CN110613713A - 3-hydroxyaminobenzoic acid and sorafenib combined medicine for treating tumor - Google Patents
3-hydroxyaminobenzoic acid and sorafenib combined medicine for treating tumor Download PDFInfo
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Abstract
The invention relates to a drug combination of 3-hydroxyaminobenzoic acid and sorafenib for treating tumors. Specifically, the present invention provides a composition comprising (a) a therapeutically effective amount of a first active ingredient, 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and (b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug. The first active ingredient and the second active ingredient can generate synergistic effect, enhance the effect of treating cancer, reduce the dosage of a single medicament and reduce the toxicity of the medicament.
Description
Technical Field
The invention relates to the field of medicines, in particular to a drug combination of 3-hydroxyaminobenzoic acid and sorafenib for treating tumors.
Background
Cancer is a very complex and fatal disease that is currently experiencing a significant health crisis in both developed and developing countries. By 2020, there will be more than 1500 million new cancer patients worldwide, which will have serious impact on society, economy and medical treatment in any country.
The clinical outcome of cancer treatment is generally disappointing, due in large part to the heterogeneity and complexity of this devastating disease. Traditional surgery and radiation therapy are used only for the treatment of localized diseases, while hormonal therapy, chemotherapy, immunotherapy and targeted therapy are used alone or in combination with other therapies. Over the years, single and combination therapies, including chemotherapy, have evolved as effective treatments. Of course, the clinical efficacy of combination therapy is not as good as expected, is generally more toxic, and is also limited by the inability of the drug components to achieve the desired spatio-temporal distribution in free molecular form, i.e., the delivery of the drug components to the correct location at the appropriate time. Unless effective drug carriers are used, inherent differences in physicochemical and pharmacokinetic properties between the drug components prevent this from happening. The emergence of tumor chemotherapy resistance or multidrug resistance has become a major challenge for tumor chemotherapy researchers. To address this inherent problem and to allow synergistic drugs to reach the same target cell to overcome efflux transporter-mediated multidrug resistance, an increasing number of researchers have been invested in this study.
Therefore, there is a need in the art to develop new drugs with improved antitumor effects and reduced side effects.
Disclosure of Invention
The invention aims to provide a combined medicine, which improves the anti-tumor effect and reduces the side effect.
In a first aspect of the invention, there is provided a composition comprising:
(a) a therapeutically effective amount of a first active ingredient, which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and
(b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug.
In another preferred embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.
In another preferred embodiment, the kinase inhibitor comprises a raf enzyme inhibitor.
In another preferred embodiment, the kinase inhibitor comprises a multi-target kinase inhibitor anticancer drug.
In another preferred embodiment, the first active ingredient is present in an amount ranging from 0.01% to 99.99% by weight of the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; preferably 10% to 99%; more preferably from 20% to 99%; more preferably 30 to 99%, still more preferably 40 to 99%.
In another preferred embodiment, the second active ingredient is present in an amount ranging from 0.01% to 99.99% by weight of the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; more preferably 1% to 90%; more preferably 1% to 80%; more preferably 1 to 70%, still more preferably 1 to 60%.
In another preferred embodiment, the weight ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-50: 0.5-15, preferably 1-30: 0.5 to 10, more preferably 1 to 20: 0.5-5, optimally 5-15: 0.5-5.
In another preferred embodiment, the molar ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-150: 1, preferably 1 to 100: 1, more preferably 1 to 70: 1, optimally 5-50: 1.
in another preferred embodiment, the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the kinase inhibitor anticancer drug is sorafenib tosylate.
In a second aspect of the invention, there is provided a pharmaceutical composition comprising a composition according to the first aspect of the invention; and a pharmaceutically acceptable carrier.
In a third aspect of the invention, there is provided a kit comprising:
(A) a first formulation comprising 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
(B) a second agent comprising a kinase inhibitor anticancer drug; and
(C) instructions for use.
In another preferred embodiment, the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the weight ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-50: 0.5-15, preferably 1-30: 0.5 to 10, more preferably 1 to 20: 0.5-5, optimally 5-15: 0.5-5.
In another preferred embodiment, the molar ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-150: 1, preferably 1 to 100: 1, more preferably 1 to 70: 1, optimally 5-50: 1.
in another preferred embodiment, the instructions specify that the first agent and the second agent are to be used in combination to prevent and/or treat cancer.
In another preferred embodiment, the first and second formulations are administered simultaneously, separately or sequentially in the prevention and/or treatment of cancer.
In another preferred embodiment, the first formulation and the second formulation are independent of each other.
In another preferred embodiment, the first and second formulations are combined.
In a fourth aspect of the invention, there is provided an active ingredient combination comprising the following components:
(1) a first active ingredient which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and
(2) a second active ingredient which is a kinase inhibitor anticancer drug.
In another preferred embodiment, at least one of the active ingredients in the active ingredient combination is independent.
In another preferred embodiment, the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
In another preferred embodiment, the weight ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-50: 0.5-15, preferably 1-30: 0.5 to 10, more preferably 1 to 20: 0.5-5, optimally 5-15: 0.5-5.
In another preferred embodiment, the molar ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-150: 1, preferably 1 to 100: 1, more preferably 1 to 70: 1, optimally 5-50: 1.
in a fifth aspect of the present invention, there is provided the use of a composition according to the first aspect of the present invention, or a pharmaceutical composition according to the second aspect of the present invention, or a kit according to the third aspect of the present invention, or a combination of active ingredients according to the fourth aspect of the present invention, for the manufacture of a medicament for the prevention and/or treatment of cancer.
In another preferred embodiment, the cancer is selected from the group consisting of: liver cancer, kidney cancer, leukemia.
In another preferred embodiment, the cancer is liver cancer.
In a sixth aspect of the invention, there is provided an in vitro non-therapeutic method of inhibiting the growth of cancer cells, said method comprising the steps of: contacting a cancer cell with a composition according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a combination of active ingredients according to the fourth aspect of the invention, to inhibit the growth of the cancer cell.
In a seventh aspect of the present invention, there is provided a method for preventing and/or treating cancer, said method comprising the steps of: administering to a subject in need thereof a composition according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention, or a kit according to the third aspect of the invention, or an active ingredient combination according to the fourth aspect of the invention.
In another preferred embodiment, the subject is a human or a non-human mammal.
Preferably, the subject is a human.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a schematic diagram of the mechanism of 3-HAA-enhanced sorafenib in treating liver cancer
FIG. 2 is a graph showing the inhibitory effect of sorafenib alone on hepatoma cells in example 1, wherein the time for treatment with sorafenib in a dose gradient experiment was 4 days (FIG. 2A) and the dose for treatment with sorafenib in a time gradient experiment was 20 μ M (FIG. 2B) in the IC50 assay, and the cell viability was measured by CCK 8.
FIG. 3 is a graph showing the inhibitory effect of 3-HAA alone on hepatoma cells in example 2, wherein the cell survival rate was measured by CCK8 in the IC50 assay at a dose-gradient experiment 3-HAA treatment time of 4 days (FIG. 3A) and a time-gradient experiment 3-HAA treatment dose of 100. mu.M (FIG. 3B).
FIG. 4 is a graph showing the synergistic inhibition of hepatoma cells by 3-HAA and sorafenib in example 3, wherein the treatment time of sorafenib and 3-HAA was 4 days in the IC50 assay, and the cell viability was measured by CCK 8.
FIG. 5 shows that 3-HAA and sorafenib cooperate to induce apoptosis of hepatoma cells in example 3, wherein the treatment time of sorafenib and 3-HAA in the apoptosis assay is 1 day.
FIG. 6 is a graph of the synergistic inhibition of 3-HAA and sorafenib on SMMC-7721 transplantable tumors from example 4, wherein FIG. 6A is the volume growth of the transplantable tumors; fig. 6B shows the weight of transplanted tumors in each group, P <0.05, P < 0.01.
FIG. 7 is the 3-HAA and sorafenib synergistic inhibition of PDX transplantable tumor in example 5, wherein FIG. 7A is the volume growth of the transplantable tumor in PDX model 1; FIG. 7B shows the volume growth of the transplanted tumor in PDX model 2.
Detailed Description
The present inventors have conducted extensive and intensive studies and have unexpectedly found that 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof and a kinase inhibitor anticancer drug act synergistically in preventing and/or treating cancer. The synergistic treatment effect is obviously better than that of the single use of the two drugs, and simultaneously, the dosage of the single drug is reduced, and the toxicity of the drug is reduced. On the basis of this, the present invention has been completed.
Term(s) for
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
As used herein, the term "pharmaceutically acceptable carrier" ingredient refers to a substance that is suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio.
The term "therapeutically effective amount," as used herein, refers to an amount that produces a function or activity in and is acceptable to humans and/or animals. It will be understood by those skilled in the art that the "therapeutically effective amount" may vary with the form of the pharmaceutical composition, the route of administration, the excipients used, the severity of the disease, and the combination with other drugs.
"prevention" and "treatment" as used herein include delaying and stopping the progression of the disease, or eliminating the disease, and do not require 100% inhibition, elimination, or reversal. In some embodiments, a composition or pharmaceutical composition of the invention prevents, reduces, inhibits and/or reverses cancer, e.g., by at least about 10%, at least about 30%, at least about 50%, or at least about 80%, as compared to levels observed in the absence of a composition or pharmaceutical composition of the invention.
A first active ingredient
In the present invention, the first active ingredient is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof. 3-hydroxyaminobenzoic acid (3-HAA) or a pharmaceutically acceptable salt thereof is an AKT and ERK pathway inhibitor. The AKT pathway inhibitor is an inhibitor that inhibits the AKT pathway by promoting DUSP6 expression and inhibiting PDK1 activity.
The 3-hydroxyaminobenzoic acid is a metabolic intermediate product of tryptophan, has a molecular weight of 153.1 and a molecular formula of C7H7NO3, and has the following structure:
as used herein, "3-hydroxyaminobenzoic acid" refers to 3-hydroxyaminobenzoic acid of formula, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components.
A second active ingredient
The second active ingredient of the invention is a kinase inhibitor anticancer drug.
In another preferred embodiment, the kinase inhibitor is a tyrosine kinase inhibitor.
In another preferred embodiment, the kinase inhibitor comprises a raf enzyme inhibitor.
In another preferred embodiment, the kinase inhibitor comprises a multi-target kinase inhibitor anticancer drug.
Preferably, the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof. More preferably, the kinase inhibitor anticancer drug is sorafenib tosylate.
As used herein, "sorafenib" refers to sorafenib, or a pharmaceutically acceptable salt thereof. It is to be understood that the term also includes mixtures of the above components.
Broad-spectrum tyrosine kinase sorafenib is a first-line chemotherapeutic drug for treating liver cancer, but the curative effect is not satisfactory, and clinical low response and acquired drug resistance are key factors causing treatment failure.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt formed by the compound of the present invention with an acid or a base, which is suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed by reacting a compound of the present invention with an acid. Suitable acids for forming the salts include, but are not limited to: inorganic acids such as toluenesulfonic acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and the like, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, and the like; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts is that formed from the compounds of the present invention and a base, suitable bases for forming salts include, but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine.
Composition, kit, active ingredient combination and pharmaceutical composition
The present invention provides a composition comprising:
(a) a therapeutically effective amount of a first active ingredient, which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and
(b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug.
In another preferred embodiment, the first active ingredient is present in an amount ranging from 0.01% to 99.99% by weight of the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; preferably 10% to 99%; more preferably from 20% to 99%; more preferably 30 to 99%, still more preferably 40 to 99%.
In another preferred embodiment, the second active ingredient is present in an amount ranging from 0.01% to 99.99% by weight of the total weight of the active ingredients of the composition; preferably 0.1% to 99.9%; more preferably 1% to 99%; more preferably 1% to 90%; more preferably 1% to 80%; more preferably 1 to 70%, still more preferably 1 to 60%.
In another preferred embodiment, the weight ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-50: 0.5-15, preferably 1-30: 0.5 to 10, more preferably 1 to 20: 0.5-5, optimally 5-15: 0.5-5.
In another preferred embodiment, the molar ratio of the 3-hydroxyaminobenzoic acid or the pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer drug is 1-150: 1, preferably 1 to 100: 1, more preferably 1 to 70: 1, optimally 5-50: 1.
if necessary, the composition can also comprise a pharmaceutically acceptable carrier to prepare a pharmaceutical composition (medicine).
Typically, the composition further comprises a pharmaceutically acceptable carrier to form a pharmaceutical composition, wherein the pharmaceutical composition comprises:
(a) a therapeutically effective amount of a first active ingredient which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
(b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug; and
(c) a pharmaceutically acceptable carrier.
The pharmaceutical composition containing the first active ingredient and the second active ingredient can be various dosage forms suitable for oral administration, and also can be various external administration preparations or other parenteral administration preparations. For example, the external administration preparation of the present invention may be further prepared by adding adjuvants such as surfactants, transdermal absorption enhancers, preservatives, solvents, antioxidants, humectants, pH regulators, colorants, fragrances, etc. (including but not limited to): liniment, tincture, oil, ointment, plaster, cataplasm, plaster, patch, plastics, membrane, gel, cataplasma, acupoint application agent, spray, aerosol, implant, emulsion, etc. For cancer, preferred dosage forms include: various dosage forms, implants and injections for oral administration.
It is to be understood that, in the present invention, the carrier is not particularly limited, and is a material commonly used in the art, and the kind, use method, and source thereof are well known to those skilled in the art.
Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.
In another preferred embodiment, in the pharmaceutical composition, the content ranges of the first active ingredient and the second active ingredient, and the mass of the first active ingredient and the second active ingredient are as described above in the composition.
The invention also provides an active ingredient composition, which comprises the following components in part by weight:
(a) a therapeutically effective amount of a first active ingredient, which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
(b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug.
In another preferred embodiment, in the pharmaceutical composition, the content ranges of the first active ingredient and the second active ingredient, and the mass of the first active ingredient and the second active ingredient are as described in the composition above.
The present invention also provides a kit comprising:
(A) a first formulation comprising 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
(B) a second agent comprising a kinase inhibitor anticancer drug; and
(C) instructions for use.
The instructions specify combining the first and second agents to prevent and/or treat cancer.
In combination with the first and second formulations in the kit of the present invention, the first and second formulations may be administered simultaneously, separately or sequentially.
The compositions, active ingredient combinations, pharmaceutical compositions, kits, foods and nutraceuticals of the present invention can be prepared using conventional methods and equipment.
Use and mode of administration
The invention provides a use of the composition, the active ingredient composition and the pharmaceutical composition in preparation of a medicament for preventing and/or treating cancer.
The composition, the active ingredient composition, the pharmaceutical composition and the first active ingredient and the second active ingredient in the kit can generate a synergistic effect on prevention and treatment of liver cancer, kidney cancer and leukemia, enhance the effect of treating cancer, reduce the dosage of a single medicament and reduce the toxicity of the medicament. Typically, a schematic diagram of the synergistic enhancement of the effect of 3-HAA and sorafenib on treating liver cancer is shown in FIG. 1.
Before, simultaneously with or after the use of the composition, the combination of active ingredients, the pharmaceutical composition and the kit according to the invention, other cancer-treating active substances (e.g. topolin, 5-fluorouracil, etc. anticancer active substances, imatinib mesylate), surgery or administration of radiotherapy against cancer, or in combination with gene therapy, or in combination with biological modulators, may be used in combination.
In the process of drug combination, the interaction of the drugs is divided into additive action, synergistic action and antagonistic action according to the effect of the drugs when the drugs are used together, the synergistic action means that the effect of the drugs when the drugs are used together is many times larger than that when the drugs are used alone, the additive action means that the effect of the drugs when the drugs are used together is equivalent to that when the drugs are used alone, and the antagonistic action means that the effect of the drugs when the drugs are used together is smaller than that when the drugs are used alone. In the present invention, it was first found that the combined use of a first active ingredient and a second active ingredient has a synergistic effect.
In inhibiting the growth of cancer cells or preventing and treating cancer, the administration mode of the present invention comprises administering the first active ingredient and the second active ingredient sequentially or simultaneously.
The pharmaceutical formulation is adapted to the mode of administration and, in using the pharmaceutical composition or formulation, a safe and effective amount of the drug is administered to the subject in need thereof (e.g., a human or non-human mammal), wherein the safe and effective daily dosage of the first active ingredient is generally at least about 0.1mg, and in most cases, no more than about 2000 mg. Preferably, the dose is 1mg to 500 mg; a safe and effective amount of the second active ingredient is generally at least about 0.01mg, and in most cases does not exceed 1500 mg. Preferably, the dosage range is 0.1mg to 1500 mg. (wherein the safe and effective amount of the first active ingredient will generally not exceed about 2000 mg/kg of body weight; preferably, the dose will be from about 100. mu.g/kg of body weight to about 1000 mg/kg of body weight; and the safe and effective amount of the second active ingredient will generally not exceed about 2000 mg/kg of body weight; preferably, the dose will be from about 10. mu.g/kg of body weight to about 1000 mg/kg of body weight.) of course, the specific dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner. When the first active ingredient and the second active ingredient are administered sequentially, the interval between the administrations is not particularly required. The compositions, active ingredient combinations, pharmaceutical compositions and kits of the present invention comprise a first active ingredient and a second active ingredient, each administered simultaneously or sequentially by the same or different routes, including but not limited to: oral administration, injection administration, intratumoral administration, implantation administration, intracavity administration, anal administration, transdermal administration and internal and external application;
preferred administration by injection includes: intravenous injection, intramuscular injection, subcutaneous injection, intracavity injection.
In vitro non-therapeutic method for inhibiting cancer cell growth
The present invention also provides an in vitro non-therapeutic method of inhibiting the growth of cancer cells, said method comprising the steps of: the growth of cancer cells is inhibited by contacting the cancer cells with a composition of the invention or a combination of the active ingredients.
Methods of preventing and/or treating cancer
The present invention also provides a method for preventing and/or treating cancer, the method comprising the steps of: administering to a subject in need thereof a composition, active ingredient combination, pharmaceutical composition or kit according to the invention.
In inhibiting the growth of cancer cells or preventing and treating cancer, the mode of administration of the present invention comprises administering the first active ingredient and the second active ingredient sequentially or simultaneously.
In another preferred embodiment, the subject is a human or a non-human mammal. Typically, the non-human mammal includes (but is not limited to): pets (e.g., dogs, cats), livestock (e.g., cattle, sheep, horses, pigs), various zoo animals (pandas, elephants, tigers), and the like.
The advantages of the invention mainly include:
1. in the combination, the first active ingredient and the second active ingredient can generate synergistic effect, enhance the effect of treating cancer, reduce the dosage of a single medicament and reduce the toxicity of the medicament.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Inhibition of hepatoma cells by sorafenib alone
Experimental methods
4 hepatoma cells (PLC8024, SMMC-7721, HepG2 and Hep3B) were treated with sorafenib in a dose gradient (doses: 0, 1.25, 2.5, 5, 10, 20 and 40. mu.M, respectively) and a time gradient (times: 0, 1, 2, 3 and 4 days, respectively), and the half inhibitory concentration (IC 50) of sorafenib on 4 hepatoma cells was calculated by CCK8 experiment.
Results of the experiment
As shown in fig. 2, IC50 of 4 hepatoma cells are: PLC 80248.4 μ M; 15.3 mu M of SMMC-7721; HepG2: 2.6. mu.M; hep3B: 3.2. mu.M. Wherein the response of PLC8024 and SMMC-7721 to sorafenib treatment is obviously lower than that of HepG2 and Hep 3B.
Example 2
Inhibition of hepatoma cells by 3-HAA alone
The half inhibitory concentration (50% Inhibition concentration, IC50) of 3-HAA (3-hydroxyaminobenzoic acid) against 4 hepatoma cells (PLC8024, SMMC-7721, HepG2 and Hep3B) was calculated by CCK8 experiment.
Results of the experiment
As shown in fig. 3, IC50 of 4 hepatoma cells are: PLC8024:147.7 μ M; SMMC-7721: 165.4. mu.M; HepG2: 73.2. mu.M; hep3B: 101.5. mu.M. Wherein the response of PLC8024 and SMMC-7721 to 3-HAA treatment is significantly lower than that of HepG2 and Hep 3B.
Example 3
3-HAA and sorafenib synergistic inhibition of hepatoma cells
Therefore, we hypothesized whether 3-HAA could serve as an adjunct to sorafenib, enhancing the therapeutic sensitivity of sorafenib. To address this guess, first
Experimental methods
The survival rate of SMMC-7721 and PLC8024 cells with low response when sorafenib alone or 3-HAA and sorafenib are used in combination is tested by a CCK8 experiment.
Results of the experiment
As can be seen in FIG. 4, 3-HAA can significantly enhance the therapeutic sensitivity of sorafenib. The IC50 of the combination of 3-HAA (30. mu.M), SMMC7721 and PLC8024 decreased from 14.5. mu.M and 8.1. mu.M to 4.9. mu.M and 2.4. mu.M, respectively. When 5 mu M of sorafenib is used alone, the cell survival rates of the two strains are respectively 88.4 +/-1.6 percent and 76.3 +/-4.7 percent, and after the two strains are combined with 50 mu M of 3-HAA, the cell survival rates of the two strains are respectively reduced to 43.8 +/-2.1 percent and 23.5 +/-2.3 percent. The apoptosis assay of figure 5 further demonstrates that the two in combination have a synergistic effect.
Example 4
3-HAA and sorafenib synergistic inhibition SMMC-7721 transplantable tumor
Experimental methods
Constructing a nude mouse transplantation tumor model of SMMC-7721 cells. 4 groups of transplanted tumor nude mice respectively serve as a control group (DMSO-fed), a 3-HAA-fed group (100mg/kg. day), a sorafenib-fed group (10mg/kg. day) and a 3-HAA and sorafenib combined-fed group (the dose of 3-HAA and sorafenib is 100mg/kg. day and 10mg/kg. day respectively), and the drug administration mode is intraperitoneal injection and daily drug administration. For 8 consecutive days.
Results of the experiment
As can be seen in FIG. 6, the combination of sorafenib and 3-HAA can exert synergistic inhibition of the growth of SMMC-7721 cell transplantable tumors without significant effect on tumor-bearing mouse body weight. When the Sorafenib of 10mg/Kg.day is injected into the abdominal cavity, the inhibition effect on the growth curve of Sorafenib low-response hepatoma cell tumor is not obvious, and when the Sorafenib low-response hepatoma cell tumor growth curve is combined with 3-HAA of 100mg/Kg.day, the tumor growth is obviously inhibited (figure 6A). Similar results were obtained for tumor weights, with a combined use of sorafenib and 3-HAA, with a mean tumor weight of 0.15. + -. 0.05g, and 27% of the control (0.41. + -. 0.08g) only (FIG. 6B).
Example 5
3-HAA and sorafenib synergistic inhibition of PDX (patient-derived transplantable tumor) transplantable tumor
Experimental methods
The synergistic tumor-inhibiting effect of 3-HAA and sorafenib is verified on a PDX model of 2 clinical patients with sorafenib resistance, and a control group (DMSO-administration), a 3-HAA administration group (100mg/kg. day), a sorafenib administration group (30mg/kg. day) and a 3-HAA and sorafenib combined administration group (the administration amounts of 3-HAA and sorafenib are 100mg/kg. day and 30mg/kg. day, respectively) are respectively set.
Results of the experiment
The results are shown in fig. 7, and it can be seen that 3-HAA also enhances the therapeutic sensitivity of sorafenib on the clinical drug-resistant liver cancer PDX model. The PDX model constructed in the research still shows treatment resistance to sorafenib 30mg/Kg.day, and the result shows that the sorafenib 30mg/Kg.day or 3-HAA 100mg/Kg.day is injected alone, the inhibition effect on the growth curve of the PDX transplanted tumor is not obvious, and the tumor growth is obviously inhibited after the sorafenib and the 3-HAA are combined (fig. 7A-B).
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A composition, characterized in that the composition comprises:
(a) a therapeutically effective amount of a first active ingredient, which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and
(b) a therapeutically effective amount of a second active ingredient which is a kinase inhibitor anticancer drug.
2. The composition of claim 1, wherein the weight ratio of the 3-hydroxyaminobenzoic acid or pharmaceutically acceptable salt thereof to the kinase inhibitor anticancer agent is 1-50: 0.5-15, preferably 1-30: 0.5 to 10, more preferably 1 to 20: 0.5-5, optimally 5-15: 0.5-5.
3. The composition of claim 1, wherein the kinase inhibitor anticancer drug is sorafenib or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising the composition of claim 1; and a pharmaceutically acceptable carrier.
5. A kit, comprising:
(A) a first formulation comprising 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof;
(B) a second agent comprising a kinase inhibitor anticancer drug; and
(C) instructions for use.
6. An active ingredient combination, characterized in that the active ingredient combination comprises the following components:
(1) a first active ingredient which is 3-hydroxyaminobenzoic acid or a pharmaceutically acceptable salt thereof; and
(2) a second active ingredient which is a kinase inhibitor anticancer drug.
7. Use of a composition according to claim 1, or a pharmaceutical composition according to claim 4, or a kit according to claim 5, or an active ingredient combination according to claim 6, for the preparation of a medicament for the prophylaxis and/or treatment of cancer.
8. The use of claim 7, wherein the cancer is selected from the group consisting of: liver cancer, kidney cancer, leukemia.
9. An in vitro non-therapeutic method of inhibiting the growth of cancer cells, said method comprising the steps of: contacting a cancer cell with the composition of claim 1, or the pharmaceutical composition of claim 4, or the combination of active ingredients of claim 6, to inhibit growth of the cancer cell.
10. A method for preventing and/or treating cancer, said method comprising the steps of: administering to a subject in need thereof a composition according to claim 1, or a pharmaceutical composition according to claim 4, or a kit according to claim 5, or an active ingredient combination according to claim 6.
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| CN201810639339.4A CN110613713B (en) | 2018-06-20 | 2018-06-20 | 3-hydroxyaminobenzoic acid and sorafenib combined medicine for treating tumor |
| PCT/CN2019/092081 WO2019242688A1 (en) | 2018-06-20 | 2019-06-20 | Combination of 3-hydroxyaminobenzoic acid and sorafenib for treating cancers |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022017186A1 (en) * | 2020-07-21 | 2022-01-27 | 天津贝猫科技有限公司 | Use of anthranilic acid derivative in preparation of drug for treating cancer |
| CN116251088A (en) * | 2022-12-19 | 2023-06-13 | 浙江大学医学院附属第一医院 | Application of 3-hydroxy-anthranilic acid in inhibiting liver cancer growth |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009063241A1 (en) * | 2007-11-13 | 2009-05-22 | Ludwig Institut Fur Krebsforschung Ag | 3-hydroxyanthranilic acid or salts thereof1 for treating cancer or infections |
| CN102836160A (en) * | 2012-10-10 | 2012-12-26 | 武汉大学 | Combined medicament for treating cancers |
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2018
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009063241A1 (en) * | 2007-11-13 | 2009-05-22 | Ludwig Institut Fur Krebsforschung Ag | 3-hydroxyanthranilic acid or salts thereof1 for treating cancer or infections |
| CN102836160A (en) * | 2012-10-10 | 2012-12-26 | 武汉大学 | Combined medicament for treating cancers |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022017186A1 (en) * | 2020-07-21 | 2022-01-27 | 天津贝猫科技有限公司 | Use of anthranilic acid derivative in preparation of drug for treating cancer |
| CN116251088A (en) * | 2022-12-19 | 2023-06-13 | 浙江大学医学院附属第一医院 | Application of 3-hydroxy-anthranilic acid in inhibiting liver cancer growth |
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| WO2019242688A1 (en) | 2019-12-26 |
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