and the combined administration of metformin and chlorpromazine
Detailed Description
In order to make the technical means, the creation features, the achievement purposes and the effects of the invention easy to understand, the following description further explains how the invention is implemented by combining the attached drawings and the detailed implementation modes.
Example 1
The cell viability assay and the combined action index analysis of the pharmaceutical composition provided in this example
1. Material
The experimental lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520 and liver cancer cells HepG2 were obtained from Wuhan university cell bank, cultured in a culture medium containing 10% fetal calf serum (containing 100U/ml penicillin and streptomycin) at 37 ℃ in A5% CO2 incubator, and passaged once every 2-3 d.
2. Experimental methods
The metformin and chlorpromazine are mixed according to the molar parts (200): (1) in the embodiment, the metformin and the chlorpromazine are mixed according to the molar ratio of 200:1 for standby.
The influence of the test medicament on the proliferation of lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520 and liver cancer cells HepG2 is detected by an MTT experimental method.
(1) Inoculating cells: a culture solution containing 10% fetal calf serum is prepared into a single cell suspension, and 1000-10000 cells per well are inoculated to a 96-well plate, wherein the volume of each well is 100 ul. At 5% CO2The drug is administered after 24h of culture in a cell incubator.
(2) Preparing the medicine: 35.53mg of chlorpromazine hydrochloride is precisely weighed and dissolved in 10ml of PBS to prepare 10mmol/l stock solution. The dosing gradients were set at 0, 2.5, 5, 10, 20, 40 umol/l. Precisely weighing 16.56mg of metformin hydrochloride, dissolving in 10ml of PBS to prepare 1mol/l, and correspondingly setting administration gradients of 0, 0.5, 1, 2, 4 and 8 mmol/l. The combined administration concentration is the sum of the administration concentrations corresponding to separate administration gradients of chlorpromazine and metformin.
(3) Post-dose culture of cells: culturing for 2 days, namely 48h, as same as the common culture conditions.
(4) Color generation: after 2 days of incubation, 20 ul of MTT solution (5mg/ml in PBS) was added to each well. Incubation was continued for 4 hours, the culture was terminated, and the culture supernatant in the wells was carefully aspirated, after centrifugation was required for suspension cells, and the culture supernatant in the wells was aspirated. Add 150ul DMSO/well and shake for 10 minutes to fully melt the crystals.
(5) Color comparison: selecting 490nm wavelength, measuring the light absorption value of each well on an enzyme linked immunosorbent assay, recording the result, and drawing a cell growth curve by taking time as an abscissa and the light absorption value as an ordinate.
The MTT experimental method is adopted to detect the cell inhibition effect of the combined medicine, and the golden average method is used to judge whether the two medicines have synergistic effect.
for synergism or antagonism are recommended，as in Table 4.1：
Figure PCTCN2019116993-APPB-000001
Table 4.1：Symbols for Synergism and Ant agonism usinf CI analysis
3. Results of the experiment
The MTT method is respectively used for investigating the proliferation inhibition effects of metformin and chlorpromazine on lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520 and liver cancer cells HepG2, the results show that the metformin and chlorpromazine have good inhibition effects on lung adenocarcinoma cells A549 (figure 1), gastric adenocarcinoma cells AGS (figure 2), lung squamous carcinoma cells H520 (figure 3) and liver cancer cells HepG2 (figure 4), and further the proliferation inhibition effects of the combination of the metformin and the chlorpromazine on the lung adenocarcinoma cells A549, the gastric adenocarcinoma cells AGS, the lung squamous carcinoma cells H520 and the liver cancer cells HepG2 are investigated, and the drug interaction index CI is obtained through calculation. As a result, it was found that metformin (0, 0.5, 1, 2, 4, 8mmol/L) used in combination with chlorpromazine (0, 2.5, 5, 10, 20, 40. mu. mol/L) exhibited a synergistic inhibitory effect on lung adenocarcinoma cell A549, gastric adenocarcinoma cell AGS, lung squamous carcinoma cell H520 and liver cancer cell HepG2 at partial concentrations (FIGS. 1 to 4). The results of the drug combination effect index experiments are shown in tables 1 to 4.
TABLE 1 combination of drug combinations for Lung adenocarcinoma cells A549 combination index Table (CI)
Figure PCTCN2019116993-APPB-000002
Remarking: the superposition (CI is more than or equal to 0.9 and less than or equal to 1.1); synergistic (CI <0.9) antagonism (CI >1.1)
TABLE 2 combination of drug combinations for gastric adenocarcinoma cell AGS index Table (CI)
Figure PCTCN2019116993-APPB-000003
Remarking: the superposition (CI is more than or equal to 0.9 and less than or equal to 1.1); synergistic (CI <0.9) antagonism (CI >1.1)
TABLE 3 combination of drug combinations for Lung squamous carcinoma cell H520 index Table (CI)
Figure PCTCN2019116993-APPB-000004
Remarking: the superposition (CI is more than or equal to 0.9 and less than or equal to 1.1); synergistic (CI <0.9) antagonism (CI >1.1)
TABLE 4 Combined Effect index Table (CI) of drug combinations on hepatoma cells HepG2
Figure PCTCN2019116993-APPB-000005
Remarking: the superposition (CI is more than or equal to 0.9 and less than or equal to 1.1); synergistic (CI <0.9) antagonistic (CI >1.1) in tables 1 to 4, different concentrations of metformin and chlorpromazine were measured at a molar ratio of 200:1, exhibits a synergistic effect at most concentrations with a drug interaction index CI value of less than 0.9. Such as: the combination of 10mmol/L of metformin and 5 mu mol/L of chlorpromazine shows synergistic effect on the lung adenocarcinoma cells A549; the combination of metformin 5mmol/L + chlorpromazine 2.5 mu mol/L or metformin 1mmol/L + chlorpromazine 5 mu mol/L shows synergistic effect on gastric adenocarcinoma cells AGS. The combination at the remaining experimental concentrations showed a simple additive effect, or antagonism.
Example 2
The pharmaceutical composition provided in this example was tested in a nude mouse model of tumor transplantation:
1. BALB-C nude mice aged 24-28 days are 20, male, and the weight of the mice is 10.01 +/-0.73 g.
2. Culturing lung adenocarcinoma cells A549, digesting and collecting cells when the cells are in exponential growth stage, and preparing 2 x 10 with sterile normal saline7One cell/ml cell suspension was injected subcutaneously into the right underarm position of male nude mice, 0.2ml each. The condition of the mice was observed daily, the tumor length and length were measured, and administration was started when the subcutaneous tumor tissue grew to 1 × 1cm in size. 20 nude mice were randomly divided into 4 groups of 5 mice each. Respectively as follows: (1) control group: an equal amount of PBS solution; (2) metformin group: 100 mg/kg; (3) chlorpromazine group: 50 mg/kg; (4) 100mg/kg of metformin and 50mg/kg of chlorpromazine; 4 groups were administered by gavage once daily, and from the start of administration, the major diameter (a) and minor diameter (b) of subcutaneous tumors were measured once a week, and the volume (V ═ a × b) was calculated according to the formula22), the mean value of the tumor volume was calculated again, the mice were sacrificed after 2 consecutive weeks, the tumors were detached, non-tumor tissues were removed and weighed, and the tumor inhibition rate (%) was calculated as (1-mean tumor weight in experimental group/mean tumor weight in control group) × 100%, and the data statistics are shown in table 5.
TABLE 5 tumor volume and quality effects of combination on Lung adenocarcinoma A549 inoculated subcutaneous tumors
Group of Control group 1 Metformin hydrochloride Chlorpromazine group Metformin + chlorpromazine
Number of mice 5 5 5 5
Mouse weight (g) 24.62±0.43 24.98±0.51 24.61±0.48 24.31±0.51
Tumor volume before treatment (cm3) 0.55±0.01 0.54±0.01 0.52±0.01 0.56±0.02
Tumor volume after one week (cm3) 0.72±0.02 0.69±0.01 0.7±0.02 0.64±0.01
Tumor volume after two weeks (cm3) 1.33±0.01 1.07±0.03 1.12±0.01 0.88±0.02
Tumor weight (g) 0.76±0.03 0.53±0.02 0.67±0.01 0.35±0.01
Tumor inhibition Rate (%) / 61.2 43.5 84.9
As shown in table 5, when metformin was administered alone, the tumor inhibition rate of the transplanted tumor was 61.2%; when chlorpromazine is singly administered, the tumor inhibition rate of the transplanted tumor is 43.5 percent; when the metformin and the chlorpromazine are used together, the tumor inhibition rate of the transplanted tumor can reach 84.9 percent. Meanwhile, in a control group, a metformin group, a chlorpromazine group and metformin + chlorpromazine, the body weights of nude mice are respectively 24.62 +/-0.43, 24.98 +/-0.51, 24.61 +/-0.48 and 24.31 +/-0.51, and the results show that the body weight of the mice is not obviously reduced while the tumor volume and the tumor weight of the mice are obviously reduced in the combined drug group, which indicates that the combined drug has no obvious influence on the physiological state of the mice and has no toxic or side effect on experimental animals.
Finally, the above embodiments are only intended to illustrate the technical solution of the present invention and not to limit the same, and although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention, which should be covered by the claims of the present invention.

Claims (9)

  1. A pharmaceutical composition effective against malignant tumors, comprising: the effective components of the pharmaceutical composition comprise, by mole, 100-400 parts of metformin and 1-5 parts of chlorpromazine.
  2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is effective against a malignant tumor: the effective components of the pharmaceutical composition comprise 200-300 parts of metformin and 1-2 parts of chlorpromazine in terms of molar parts.
  3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is effective against a malignant tumor: the effective components of the pharmaceutical composition consist of 200 parts of metformin and 1 part of chlorpromazine in molar parts.
  4. A pharmaceutical composition effective against malignant tumors according to any one of claims 1 to 3, wherein: the pharmaceutical composition is prepared by mixing effective components and pharmaceutic adjuvants, and the dosage form of the pharmaceutical composition is oral preparation, injection or sustained release preparation.
  5. The use of the pharmaceutical composition according to claim 4 for treating malignant tumor.
  6. Use according to claim 5, characterized in that: the anti-tumor drug is a drug for treating lung adenocarcinoma, gastric adenocarcinoma, lung squamous carcinoma, liver cancer, cervical cancer, breast cancer, esophageal cancer, colon cancer, pancreatic cancer, nasopharyngeal cancer, peritoneal cancer, mesothelioma, kidney cancer, bladder cancer, prostate cancer, urethral cancer, endometrial cancer, ovarian cancer, malignant glioma, bone tumor, fibrosarcoma, retinoblastoma, leukemia and lymphoma.
  7. Use according to claim 5, characterized in that: the anti-tumor drug is a drug capable of inhibiting tumor cell proliferation and metastasis.
  8. Use according to claim 5, characterized in that: the anti-tumor drug is a drug capable of inhibiting proliferation of lung adenocarcinoma cells A549, gastric adenocarcinoma cells AGS, lung squamous carcinoma cells H520, liver cancer cells HepG2, cervical cancer Hela, breast cancer MCF-7, esophageal cancer EC109, colon cancer LOVO, pancreatic cancer As-PC1, nasopharyngeal cancer CNE2, bladder cancer T24, renal cancer OS-RC-2, prostate cancer PC3, endometrial cancer KLE, ovarian cancer Hey, glioblastoma U87, bone tumor U2-OS, fibrosarcoma Ag104, retinoblastoma y79, leukemia NOMO-1 and lymphoma Daudi.
  9. Use according to claim 5, characterized in that: the anti-tumor medicine is a medicine capable of reducing the volume and weight of a tumor.
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