WO2020040502A1 - 금속이온에 결합된 이온화합물을 포함하는 암 치료용 약학 조성물 - Google Patents
금속이온에 결합된 이온화합물을 포함하는 암 치료용 약학 조성물 Download PDFInfo
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- WO2020040502A1 WO2020040502A1 PCT/KR2019/010485 KR2019010485W WO2020040502A1 WO 2020040502 A1 WO2020040502 A1 WO 2020040502A1 KR 2019010485 W KR2019010485 W KR 2019010485W WO 2020040502 A1 WO2020040502 A1 WO 2020040502A1
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Definitions
- the present invention relates to a pharmaceutical composition for treating cancer, and more particularly, the pharmaceutical composition for treating cancer includes an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid and lactate are combined with one metal ion.
- the pharmaceutical composition for treating cancer includes an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid and lactate are combined with one metal ion.
- different compounds are simultaneously uptake into cancer cells, and they act through different mechanisms on cancer cells, and thus, the metabolic processes of cancer cells are overlapped and complex, thereby focusing on one specific mutation or cancer cell growth signal.
- the present invention relates to a pharmaceutical composition for treating cancer that is more effective than an anticancer agent, and is less susceptible to drug resistance, thereby more effectively inhibiting cancer cell proliferation, invasion, metastasis, and the like.
- Surgical treatment, chemotherapy or radiation therapy which is possible in early and intermediate cancers, is the first priority for treating cancers with high mortality.
- current cancer therapies generally have a variety of side effects, such as only the initial cancer treatment or the likelihood of recurrence and destruction of normal cells in addition to cancer cells.
- the side effects of active treatment may be more serious. Therefore, a treatment that slows the progress of cancer cells and reduces side effects and improves the quality of life is often selected.
- chemotherapy is a method of destroying or inhibiting DNA or related enzymes (Enzyme) necessary for the proliferation of cancer cells by administering drugs orally or by injection.
- Chemotherapy is used as a standard therapy for treating metastatic cancer in that it can reach cancer and treat metastatic cancer in any part of the body, compared to radiotherapy or surgical operation.
- chemotherapy can not cure cancer, but it plays an important role in relieving symptoms, improving the quality of life and extending the life of the patient.
- the problem with most chemotherapy drugs is not only cancer cells, but also normal cells, especially bone marrow, hair follicles, and gastrointestinal endothelial cells that are proliferating in the human body.
- Normal cells produce energy by completely oxidizing glucose to water and carbon dioxide by oxidative phosphorylation in the presence of oxygen, whereas cancer cells oxidize glucose to pyruvate in a hypoxia environment (Hypoxia). After that, the route to reduce to lactate (lactate) is selected. Thus, cancer cells consume greater amounts of glucose than normal cells, revealing that they consume less oxygen than normal cells and revealing the presence of enormous amounts of lactate in the ascites of cancer patients. It was found that the metabolic pathway that produces ATP was used through the glycolytic process of producing excessive amounts of.
- cancer cells particularly solid cancer cells
- ATPs energy sources
- the Warburg effect can also be attributed to the adaptation of cancer cells to the hypoxia microenvironment, which inhibits the proteosomal degradation of HIF1 (a transcription factor induced when cells lack oxygen). Stabilizes HIF1 and induces its activation as a transcription factor.
- HIF1 protein type 1 that transports sugars
- MCT4 monocarboxylic acid transporter
- HIF1 Lactate dehydrogenase A
- LDHA Lactate dehydrogenase A
- PDH pyruvate dehydrogenase
- HIF1 is a very important factor inducing the Warburg effect through direct expression control of various factors related to glucose influx and glycolysis.
- cancer cells quickly release lactate, which is the end result of glycolysis, to prevent acidification by itself, and the released lactate is produced from cytotoxic T cells and dendritic cells, resulting in anti-cancer effects.
- cytokine Cytokine
- NKp46 a cognitive receptor for NK cells, a natural killer cell
- immunokillers and inhibitors Inhibits apoptosis of cancer cells.
- endothelial cells around cancer cells infiltrate the released lactate and activate IL-8 (a protein that acts as a chemical inducer that activates inflammatory cells and attracts them to the site of inflammation) and VEGF (angiogenesis factor).
- IL-8 a protein that acts as a chemical inducer that activates inflammatory cells and attracts them to the site of inflammation
- VEGF angiogenesis factor
- angiogenesis Induces the expression and promotes the migration of vascular endothelial cells, resulting in angiogenesis (Angiogenesis).
- This metabolic reprogramming of cancer cells is an evolutionarily chosen metabolic transformation strategy to produce precursors such as nucleotides, lipids and amino acids needed for the synthesis of cellular components of rapidly growing cancer cells rather than simply producing ATP. It is understood that growing cancer cells use this metabolic pathway strategically.
- the development of cancer by various carcinogenic factors that induce the formation and growth of existing cancers is closely related to cancer cell metabolism, and reprogramming of cell metabolism may be an important anticancer target to effectively treat cancer. .
- the development of metabolic target therapeutics for controlling glucose metabolism of cancer cells has been intensively performed. Development of cancer treatments using drugs effectively is being carried out.
- an object of the present invention is a pharmaceutical for cancer treatment comprising an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid and lactate are combined with one metal ion selected from Ca, Zn, Mg and Fe. It is to provide a composition.
- the present inventors have focused on the main metabolic pathways unique to cancer cells in order to develop a method for effectively inhibiting the proliferation and metastasis of cancer cells.
- Aerobic glycolysis is a cancer cell that uses oxygen instead of oxygen instead of oxidative phosphorylation, an energy metabolic process that requires oxygen.
- Normal cells can survive in hypoxia environments, such as insurmountable solid cancers, and inactivate apoptosis control processes that originate from the mitochondria.
- the second notable metabolic pathway of cancer cells relates to the large amount of lactate produced through glycolysis, and the lactate is quickly discharged out of the cancer cells to prevent the cancer cells from acidifying themselves.
- Acidification Acidosis
- the activity of NK and CTL cells are inhibited by the acidified environment, and eventually lead to angiogenesis, metastasis of cancer cells and immunosuppression.
- calcium is known to be maintained at low concentrations in cancer cells. Reducing the supply of calcium to the mitochondria in cancer cells inhibits cancer cell proliferation due to energy depletion, while increasing the calcium supply overloads the mitochondria and kills the cancer cells. Therefore, it was noted that cancer cells react more sensitively to calcium than normal cells, and when homeostasis of calcium in the cancer cells is destroyed, cancer cells die beyond the inhibition of proliferation.
- the present invention is a metal ion selected from Ca, Zn, Mg, Fe is selected from two compounds selected from ascorbic acid, dichloroacetic acid and lactate, which is an ionic compound effectively acting on the main metabolic pathways unique to cancer cells. It provides a pharmaceutical composition for treating cancer comprising an ionic compound combined with.
- the pharmaceutical composition for treating cancer according to the present invention comprises an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid and lactate are combined with one metal ion selected from Ca, Zn, Mg, and Fe as an active ingredient. It can be used as a metabolic anticancer agent, and can effectively inhibit the proliferation of cancer cells.
- the pharmaceutical composition for treating cancer according to the present invention includes compounds having different mechanisms, such as cancer cell growth inhibitory compound and cancer cell metastasis inhibiting compound, thereby simultaneously acting on major metabolic enzymes to duplicate the metabolism of cancer cells.
- compounds having different mechanisms such as cancer cell growth inhibitory compound and cancer cell metastasis inhibiting compound, thereby simultaneously acting on major metabolic enzymes to duplicate the metabolism of cancer cells.
- cancer cell growth inhibitory compound and cancer cell metastasis inhibiting compound thereby simultaneously acting on major metabolic enzymes to duplicate the metabolism of cancer cells.
- the pharmaceutical composition for treating cancer according to the present invention can improve uptake of cancer cells when administered in the body as an ionic compound.
- the pharmaceutical composition for treating cancer according to the present invention improves cancer cell uptake by converting an acidic compound into a neutral metal salt form, and is less susceptible to drug resistance, and acts as a cancer cell proliferation, infiltration and metastasis. Can be effectively suppressed.
- the present invention may provide a method for treating cancer and a method for inhibiting cancer metastasis using the pharmaceutical composition for treating cancer according to the present invention.
- the present invention can provide a food composition for cancer metastasis suppression or cancer improvement, including the pharmaceutical composition for treating cancer according to the present invention.
- the pharmaceutical composition for treating cancer according to the present invention has low side effects in the body, so that it can be used as an additive in food and high dose administration.
- Figure 1a is a graph showing the calcium concentration in cancer cells treated with the calcium salt of Examples 1 to 3.
- FIG. 1B is an image showing calcium in cancer cells treated with the calcium salts of Examples 1 to 3.
- FIG. 1B is an image showing calcium in cancer cells treated with the calcium salts of Examples 1 to 3.
- Figure 2 is a graph showing the lactate concentration in cancer cells treated with the calcium salt of Examples 1 to 3.
- Figure 3 is a graph showing the concentration of lactate released in cancer cells treated with the calcium salt of Examples 1 to 3.
- Figure 4 is a graph showing the concentration of ascorbic acid in cancer cells treated with calcium salts of Examples 1 and 2 and Comparative Examples 1 and 2.
- Figure 5 is a graph showing the pH in cancer cells treated with the calcium salt of Examples 1 to 3.
- Figure 6 is a graph showing the pyruvic acid concentration in cancer cells treated with the calcium salt of Examples 1 to 3.
- Figure 7 is a graph showing the ⁇ -KG concentration in cancer cells treated with the calcium salt of Examples 1 to 3.
- Figure 8 is a graph showing the expression amount of PARP, ⁇ -catenin, VEGF and ⁇ -actin expressed from cancer cells treated with the calcium salt of Examples 1 to 3.
- Example 11 is an image confirming the cell colonization ability by treating the calcium salt of Example 1 to colorectal cancer cell line.
- Figure 13 is a graph confirming the co-delivery effect by treating the calcium salt and 5-FU anticancer agent of Example 1 to the colon cancer cell line HCT-116.
- Example 14 is a graph confirming the co-delivery effect by treating calcium salt and 5-FU anticancer agent of Example 2 to HCT-116, a colorectal cancer cell line.
- Figure 15 is a graph confirming the co-delivery effect by treating the calcium salt and SN-38 anticancer agent of Example 1 to the colon cancer cell line HCT-116.
- Figure 16 is a graph confirming the co-delivery effect by treating calcium salt and SN-38 anticancer agent of Example 2 to HCT-116, a colon cancer cell line.
- 17 is a graph confirming the co-delivery effect by treating calcium salt and Paclitaxel anticancer agent of Example 1 to HCT-116, a colorectal cancer cell line.
- Example 18 is a graph confirming the combined delivery effect by treating calcium salt and Paclitaxel anticancer agent of Example 2 to HCT-116, a colon cancer cell line.
- Figure 19a is a photograph of the observation result after injecting the calcium salt of Example 1 to the mouse model (DLD-1 orthotopic model) after 1 week
- Figure 19b is a mouse model of the calcium salt of Example 1 (DLD- 1 orthotopic model) is a graph measuring the weight of cancer tissue dissected 1 week after administration.
- 20 is an image photograph of the growth saturation of cancer by date after luminescence imaging measurement after administering calcium salts of Examples 1 to 3 in a mouse model implanted with A549 / LUC cells in the lung.
- FIG. 21 is a graph showing the image of FIG. 20 by measuring a region of interest (ROI) which is a program of an IVIS spectrum (Xenogen).
- ROI region of interest
- Xenogen IVIS spectrum
- FIG. 22 is a graph showing the survival rate after the administration of the calcium salts of Examples 1 to 3 in a mouse model implanted with A549 / LUC cells in the lung.
- the present invention is an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid, and lactate are combined with one metal ion selected from Ca, Zn, Mg, and Fe. It provides a pharmaceutical composition for treating cancer comprising as an active ingredient.
- the ascorbic acid (L-ascorbic acid) is a vitamin C, Nobel Prize winner Linus Pauling has already been identified as a non-toxic anticancer drug.
- ascorbic acid does not show any particular toxicity even when administered to the human body in excess (50g or more), and due to the structure similar to glucose can competitively suppress glucose addition of cancer cells (glucose addition).
- high doses of ascorbic acid can induce cancer cell necrosis by dropping glutathione or NADPH in cancer cells and generating free radicals (ROS).
- ROS free radicals
- ascorbic acid can induce cancer cells to differentiate into normal cells and inhibit the spread of cancer cells to peri-cancerous tissues through the blocking of enzymes that help collagen synthesis and cancer metastasis.
- apoptosis of cancer cells may be induced by a decrease in the potential of the mychondrial membrane, expression of Tf transporters, reduction of iron uptake, and an increase in free radicals (ROS) in cancer cells.
- ROS free radicals
- the stability of the body is increased, the uptake into cancer cells is increased, which is more than the anticancer effect of conventional ascorbic acid, and can induce cancer cell self-killing even at relatively low concentrations. .
- hypoxia-inducible factor-1 HIF-1
- HIF-1 hypoxia-inducible factor-1
- Pyruvate Dehydogenase Kinase which is expressed by pyruvate kinase.
- Rubinate dehydrogenase complex (Pyruvate Dehydrogenase Complex) is inhibited.
- pyruvic acid is not converted into acetyl-CoA, and pyruvic acid accumulates, resulting in a decrease in energy synthesis of mitochondria.
- pyruvate accumulates in excess, pyruvate is converted into lactate and lactate accumulates around cancer cells.
- lactate accumulation occurs, starting with the expression of pyruvate kinase.
- the dichloroacetic acid is not toxic and may block the aerobic glycolysis pathway described above.
- the expression of pyruvate kinase can be inhibited to inhibit the accumulation of lactate.
- reconstitution of the TCA cycle Tricarboxylic Acid Cycle
- glucose metabolism reprogramming ie normalization of mitochondrial metabolism
- the dichloroacetic acid can be combined with a suitable metal ion, thereby improving the anticancer effect of the existing dichloroacetic acid, induce mitochondrial metabolism normalization, induce free radicals (ROS) can kill cancer cells.
- ROS free radicals
- dichloroacetic acid is combined with a suitable metal ion, thereby reducing the accumulation of lactate can inhibit the acidification (Tumor acidosis) of cancer cells.
- the lactate includes lactic acid (Latic acid), D-lactate and L-lactate, it also means to include D-lactic acid and L-lactic acid.
- L-lactate dehydrogenase B an enzyme that converts lactate or lactic acid to pyruvic acid and simultaneously NAD + to NADH
- LDHA L-lactate dehydrogenase A; reverse reaction enzyme of LDHB
- MCT monocarboxylate transporters
- inhibitortion of LDHA or “activation of LDHB” means the conversion of lactate to pyruvic acid.
- inhibition of expression of MCT means inhibiting the expression of MCT involved in the inflow and outflow of lactate, thereby activating the expression of NKp46 and activating apoptosis of cancer cells.
- lactate by combining the lactate with a suitable metal ion it can be introduced into cancer cells to acidify the inside to induce cell death.
- the metal ion may be one selected from Ca, Zn, Mg, and Fe. Preferably it is Ca, Mg, Fe, More preferably, it is a Ca2 + ion, It is not limited to this.
- the Ca 2+ ions affects calcium homeostasis of cancer cells, and induces calcium accumulation in the mitochondria, thereby generating excess free radicals in cancer cells. Can cause cancer cell death.
- cancer cells in the mitochondria responsible for energy production calcium is directly linked to alpha-ketoglutarate dehydrogenase, an important factor in the normal operation of the TCA circuit, the loss of calcium homeostasis is a cancer cell Is known to be particularly important in reducing Excessive increase in intracellular calcium levels activates endonuclease and many proteases, leads to mitochondrial metabolism, releases cytochrome C, activates caspase 9, and subsequently activates carspace 3 and 7. This leads to apoptosis.
- Ionic compound refers to a compound in which ions having charges opposite to each other by electrostatic force are formed through ionic bonds, which generally exhibit electrical neutrality.
- the ionic compounds included in the pharmaceutical composition according to the invention are preferably calcium salts of ascorbic acid and dichloroacetic acid, calcium salts of ascorbic acid and lactate, calcium salts of dichloroacetic acid and lactate, ascorbic acid and Magnesium salts of dichloroacetic acid, magnesium salts of ascorbic acid and lactate, magnesium salts of dichloroacetic acid and lactate, magnesium salts of ascorbic acid and dichloroacetic acid, magnesium salts of ascorbic acid and lactate, dichloroacetic acid and lactate Magnesium salt of ascorbic acid and iron salts of dichloroacetic acid, iron salts of ascorbic acid and lactate, iron salts of dichloroacetic acid and lactate, more preferably ascorbic acid and dichloroacetic acid Calcium salts, ascorbic acid and lactate calcium salts, dichloro Which may be a one, but are not limited to, of the calcium salt of acetate and lactate.
- the "calcium salt” refers to an ionic compound produced or synthesized in a form in which the compound is combined with calcium ions
- the “magnesium salt” refers to an ionic compound produced or synthesized in a form in which the compound is combined with magnesium ions
- the term “iron salt” means an ionic compound produced or synthesized in a form in which the compound is combined with iron ions.
- compositions according to the invention can be used for radiation therapy or in combination therapy with anticancer agents.
- anticancer agents since the expression of PARP, HIF-1 ⁇ and VEGF, which imparts radiation resistance to cancer cells during radiation irradiation, is reduced, the anticancer activity of radiation is enhanced when combined with irradiation, thereby increasing the radiation dose. It can be made to exhibit the same level of anti-cancer activity while reducing.
- the irradiation dose of radiation that can be used is not particularly limited to 2 to 10Gy per day, the radiation may be irradiated once a day, may be irradiated over several days by dividing the dose.
- the pharmaceutical composition according to the present invention comprises two kinds of compounds selected from ascorbic acid, dichloroacetic acid, and lactate by combining an ionic compound with one metal ion selected from Ca, Zn, Mg, and Fe.
- Compounds can be simultaneously uptake in cancer cells without sacrificing their respective anticancer effects. This effect may be superior to the existing anti-cancer drug combination (Combi-therapy).
- the pharmaceutical composition according to the present invention when combined with the pharmaceutical composition according to the present invention and an anticancer agent, it may exhibit a better anticancer effect than the anticancer effect by the administration of a single anticancer agent.
- the anticancer agent which may be co-administered with the pharmaceutical composition according to the present invention is not particularly limited so long as it does not directly affect the overall metabolic process of cancer cells, and is known as an example of an anticancer agent Imatinib, 5-FU ( 5-Florouracil, Irinotecan, Sunnytinib, Sunitinib, Oxaliplatin, Paclitaxel, Lapatinib, Trastuzumab, Herceptin, Gefitinib, Erlotinib, Erlotinib (Erlotinib), Methotrexate, Carboplatin, Docetaxel, Everolimus, Sorafenib, Inhibitor of carbonic anhydrase, Monocarboxyl Inhibitors of the monocarboxylate transporter, Pembrolizumab, Atezolizumab, PD-1 anticancer drugs, Nivolumab, PARP-1 (Poly (ADP-ribose) polymerase 1) ) In
- the cancer is a cancer that can be suppressed proliferation, infiltration, metastasis, etc. by the disturbance of metabolic processes, for example lung cancer, breast cancer, colon cancer, gastric cancer, brain cancer, pancreatic cancer, thyroid cancer, skin cancer, bone marrow cancer, lymphoma, Cancer may be selected from the group consisting of uterine cancer, cervical cancer, kidney cancer and melanoma.
- the pharmaceutical composition of the present invention may be prepared in the form of a pharmaceutical composition for treating cancer further comprising a suitable carrier, excipient or diluent commonly used in the manufacture of the pharmaceutical composition.
- a suitable carrier excipient or diluent commonly used in the manufacture of the pharmaceutical composition.
- the pharmaceutical composition powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, external preparations, external patches, suppositories, and sterile injectable solutions, respectively, according to a conventional method.
- Formulated in the form of can be used.
- carriers, excipients and diluents which may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, Calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil and the like.
- Solid form preparations for oral administration include tablets, depots, pills, powders, granules, capsules, oral patches, and such solid form preparations, for example at least one excipient in the extract and its fractions, for example , Starch, calcium carbonate (calcium carbonate), sucrose (sucrose) or lactose (lactose), gelatin and the like can be prepared by mixing.
- lubricants such as magnesium styrate and talc may also be used.
- Liquid preparations for oral use may include various excipients such as wetting agents, sweeteners, fragrances, preservatives, etc., in addition to water and liquid paraffin, which are simple diluents commonly used for suspensions, solutions, emulsions, and syrups. have.
- Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, external patches, suppositories, and the like.
- the non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
- As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
- the content of the ionic compound included in the pharmaceutical composition of the present invention is not particularly limited, but may be included in an amount of 0.0001 to 50% by weight, more preferably 0.01 to 20% by weight based on the total weight of the final composition.
- the concentration of metal ion in one dose of the pharmaceutical composition may be 0.1 to 300 mM.
- the pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount, the term "pharmaceutically effective amount" of the present invention to treat or prevent a disease at a reasonable benefit / risk ratio applicable to medical treatment or prevention
- Sufficient amount means an effective dose level refers to the severity of the disease, the activity of the drug, the age, weight, health, sex of the patient, the sensitivity to the drug of the patient, the time of administration of the composition of the invention used, the route of administration and the rate of release Period of time, factors including drugs used in combination or coincidental with the composition of the invention used, and other factors well known in the medical art.
- the pharmaceutical compositions of the present invention may be administered alone or in combination with known anticancer agents or ingredients known to exhibit anticancer activity. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect in a minimum amount without side effects.
- the dosage of the pharmaceutical composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the age, weight, sex, history, or type of substance used as an active ingredient of the patient.
- the pharmaceutical composition of the present invention may be administered at about 1 ng to about 2,000 mg / kg, preferably 1 mg to about 400 mg / kg, per adult, and the frequency of administration of the composition of the present invention is specifically Although not limited, it can be administered once a day or several times in divided doses.
- the dose or frequency of administration is not intended to limit the scope of the invention in any aspect.
- the present invention provides a method of treating cancer, comprising administering the pharmaceutical composition to a subject having cancer in a pharmaceutically effective amount.
- the term "individual” of the present invention may include without limitation mammals, farmed fish, and the like, including cancer, mice, livestock, humans, and the like.
- treatment of the present invention refers to any action to improve or benefit the symptoms of cancer by administering a pharmaceutical composition comprising the ionic compound of the present invention as an active ingredient to a subject having cancer.
- the type of cancer to be treated is the same as described above.
- composition may be administered in single or multiple doses in a pharmaceutically effective amount.
- the composition may be administered in the form of a liquid, powder, aerosol, injection, infusion (ring gel), capsule, pill, tablet, suppository or patch.
- the route of administration of the pharmaceutical composition for treating cancer of the present invention may be administered via any general route as long as it can reach the target tissue.
- the pharmaceutical composition of the present invention is not particularly limited, but as desired, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, transdermal patch administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration It may be administered via such a route.
- oral administration can be administered in an unformulated form, and since the lactate metal salt can be denatured or degraded by gastric acid, the oral composition is formulated to coat the active agent or to protect it from degradation in the stomach. It may also be administered orally in the form of oral patches. In addition, it can be administered in a long acting injection (Long acting injection) to maximize the efficacy in the injection administration.
- the composition may be administered by any device in which the active agent may migrate to the target cell.
- the pharmaceutical composition of the present invention can be formulated into a sustained release formulation to effectively sustain the concentration of the drug, that is, the ionic compound in the body.
- the rate at which the drug is released in the body can be controlled while maintaining the drug by administration once or once a week.
- the sustained release formulation may include a carrier, an excipient, and a diluent, as described above.
- a cancer metastasis including an ionic compound in which two compounds selected from ascorbic acid, dichloroacetic acid and lactate is combined with one metal ion selected from Ca, Zn, Mg, and Fe It provides a pharmaceutical composition for inhibition.
- the ionic compound provided in the present invention can inhibit various properties that can induce cancer cell metastasis, such as cancer cell metastasis, invasion, neovascularization, and colonization ability, as an active ingredient of the pharmaceutical composition for inhibiting cancer metastasis Can be used.
- the ionic compound and the metal ion are the same as described above.
- the target cancer of the metastasis is the same as defined above, for example, the pharmaceutical composition for inhibiting cancer metastasis is metastatic lung cancer, breast cancer, colon cancer, stomach cancer, brain cancer, pancreatic cancer, thyroid cancer, skin cancer, bone marrow cancer, lymphoma, And melanoma may be used to inhibit the development of one or more metastatic cancers.
- the present invention provides a method for inhibiting metastasis of cancer, comprising administering the pharmaceutical composition to a subject in anticipated metastasis of the cancer.
- cancer refers to a condition in which cancer or a malignant tumor has spread to other tissues away from the organ.
- the metastasis can be suppressed.
- the type of cancer to be metastasis suppressed the type of drug to be administered, the route of drug administration and the like are the same as described above.
- the present invention provides a pharmaceutical composition for preventing or improving fatigue related to cancer, including the ionic compound as an active ingredient.
- cancer-related fatigue is one of the most frequent side effects during or after the treatment of cancer, and for example, cancer-related fatigue (CRF).
- CPF cancer-related fatigue
- cancer fatigue syndrome refers to a symptom that is painful and persistent, irrelevant to recent activities, and interferes with daily functioning as a subjective sense of fatigue and exhaustion caused by cancer and its treatment.
- the ionic compound according to the present invention is prepared by combining two or more compounds containing ascorbic acid and metal ions, and when applied to cancer patients to restore immune function, reduce muscle pain, stress It can be used to prevent or ameliorate cancer fatigue syndrome by exhibiting an effect of reducing fatigue. These effects can also increase the survival rate of cancer patients.
- the present invention provides a food composition for cancer improvement comprising the ionic compound as an active ingredient.
- the ionic compound is the same as described above.
- the ionic compounds can be prepared and consumed in the form of foods that can improve cancer while still being common sense.
- the content of the calcium salt contained in the food is not particularly limited, but may be included as an example of 0.001 to 10% by weight, and other examples 0.1 to 1% by weight relative to the total weight of the food composition.
- the food is a beverage, it may be included in a ratio of 1 to 10g, 2 to 20g as another example based on 100ml as an example.
- the composition may include additional ingredients that are commonly used in food compositions to improve the smell, taste, time and the like.
- additional ingredients may include vitamins A, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like.
- minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), and copper (Cu) may be included. It may also contain amino acids such as lysine, tryptophan, cysteine, valine and the like.
- preservatives potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetic acid, etc.
- fungicides bleaching powder and highly bleaching powder, sodium hypochlorite, etc.
- antioxidants butylhydroxyanisol (BHA), butylhydroxytoluene ( BHT), etc.
- colorants such as tar pigments
- colorants such as sodium nitrite, sodium nitrite
- bleach sodium sulfite
- seasonings such as MSG glutamate
- sweeteners ducin, cyclate, saccharin, sodium, etc.
- Food additives such as flavorings (vanillin, lactones, etc.), swelling agents (alum, aluminium, D-potassium hydrogenate, etc.), reinforcing agents, emulsifiers, thickeners (pigments), coatings, gum herbicides, foam inhibitors, solvents, improvers, etc.
- the additive is selected according to the
- the ionic compound can produce a functional food for cancer improvement.
- the food composition may be used to produce a processed food that can improve cancer, for example, sweets, beverages, alcoholic beverages, fermented foods, canned food, milk processed foods, meat processed foods or noodles processed foods It can be prepared as a dietary supplement.
- the confectionery includes biscuits, pies, cakes, bread, candy, jelly, gum, cereals (including meal substitutes such as grain flour).
- Beverages include drinking water, carbonated drinks, functional hot drinks, juices (eg, apples, pears, grapes, aloes, citrus fruits, peaches, carrots, tomato juices, and the like), sikhye, and the like.
- Alcoholic beverages include sake, whiskey, shochu, beer, liquor, fruit wine, and the like.
- Fermented foods include soy sauce, miso, and red pepper paste.
- Canned food includes canned seafood (eg, canned tuna, mackerel, saury, canned seashells, etc.), canned animal products (eg beef, pork, chicken, turkey canned, etc.), canned produce (corn, peaches, canned apples, etc.).
- Milk processed foods include cheese, butter, yogurt, and the like.
- Processed meat products include pork cutlet, beef cutlet, chicken cutlet and sausage. Includes sweet and sour pork, nuggets, breadfruits and more.
- Noodle-processed foods include dried noodles, carded noodles, ramen noodles, udon noodles, cold noodles, sealed packaged noodles, and the like.
- the composition may be used in retort food, soups and the like.
- the term "functional food” of the present invention is the same term as a food for special health use (FOSHU), and the medicine, medical effect processed to efficiently display the bioregulatory function in addition to nutrition It means a high food, the food may be prepared in various forms such as tablets, capsules, powders, granules, liquid, pill to obtain a useful effect in the improvement of cancer.
- FOSHU special health use
- a dichloroacetic acid solution was prepared by dissolving 129 mg of dichloroacetic acid in 125 ml of distilled water, and an ascorbic acid solution was prepared by dissolving 176 mg of ascorbic acid in 125 ml of distilled water. Ascorbic acid solution was added to the dichloroacetic acid solution with gentle stirring. Then, 105 mg of calcium carbonate (CaCO 3 ) was slowly added and stirred at room temperature for 30 minutes, and then the reaction temperature was gradually raised to 60 ° C. until no further CO 2 was generated.
- CaCO 3 calcium carbonate
- a lactic acid solution was prepared by dissolving 90 mg of l-lactic acid in 125 ml of distilled water, and an ascorbic acid solution was prepared by dissolving 176 mg of ascorbic acid in 125 ml of distilled water.
- Ascorbic acid solution was added to the lactic acid solution with gentle stirring.
- 105 mg of calcium carbonate (CaCO 3 ) was slowly added and stirred at room temperature for 30 minutes, and then the reaction temperature was gradually raised to 60 ° C. until no further CO 2 was generated.
- Dichloroacetic acid and lactate prepared according to Preparation Example 1-3 is calcium salt combined with calcium ion.
- Example 1 To human colon cancer cell lines (HCT-116) of 5 x 10 6 cell number cultured at 37 ° C. and 5% CO 2 conditions in cancer cell culture medium (RPMI1640 medium containing 10% FBS and 1% penicillin / streptomycin).
- the calcium salts of Examples 1 to 3 were each treated with 1 mM and incubated for 24 hours.
- the cultured cancer cells were pulverized with a homogenizer and centrifuged, and the concentration of calcium contained in the lysate was measured using a calcium analysis kit (Biovision, SanFrancisco, CA), and is shown in FIG. 1A. In this case, cancer cells that did not receive calcium salt were used as a control.
- the concentration of calcium in the cancer cells treated with the calcium salt of Examples 1 to 3 increased. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can penetrate into cancer cells.
- the concentration of lactate in the cancer cells treated with the calcium salts of Examples 1 to 3 was increased. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can penetrate into cancer cells and increase the concentration of lactate.
- the concentration of lactate released in cancer cells treated with the calcium salts of Examples 1 to 3 is substantially reduced. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can reduce the concentration of lactate released from the cancer cells to the outside.
- the concentration of ascorbic acid was increased in the cancer cells treated with Examples 1 and 2, while the cancer cells treated with Comparative Examples 1 and 2 were cancer cells treated with Examples 1 and 2.
- the increased concentration of ascorbic acid was low. Accordingly, it was confirmed that the composition for cancer treatment containing the ionic compound bound to the metal ion according to the present invention is easy to penetrate into cancer cells.
- the calcium salts of Examples 1 to 3 were treated to cancer cells to determine the effects on cancer metabolism.
- Example 1 1 mM
- Example 2 1 mM
- Example 3 1 mM
- the cultured cells were pulverized with a homogenizer and centrifuged, and the concentration of pyruvic acid contained in the lysate was measured using a pyruvic acid analysis kit (Biovision, SanFrancisco, CA), and is shown in FIG. 6. At this time, cancer cells that did not process anything was used as a control.
- the concentration of pyruvic acid was increased in the cancer cells treated with the calcium salts of Examples 1 to 3. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can increase the concentration of pyruvic acid by penetrating into cancer cells.
- Example 1 1 mM
- Example 2 1 mM
- Example 3 1 mM
- the cultured cells were crushed by a homogenizer and centrifuged, and the concentration of alpha ketoglutamic acid contained in the lysate was measured using an alpha ketoglutamic acid analysis kit (Biovision, SanFrancisco, CA) and shown in FIG. 7. At this time, cancer cells that did not process anything was used as a control.
- the concentration of alpha ketoglutamic acid was increased in the cancer cells treated with the calcium salts of Examples 1 to 3. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can increase the concentration of alpha ketoglutamic acid by infiltrating into cancer cells and inducing oxidative phosphorylation of mitochondria.
- HCT-116 human colon cancer cell lines (HCT-116) of 5 x 10 6 cell number cultured at 37 ° C. and 5% CO 2 conditions in cancer cell culture medium (RPMI1640 medium containing 10% FBS and 1% penicillin / streptomycin).
- RPMI1640 medium containing 10% FBS and 1% penicillin / streptomycin.
- Various concentrations of the calcium salts of Examples 1, 2 and 3 were respectively treated and incubated for 24 hours. Cultured cells were crushed by a homogenizer and centrifuged, and the expression levels of the poly (ADP-ribose) polymerase 1 (PARP-1), ⁇ -catenin, VEGF and ⁇ -actin proteins contained in the lysate were measured. It measured using the blot and shown in FIG.
- PARP-1 poly (ADP-ribose) polymerase 1
- cancer cells treated with the calcium salts of Examples 1 to 3 had low expression levels of PARP-1.
- PARP-1 is commonly used as apoptosis marker because cleavage occurs by caspase-3, which is activated when cells undergo programmed cell death, apoptosis.
- Example 1 at 0.18 mg / ml
- Example 2 at 0.34 mg / ml
- Example 3 at 0.3 mg / ml
- the full length PAPR-1 decreased the most, leading to concentration-dependent death of cancer cells. Confirmed. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can reduce the expression of full length PAPR-1 and induce cancer cell death.
- cancer cells treated with the calcium salts of Examples 1 to 3 reduced the protein level of ⁇ -catenin in a concentration-dependent manner.
- ⁇ -catenin is a transcription factor that is mutated or overexpressed in various carcinomas such as colorectal cancer, lung cancer, breast cancer, and ovarian cancer and plays an important role in cell growth, cancer metastasis, and survival such as c-myc, cyclin D1, MMP7, and survivin. It is known to regulate the expression of proteins. Accordingly, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention can inhibit the growth of cancer cells by reducing the protein of ⁇ -catenin.
- VEGF signaling system plays an important role in cell growth, invasion, and metastasis by regulating the lower MAPK signaling and PI3K / Akt signaling. In particular, it promotes cancer cell metastasis by increasing gene expression of matrix metalloproteinases (MMPs), which are essential for cancer cell metastasis. Therefore, it was confirmed that the composition for treating cancer containing the ionic compound bound to the metal ion according to the present invention exhibited the effect of inhibiting the metastasis of cancer cells by inhibiting the action of factors inducing angiogenesis.
- MMPs matrix metalloproteinases
- DCF-DA Dichlorofluorescin diacetate
- RPMI1640 medium containing 10% FBS and 1% penicillin / streptomycin
- cancer cells treated with calcium salts of Examples 1 to 3 increased free radicals, suggesting the possibility of inducing cell death, compared to the control without any treatment.
- a human colon cancer cell line (HCT-116) of 3 x 10 4 cells was laid on a 6-well plate for 24 hours. After incubation, calcium salts of various concentrations of Example 1 (1 mM), Example 2 (1 mM) and Example 3 (1 mM) were treated for 24 hours, washed twice with DPBS, and trypsin-EDTA (trypsin-EDTA). ), Stained with Annexin-V / PI protocol, and measured by cell death using a FACSCanto TM II flow cytometer (Becton-Dickinson, Franklin Lakes, Nj, USA), primary argon laser.
- FACSCanto TM II flow cytometer Becton-Dickinson, Franklin Lakes, Nj, USA
- phosphatidyl serine In normal living cells, phosphatidyl serine (PS) is located inside the cell membrane. However, at the time of apoptosis, PS is exposed to the outside of the cell membrane, and annexin V binds to and fluoresces with PS. propidium iodide (PI) enters the cell and stains the nucleus. Cells in the early stages of apoptosis are stained only with annexin-V and not with PI, while cells in the late stages of apoptosis or cells undergoing necrosis. These cells show that the integrity of the cell membrane is impaired, so that annexin-V and PI are stained at the same time, and living cells are not stained at all. As shown in FIG. 10, cancer cells treated with the calcium salts of Examples 1 to 3 than the control without any treatment suggested the possibility of inducing apoptosis.
- colorectal cancer cell line DLD-1
- breast cancer cell line MDA-MB-231
- brain cancer cell line U87MG
- Salts were added to each well by concentration (20 mg / ml, 4 mg / ml, 0.8 mg / ml, 0.16 mg / ml, 0.032 mg / ml, 0.0064 mg / ml, 0.00128 mg / ml, 0.000256 mg / ml)
- Ascorbic acid and dichloroacetic acid were also diluted in the same way and added to the wells for relative comparison.
- IC 50 50% inhibitory concentration
- IC 50 (mg / ml) of colorectal cancer cell line IC 50 of breast cancer cell line (mg / ml) IC 50 of brain cancer cell line (mg / ml)
- Example 1 0.07 0.04 0.5
- Example 2 0.07 0.05 0.6
- Example 3 0.86 0.05 0.8
- Dichloroacetic acid 1.21 0.43 3.71 Ascorbic acid 0.09 0.06 0.9
- the calcium salts of Examples 1 and 2 are all lower in IC 50 values for colorectal cancer, breast cancer, and brain cancer cell lines compared to ascorbic acid and dichloroacetic acid. It was confirmed that the cancer cell killing effect superior to acetic acid.
- Example 3 Calcium salt of Example 3, the IC 50 value for colorectal cancer, breast cancer, brain cancer cell line shows a lower value than dichloroacetic acid, it was confirmed that has a superior cancer cell killing effect than dichloroacetic acid.
- the calcium salt of Example 3 shows that the IC 50 value for the colorectal cancer cell line is higher than that of ascorbic acid, but the IC 50 value for breast cancer and brain cancer cell line shows a lower value than the ascorbic acid, It was confirmed that having a superior breast cancer and brain cancer cell killing effect.
- Seven cancer cell lines including two types of colorectal cancer cell lines (colon cancer cell lines (HCT-116, HT-29), lung cancer cell lines (A-549), liver cancer cell lines (HepG2), pancreatic cancer cell lines (PANC-1), gastric cancer cell lines ( SNU-638) and ovarian cancer cell line (A2780)) were evaluated for inhibiting cancer cell proliferation of Examples 1 and 2.
- colon cancer cell lines HCT-116, HT-29
- lung cancer cell lines A-549
- liver cancer cell lines HepG2
- pancreatic cancer cell lines PANC-1
- gastric cancer cell lines SNU-638
- ovarian cancer cell line A2780
- Example 1 and Example 2 concentrations (5, 2.5, 1.25, 0.625, 0.313, 0.156, 0.078 mM). Ascorbic acid and dichloroacetic acid were treated in the same manner for relative comparison.
- Cell lines treated with the drug were incubated for 48 hours at 37 ° C., 5% CO 2 incubator, and 10 ⁇ l of 5 mg / ml MTT reagent was added to each well. After incubation for 4 hours, the culture medium was removed, and 100 ⁇ l of each well was treated with DMSO to dissolve the MTT dye precipitate, and the absorbance was measured at 540 nm using a microplate reader.
- 50% inhibitory concentration (IC 50 ) was defined as the concentration of the drug such that the survival rate is 50%, it is shown in Table 2 using the IC 50 value as an indicator of the anticancer effect.
- the calcium salts of Examples 1 and 2 showed anticancer efficacy in lung cancer, liver cancer, pancreatic cancer, gastric cancer and ovarian cancer in addition to colon cancer.
- the IC 50 value was lower than that of dichloroacetic acid, and thus had superior cancer cell killing effect compared to dichloroacetic acid.
- Example 1 Calcium salt of Example 1, although the IC 50 value for colorectal cancer (HCT-116), pancreatic cancer, ovarian cancer cell line shows higher value than ascorbic acid, colorectal cancer (HT-29), lung cancer, liver cancer, stomach cancer IC 50 value for the cell line was lower than that of ascorbic acid, and it was confirmed that it has excellent colon cancer (HT-29), lung cancer, liver cancer, gastric cancer cell killing effect compared to ascorbic acid.
- HCT-116 colorectal cancer
- HT-29 colorectal cancer
- lung cancer liver cancer
- stomach cancer IC 50 value for the cell line was lower than that of ascorbic acid, and it was confirmed that it has excellent colon cancer (HT-29), lung cancer, liver cancer, gastric cancer cell killing effect compared to ascorbic acid.
- Calcium salt of Example 2 has a higher IC 50 value for colorectal cancer (HCT-116) and pancreatic cancer cell lines than for ascorbic acid, but for colorectal cancer (HT-29), lung cancer, liver cancer, gastric cancer, and ovarian cancer IC 50 value for the cell line was lower than that of ascorbic acid, and it was confirmed that it had superior colon cancer (HT-29), lung cancer, liver cancer, gastric cancer, and ovarian cancer cell killing effect compared to ascorbic acid.
- HCT-116 colorectal cancer
- HT-29 colorectal cancer
- Human colorectal cancer cell line HCT-116 and each ascorbic acid (0 mM, 0.2 mM, 0.5 mM), calcium salts of Examples 1 and 2 (0 mM, 0.2 mM, 0.5 mM), dichloroacetic acid (0 mM, 2 mM, 5 mM), inoculated into a solid medium containing the calcium salt of Example 3 (0 mM, 2 mM, 5 mM) and incubated for 72 hours, after the incubation was completed, the cells were fixed, and then Cancer cells in which colonies were formed by staining with matocillin were observed and shown in FIG. 11.
- composition for treating cancer containing the metal ion-bonded ionic compound according to the present invention can reduce the survival rate of cancer cells such as colon cancer, breast cancer and brain cancer.
- cancer cells such as colon cancer, breast cancer and brain cancer.
- a combination of known anticancer agents and calcium salts of Examples 1 to 3 was used to verify the therapeutic effect on various cancer cell lines.
- Colorectal cancer cell line (HCT-116) was dispensed with 1 X 10 3 cells in each of the 6-well plates containing RPMI1640 medium, and the medium was freshly replaced.
- Calcium salt of 2 (0.2 mM), calcium salt of Example 3 (2 mM) and 5 ⁇ M of 5-FU alone were treated to each well, and 5-FU and calcium salt of Example 1 0.2 mM), 5-FU at 5 ⁇ M concentration and calcium salt of Example 2 (0.2 mM), 5-FU at 5 ⁇ M concentration, and calcium salt of Example 3 (2 mM), followed by colonization of cells
- the formation ability was compared and shown in FIG.
- a human colorectal cancer cell line (HCT-116) treated with no drug was used.
- the colon cancer cell line which did not process anything formed about one hundred colonies, but the combination of 5-FU and the calcium salts of Examples 1 to 3 was treated with 5-FU alone rather than 5-FU alone. It was observed that the effect of inhibiting the colonizing ability of the cancer was more excellent.
- Example 1 or Example 2 After dispensing 2 X 10 3 HCT-116 cells in each 96 well plate and incubating for 24 hours, various concentrations of Example 1 or Example 2 and the chemocancer Fluorouracil (5-FU), SN-38, Paclitaxel (PTX) is used in combination. After 48 hours of exposure, the combinational index (CI) was used to evaluate the cell growth inhibition rate (%) and the combined delivery effect of the combination anticancer drug combination. The synergistic effect was CI ⁇ 0.85, the additive effect was 0.85 ⁇ CI ⁇ 1.15, and the antagonistic (antagonistic) effect was CI> 1.15. In combination with Example 1 or Example 2 and the chemotherapy agent Fluorouracil (5-FU), SN-38, Paclitaxel (PTX) at most concentrations, it was confirmed that the synergistic effect was shown.
- Example 1 and 5-FU or Example 2 and 5-FU After treating Example 1 and 5-FU or Example 2 and 5-FU in combination with HCT-116 cells for 48 hours, cell growth inhibition rate (%) and CI values are shown in Tables 4 and 5, respectively. By subdividing the values, synergistic, additive or antagonistic effects are shown in FIGS. 13 and 14, respectively.
- Embodiment 1 or Embodiment 2 and 5-FU the Example 1 or Example 2 If the same than the IC 50 value, or the combination treatment at lower concentrations eoteuna indicate some antagonistic effects, Embodiment 1 or 2 of the IC 50 than In the case of co-treatment at high concentrations above 1,000 ⁇ M, most synergistic effects were observed under various concentration conditions.
- Example 1 and SN-38 or Example 2 and SN-38 in combination with HCT-116 cells After treating Example 1 and SN-38 or Example 2 and SN-38 in combination with HCT-116 cells for 48 hours, cell growth inhibition rate (%) and CI values are shown in Tables 6 and 7, respectively. By subdividing the synergy, addition or antagonistic effect is shown in Figure 15 and 16, respectively.
- Example 2 synergistic effects with SN-38 were observed at most concentration combinations, especially below the IC 50 value (430 ⁇ M) of Example 2 and below the IC 50 value (0.25 ⁇ M) of SN-38. Synergy was also observed in the combination of concentrations.
- Example 1 and Paclitaxel or Example 2 and Paclitaxel After treating Example 1 and Paclitaxel or Example 2 and Paclitaxel for 48 hours in combination with HCT-116 cells, cell growth inhibition rate (%) and CI values are shown in Table 8 and Table 9, respectively. , Addition or antagonistic effects are shown in FIGS. 17 and 18, respectively. Combinations of concentrations below the IC 50 value (311 ⁇ M) of Example 1 or below the IC 50 value (430 ⁇ M) of Example 2 with Paclitaxel of 0.1 ⁇ M (100 nM) or less result in synergistic effects in most combinations of concentrations. Showed. Example 1, performed when the second example of the combined use of lower concentration than the IC 50 value and the Paclitaxel concentration lower than the IC 50 value (7.8 nM) treatment a synergistic effect was observed in most combinations concentration.
- a colon cancer mouse model (DLD-1 orthotopic model) was constructed by transplanting general DLD-1 cells into the large intestine, and a lung cancer mouse model (A549 / LUC orthotopic model) was constructed by transplanting heterologous isotopes into the lung. Each mouse model was then dosed with drugs as shown in Table 10 below.
- Example 1 The calcium salt of Example 1 was administered to the same mouse model (DLD-1 orthotopic model) constructed in Experimental Example 5-1, dissected 1 week later, and the growth state of the cancer cells was observed in FIG. 19A. Cancer tissue weight was measured to confirm the anticancer efficacy of the inventive substance in vivo and is shown in FIG. 19B.
- the calcium salts of Examples 1 to 3 were respectively administered to the same mouse model (A549 / LUC orthotopic model) constructed in Experimental Example 5-1, and the tissue distribution, metastasis, and anticancer efficacy of the inventive substances were confirmed in vivo.
- the image photograph is shown in FIG.
- the results obtained by measuring the in vivo image by measuring a region of interest (ROI), which is a program of the IVIS spectrum (Xenogen) are shown in FIG. 21, and in FIG. 22, a mouse model (A549 / The survival rate of the LUC orthotopic model was measured.
- ROI region of interest
- Xenogen a program of the IVIS spectrum
- Example 1 the calcium salt of Examples 1 to 3 was confirmed to have excellent anti-cancer efficacy, metastasis suppression ability and excellent survival rate compared to the control.
- Example 1 the growth and metastasis of cancer tissues were not shown at all, even after the drug administration period was stopped, which suggests that mitochondria in the cancer cells have been normalized.
- the experimental results described above confirmed that the ionic compound bound to the metal ion according to the present invention can increase the uptake for cancer cells, it was confirmed that it can be acidified by lowering the pH in the cancer cells, 1 It was confirmed that the ionic compound in which two compounds were combined with metal ions than the compounds of each species (ascorbic acid or dichloroacetic acid) was more effective in killing cancer cells.
- the ionic compound was found to increase the pyruvic acid and alpha ketoglutamic acid, thereby inhibiting glycolysis of cancer cells, cancer cell proliferation and metastasis through the change in the expression level of ⁇ -catenin, PARP, and VEGF Confirmed that it can be reduced.
- the proliferation test of cancer cell lines it was confirmed that when combined with a conventional anticancer agent can exhibit a better anticancer effect.
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Abstract
Description
구분 | 대장암 세포주의IC50(㎎/㎖) | 유방암 세포주의IC50(㎎/㎖) | 뇌암 세포주의 IC50(㎎/㎖) |
실시예 1 | 0.07 | 0.04 | 0.5 |
실시예 2 | 0.07 | 0.05 | 0.6 |
실시예 3 | 0.86 | 0.05 | 0.8 |
다이클로로아세트산 | 1.21 | 0.43 | 3.71 |
아스코빅산 | 0.09 | 0.06 | 0.9 |
구분 | HCT-116 대장암 세포주의 IC50mM (㎎/㎖) | HT-29 대장암 세포주의 IC50mM (㎎/㎖) | A549 폐암 세포주의 IC50mM (㎎/㎖) | HepG2 간암 세포주의 IC50mM (㎎/㎖) | PANC-1 췌장암 세포주의 IC50mM(㎎/㎖) | SNU-638 위암 세포주의 IC50mM (㎎/㎖) | A2780 난소암 세포주의 IC50mM (㎎/㎖) |
실시예 1 | 0.35(0.12) | 0.83(0.29) | 2.3(0.79) | 2.1(0.72) | 0.42(0.14) | 1.40(0.48) | 0.17(0.06) |
실시예 2 | 0.33(0.11) | 0.66(0.23) | 3.1(1.06) | 2.3(0.79) | 0.40 (0.14) | 1.44(0.49) | 0.14(0.05) |
아스코빅산 | 0.27(0.09) | 0.93(0.32) | >5(>1.7) | 4.2(1.44) | 0.37(0.13) | 2.48(0.85) | 0.15(0.05) |
다이클로로아세트산 | >5(>1.7) | >5(>1.7) | >5(>1.7) | >5(>1.7) | >5(>1.7) | >5(>1.7) | >5(>1.7) |
구분 | HCT-116 세포 | HT-29 세포 | DLD-1 세포 |
실시예 1 | 311 μM | 1,326 μM | 360 μM |
실시예 2 | 430 μM | 1,795 μM | 340 μM |
Fluorouracil(5-FU) | 6 μM | N.T. | N.T. |
SN-38 | 0.25 μM | N.T. | N.T. |
Paclitaxel(PTX) | 7.8 nM | N.T. | N.T. |
5-FU(μM) | 실시예 1(μM) | Inhibition Effect(%) | Combinational Index (CI) | Combinational therapeutic effect |
15 | 2100 | 93.577 | 0.4427 | Synergistic |
15 | 1050 | 85.3 | 0.6173 | Synergistic |
15 | 525 | 58.118 | 1.9302 | Antagonistic |
15 | 262.5 | 47.054 | 2.5103 | Antagonistic |
15 | 131.25 | 47.275 | 1.9424 | Antagonistic |
15 | 65.625 | 50.392 | 1.3341 | Antagonistic |
15 | 32.8125 | 52.792 | 1.0142 | Additive |
7.5 | 2100 | 94.005 | 0.4066 | Synergistic |
7.5 | 1050 | 85.172 | 0.6068 | Synergistic |
7.5 | 525 | 51.246 | 2.3129 | Antagonistic |
7.5 | 262.5 | 41.521 | 2.4865 | Antagonistic |
7.5 | 131.25 | 43.522 | 1.5783 | Antagonistic |
7.5 | 32.8125 | 44.392 | 1.0383 | Additive |
3.75 | 2100 | 94.164 | 0.3932 | Synergistic |
3.75 | 1050 | 78.44 | 0.9802 | Additive |
3.75 | 525 | 40.269 | 3.5082 | Antagonistic |
3.75 | 262.5 | 35.077 | 2.7914 | Antagonistic |
3.75 | 131.25 | 34.349 | 1.9729 | Antagonistic |
3.75 | 65.625 | 32.398 | 1.7429 | Antagonistic |
3.75 | 32.8125 | 36.111 | 1.0986 | Additive |
5-FU(μM) | 실시예 2 (μM) | Inhibition Effect(%) | Combinational Index (CI) | Combinational therapeutic effect |
15 | 2100 | 91.559 | 0.0510 | Synergistic |
15 | 1050 | 78.756 | 0.2765 | Synergistic |
15 | 525 | 53.337 | 1.9886 | Antagonistic |
15 | 262.5 | 51.423 | 1.6698 | Antagonistic |
15 | 131.25 | 51.283 | 1.3570 | Antagonistic |
15 | 65.625 | 50.93 | 1.2254 | Antagonistic |
15 | 32.8125 | 52.97 | 0.9683 | Additive |
7.5 | 2100 | 91.863 | 0.0423 | Synergistic |
7.5 | 1050 | 72.226 | 0.4879 | Synergistic |
7.5 | 525 | 48.921 | 2.2351 | Antagonistic |
7.5 | 262.5 | 48.929 | 1.4258 | Antagonistic |
7.5 | 131.25 | 44.414 | 1.4760 | Antagonistic |
7.5 | 65.625 | 45.648 | 1.0689 | Additive |
7.5 | 32.8125 | 44.877 | 0.9954 | Additive |
3.75 | 2100 | 92.904 | 0.0294 | Synergistic |
3.75 | 1050 | 77.042 | 0.2624 | Synergistic |
3.75 | 525 | 47.495 | 2.1676 | Antagonistic |
3.75 | 262.5 | 39.686 | 2.4200 | Antagonistic |
3.75 | 131.25 | 41.142 | 1.3573 | Antagonistic |
3.75 | 65.625 | 38.763 | 1.1837 | Antagonistic |
3.75 | 32.8125 | 37.047 | 1.0919 | Additive |
SN-38 (μM) | 실시예 1 (μM) | Inhibition Effect (%) | Combinational Index (CI) | Combinational therapeutic effect |
5 | 420 | 88.9229 | 0.1687 | Synergistic |
2.5 | 420 | 92.8722 | 0.0988 | Synergistic |
1.25 | 420 | 88.92 | 0.1570 | Synergistic |
0.625 | 420 | 79.8278 | 0.3557 | Synergistic |
0.3125 | 420 | 70.0759 | 0.6285 | Synergistic |
0.1563 | 420 | 62.0811 | 0.9237 | Additive |
0.0781 | 420 | 60.9107 | 0.9615 | Additive |
5 | 210 | 92.1143 | 0.0564 | Synergistic |
2.5 | 210 | 93.5517 | 0.0442 | Synergistic |
1.25 | 210 | 89.0431 | 0.0823 | Synergistic |
0.625 | 210 | 80.006 | 0.1782 | Synergistic |
0.3125 | 210 | 72.083 | 0.2873 | Synergistic |
0.1563 | 210 | 65.6346 | 0.3963 | Synergistic |
0.0781 | 210 | 64.1575 | 0.4177 | Synergistic |
0.2 | 2100 | 80.0428 | 1.7292 | Antagonistic |
0.2 | 1050 | 68.4032 | 1.6791 | Antagonistic |
0.2 | 525 | 67.5245 | 0.8846 | Additive |
0.2 | 262.5 | 66.2025 | 0.4816 | Synergistic |
0.2 | 131.25 | 65.0057 | 0.2670 | Synergistic |
0.2 | 65.625 | 65.2717 | 0.1420 | Synergistic |
0.2 | 32.8125 | 64.9823 | 0.0833 | Synergistic |
0.05 | 2100 | 69.6012 | 3.1419 | Antagonistic |
0.05 | 1050 | 49.7876 | 3.8746 | Antagonistic |
0.05 | 525 | 52.6036 | 1.7291 | Antagonistic |
0.05 | 262.5 | 50.4937 | 0.9707 | Additive |
0.05 | 131.25 | 52.4243 | 0.4599 | Synergistic |
0.05 | 65.625 | 50.3585 | 0.2763 | Synergistic |
0.05 | 32.8125 | 46.66 | 0.2076 | Synergistic |
SN38 (μM) | 실시예 2 (μM) | Inhibition Effect (%) | Combinational Index (CI) | Combinational therapeutic effect |
5 | 420 | 91.9418 | 0.0018 | Synergistic |
2.5 | 420 | 93.77 | 0.0006 | Synergistic |
1.25 | 420 | 90.6416 | 0.0015 | Synergistic |
0.625 | 420 | 81.2855 | 0.0092 | Synergistic |
0.3125 | 420 | 75.304 | 0.0177 | Synergistic |
0.1563 | 420 | 70.6913 | 0.0256 | Synergistic |
0.0781 | 420 | 66.2695 | 0.0357 | Synergistic |
5 | 210 | 91.8629 | 0.0015 | Synergistic |
2.5 | 210 | 93.5454 | 0.0005 | Synergistic |
1.25 | 210 | 89.4457 | 0.0014 | Synergistic |
0.625 | 210 | 80.0402 | 0.0082 | Synergistic |
0.3125 | 210 | 71.5298 | 0.0207 | Synergistic |
0.1563 | 210 | 64.2447 | 0.0036 | Synergistic |
0.0781 | 210 | 62.6747 | 0.0320 | Synergistic |
0.2 | 2100 | 63.246 | 0.2178 | Synergistic |
0.2 | 1050 | 66.3675 | 0.0888 | Synergistic |
0.2 | 525 | 66.7414 | 0.0510 | Synergistic |
0.2 | 262.5 | 64.8357 | 0.0429 | Synergistic |
0.2 | 131.25 | 66.2566 | 0.0270 | Synergistic |
0.2 | 65.625 | 66.9537 | 0.0204 | Synergistic |
0.2 | 32.8125 | 65.6318 | 0.0222 | Synergistic |
0.05 | 2100 | 37.5149 | 1.9999 | Antagonistic |
0.05 | 1050 | 49.7181 | 0.3514 | Synergistic |
0.05 | 525 | 52.0429 | 0.1592 | Synergistic |
0.05 | 262.5 | 49.6147 | 0.1242 | Synergistic |
0.05 | 131.25 | 51.3344 | 0.0707 | Synergistic |
0.05 | 65.625 | 38.8751 | 0.2581 | Synergistic |
0.05 | 32.8125 | 42.255 | 0.1 | Synergistic |
PTX (μM) | 실시예 1 (μM) | Inhibition effect(%) | Combinational Index (CI) | Combinational therapeutic effect |
2000 | 21 | 74.5377 | 4.8733 | Antagonistic |
1000 | 21 | 75.7045 | 1.9814 | Antagonistic |
500 | 21 | 76.1604 | 0.9214 | Additive |
250 | 21 | 75.5324 | 0.5284 | Synergistic |
125 | 21 | 74.1361 | 0.3504 | Synergistic |
62.5 | 21 | 72.2105 | 0.2551 | Synergistic |
31.25 | 21 | 73.5272 | 0.1162 | Synergistic |
2000 | 105 | 72.7134 | 6.8186 | Antagonistic |
1000 | 105 | 72.7584 | 3.4499 | Antagonistic |
500 | 105 | 73.298 | 1.6396 | Antagonistic |
250 | 105 | 70.7832 | 1.3048 | Antagonistic |
125 | 105 | 70.1536 | 0.7942 | Synergistic |
62.5 | 105 | 68.7768 | 0.5640 | Synergistic |
31.25 | 105 | 72.8483 | 0.2346 | Synergistic |
0.01 | 2100 | 74.538 | 4.8733 | Antagonistic |
0.01 | 1050 | 75.705 | 1.9814 | Antagonistic |
0.01 | 525 | 76.16 | 0.9214 | Additive |
0.01 | 262.5 | 75.532 | 0.5284 | Synergistic |
0.01 | 131.25 | 74.136 | 0.3504 | Synergistic |
0.01 | 65.625 | 72.211 | 0.2551 | Synergistic |
0.01 | 32.8125 | 73.527 | 0.1162 | Synergistic |
0.05 | 2100 | 72.758 | 3.4499 | Antagonistic |
0.05 | 1050 | 73.298 | 1.6396 | Antagonistic |
0.05 | 525 | 70.783 | 1.3048 | Antagonistic |
0.05 | 262.5 | 70.154 | 0.7942 | Synergistic |
0.05 | 131.25 | 68.777 | 0.5640 | Synergistic |
0.05 | 65.625 | 72.848 | 0.2346 | Synergistic |
0.1 | 2.1 | 63.569 | 0.4335 | Synergistic |
0.05 | 2.1 | 67.66 | 0.1804 | Synergistic |
0.025 | 2.1 | 66.42 | 0.1010 | Synergistic |
0.0125 | 2.1 | 67.57 | 0.0511 | Synergistic |
0.00625 | 2.1 | 65.797 | 0.0338 | Synergistic |
0.00313 | 2.1 | 68.827 | 0.0166 | Synergistic |
0.00156 | 2.1 | 68.866 | 0.0114 | Synergistic |
0.1 | 10.5 | 70.818 | 0.3181 | Synergistic |
0.05 | 10.5 | 70.508 | 0.1741 | Synergistic |
0.025 | 10.5 | 71.703 | 0.0903 | Synergistic |
0.0125 | 10.5 | 70.75 | 0.0603 | Synergistic |
0.00625 | 10.5 | 72.076 | 0.0359 | Synergistic |
0.00313 | 10.5 | 71.37 | 0.0299 | Synergistic |
0.00156 | 10.5 | 71.494 | 0.0250 | Synergistic |
0.005 | 210 | 66.813 | 0.8892 | Additive |
0.005 | 105 | 69.533 | 0.2995 | Synergistic |
0.005 | 52.5 | 66.54 | 0.2454 | Synergistic |
0.005 | 26.25 | 60.005 | 0.3220 | Synergistic |
0.005 | 13.125 | 46.752 | 0.9711 | Additive |
0.1 | 21 | 71.369 | 0.4485 | Synergistic |
0.05 | 21 | 66.478 | 0.4952 | Synergistic |
0.025 | 21 | 66.499 | 0.2651 | Synergistic |
0.0125 | 21 | 57.197 | 0.4975 | Synergistic |
0.00625 | 21 | 44.714 | 1.3230 | Antagonistic |
0.001 | 210 | 63.569 | 0.4335 | Synergistic |
0.001 | 105 | 67.6599 | 0.1804 | Synergistic |
0.001 | 52.5 | 66.4198 | 0.1010 | Synergistic |
0.001 | 26.25 | 67.5701 | 0.0511 | Synergistic |
0.001 | 13.125 | 65.7969 | 0.0338 | Synergistic |
0.001 | 6.5625 | 68.8272 | 0.0166 | Synergistic |
0.001 | 3.28125 | 68.8664 | 0.0114 | Synergistic |
0.005 | 210 | 70.8176 | 0.3181 | Synergistic |
0.005 | 105 | 70.5084 | 0.1741 | Synergistic |
0.005 | 52.5 | 71.7034 | 0.0903 | Synergistic |
0.005 | 26.25 | 70.7495 | 0.0603 | Synergistic |
0.005 | 13.125 | 72.0755 | 0.0359 | Synergistic |
0.005 | 6.5625 | 71.3732 | 0.0299 | Synergistic |
0.005 | 3.28125 | 71.4937 | 0.0250 | Synergistic |
0.1 | 10.5 | 66.8129 | 0.8892 | Additive |
0.05 | 10.5 | 69.5334 | 0.2995 | Synergistic |
0.025 | 10.5 | 66.5395 | 0.2454 | Synergistic |
0.0125 | 10.5 | 60.0051 | 0.3220 | Synergistic |
0.00625 | 10.5 | 46.7518 | 0.9711 | Additive |
PTX (μM) | ASCA201 (μM) | Inhibition effect(%) | Combinational Index (CI) | Combinational therapeutic effect |
2000 | 21 | 67.4203 | 15.8618 | Antagonistic |
1000 | 21 | 70.5542 | 4.8706 | Antagonistic |
500 | 21 | 69.9203 | 2.6664 | Antagonistic |
250 | 21 | 68.756 | 1.6081 | Antagonistic |
125 | 21 | 66.3676 | 1.1675 | Antagonistic |
62.5 | 21 | 66.8142 | 0.5458 | Synergistic |
31.25 | 21 | 69.2026 | 0.1881 | Synergistic |
2000 | 105 | 74.696 | 4.7156 | Antagonistic |
1000 | 105 | 72.0231 | 3.7650 | Antagonistic |
500 | 105 | 71.9147 | 1.9194 | Antagonistic |
250 | 105 | 70.6184 | 1.1936 | Antagonistic |
125 | 105 | 69.9301 | 0.6703 | Synergistic |
62.5 | 105 | 69.7345 | 0.3485 | Synergistic |
31.25 | 105 | 68.4207 | 0.2177 | Synergistic |
0.1 | 10.5 | 65.418 | 1.0785 | Additive |
0.05 | 10.5 | 64.7243 | 0.5989 | Synergistic |
0.025 | 10.5 | 65.3698 | 0.2722 | Synergistic |
0.0125 | 10.5 | 59.8142 | 0.3069 | Synergistic |
0.00625 | 10.5 | 40.9398 | 2.0862 | Antagonistic |
0.003125 | 10.5 | 32.0304 | 3.9015 | Antagonistic |
0.1 | 21 | 68.0909 | 0.7153 | Synergistic |
0.05 | 21 | 66.5773 | 0.4656 | Synergistic |
0.025 | 21 | 63.4886 | 0.3611 | Synergistic |
0.0125 | 21 | 58.1434 | 0.3899 | Synergistic |
0.00625 | 21 | 43.5657 | 1.4500 | Antagonistic |
0.001 | 210 | 65.3911 | 0.0264 | Synergistic |
0.001 | 105 | 65.9839 | 0.0173 | Synergistic |
0.001 | 52.5 | 67.8681 | 0.0105 | Synergistic |
0.001 | 26.25 | 67.6829 | 0.0092 | Synergistic |
0.001 | 13.125 | 67.3283 | 0.0089 | Synergistic |
0.001 | 6.5625 | 66.7196 | 0.0093 | Synergistic |
0.001 | 3.28125 | 67.6246 | 0.0079 | Synergistic |
0.005 | 210 | 67.7855 | 0.0499 | Synergistic |
0.005 | 105 | 67.0877 | 0.0484 | Synergistic |
0.005 | 52.5 | 67.6759 | 0.0412 | Synergistic |
0.005 | 26.25 | 67.9123 | 0.0383 | Synergistic |
0.005 | 13.125 | 69.3483 | 0.0299 | Synergistic |
0.005 | 6.5625 | 69.5098 | 0.0288 | Synergistic |
0.005 | 3.28125 | 68.3333 | 0.0346 | Synergistic |
1 | 21 | 70.5542 | 4.8706 | Antagonistic |
0.5 | 21 | 69.9203 | 2.6664 | Antagonistic |
0.25 | 21 | 68.756 | 1.6081 | Antagonistic |
0.125 | 21 | 66.3676 | 1.1675 | Antagonistic |
0.0625 | 21 | 66.8142 | 0.5458 | Synergistic |
0.0313 | 21 | 69.2026 | 0.1881 | Synergistic |
2 | 105 | 74.696 | 4.7156 | Antagonistic |
1 | 105 | 72.0231 | 3.7650 | Antagonistic |
0.5 | 105 | 71.9147 | 1.9194 | Antagonistic |
0.25 | 105 | 70.6184 | 1.1936 | Antagonistic |
0.125 | 105 | 69.9301 | 0.6703 | Synergistic |
0.0625 | 105 | 69.7345 | 0.3485 | Synergistic |
0.0313 | 105 | 68.4207 | 0.2177 | Synergistic |
동물실험모델 | 약물 | 농도 | 약물투여방법 | 개체수 |
마우스 모델(DLD-1 orthotopic model) | 대조군 | - | 매일 1회(Qdx4), 정맥주사(IV), 1주 투여 | 4 |
마우스 모델(DLD-1 orthotopic model) | 실시예 1 | 100mg/kg(Dissolved in saline) | 매일 1회(Qdx4), 정맥주사(IV), 1주 투여 | 4 |
마우스 모델(A549/LUC orthotopic model) | 대조군 | - | 매일 1회(Qdx4), 정맥주사(IV), 5주 투여 | 3 |
마우스 모델(A549/LUC orthotopic model) | 실시예 1 | 100mg/kg(Dissolved in saline) | 매일 1회(Qdx4), 정맥주사(IV), 5주 투여 | 3 |
마우스 모델(A549/LUC orthotopic model) | 실시예 2 | 100mg/kg(Dissolved in saline) | 매일 1회(Qdx4), 정맥주사(IV), 5주 투여 | 3 |
마우스 모델(A549/LUC orthotopic model) | 실시예 3 | 100mg/kg(Dissolved in saline) | 매일 1회(Qdx4), 정맥주사(IV), 5주 투여 | 3 |
Claims (14)
- 아스코빅산(Ascorbic acid), 다이클로로아세트산(Dichloroacetic acid) 및 락테이트(Lactate) 중 선택된 2종의 화합물이 Ca, Zn, Mg 및 Fe로부터 선택되는 1종의 금속이온과 결합된 이온화합물을 유효성분으로 포함하는 암 치료용 약학 조성물.
- 제1항에 있어서,상기 금속이온은 Ca2+인 암 치료용 약학 조성물.
- 제1항에 있어서,상기 약학 조성물은 방사선 조사 또는 항암제와의 병용치료에 사용되는 것인 암 치료용 약학 조성물.
- 제3항에 있어서,상기 방사선은 1일 2 내지 10Gy의 조사량으로 암환자에게 조사하면서, 상기 약학 조성물과 병용처리되는 것인 암 치료용 약학 조성물.
- 제3항에 있어서,상기 항암제는 이매티닙(Imatinib), 5-FU(5-Florouracil), 이리노테칸(Irinotecan), 서니티닙(Sunitinib), 옥살리플라틴(Oxaliplatin), 파클리탁셀(Paclitaxel), 라파티닙(Lapatinib), 트라스트주맵(Trastuzumab, Herceptin), 제피티닙(Gefitinib), 에를로티닙(Erlotinib), 메토트렉세이트(Methotrexate), 카보플라틴(Carboplatin), 도세탁셀(Docetaxel), 에버롤리무스(Everolimus), 소라페닙(Sorafenib), 카르보닉 언하이드라제(carbonic anhydrase)의 억제제, 모노카르복실레이트 트랜스포터(monocarboxylate transporter)의 억제제, 펌브로 펨브롤리주맙(Pembrolizumab), 아테졸리주맙(Atezolizumab), PD-1계열 항암제, 니볼루맙(Nivolumab), PARP-1(Poly(ADP-ribose) polymerase 1)의 억제제, PARP-2(Poly(ADP-ribose) polymerase 2)의 억제제, 올라파립(Olaparib), 루카파립(Rucaparib), 니카파립(Niraparib), 베바시주맙(Bevacizumab) 및 VEGF 억제제로 구성된 군으로부터 선택되는 하나 이상의 항암제인 것인 암 치료용 약학 조성물.
- 제1항에 있어서,상기 암은 폐암, 유방암, 대장암, 위암, 뇌암, 췌장암, 갑상선암, 피부암, 골수암, 림프종, 자궁암, 자궁경부암, 신장암 및 흑색종으로 구성된 군으로부터 선택되는 암인 것인 암 치료용 약학 조성물.
- 제1항에 있어서,상기 약학 조성물은 약학적으로 허용되는 담체, 부형제 또는 희석제를 추가로 포함하는 것인 암 치료용 약학 조성물.
- 제1항에 있어서,상기 약학 조성물은 액제, 산제, 에어로졸, 주사제, 수액제(링겔), 패치, 캡슐제, 환제, 정제, 데포(depot) 또는 좌제의 형태로 제형화되는 것인 암 치료용 약학 조성물.
- 아스코빅산(Ascorbic acid), 다이클로로아세트산(Dichloroacetic acid) 및 락테이트(Lactate) 중 선택된 2종의 화합물이 Ca, Zn, Mg 및 Fe로부터 선택되는 1종의 금속이온과 결합된 이온화합물을 유효성분으로 포함하는 암 전이억제용 약학 조성물.
- 제9항에 있어서,상기 금속이온은 Ca2+인 암 전이억제용 약학 조성물.
- 제9항에 있어서,상기 암은 폐암, 유방암, 대장암, 위암, 뇌암, 췌장암, 갑상선암, 피부암, 골수암, 림프종, 자궁암, 자궁경부암, 신장암 및 흑색종으로 구성된 군으로부터 선택되는 암인 것인 암 전이억제용 약학 조성물.
- 아스코빅산(Ascorbic acid), 다이클로로아세트산(Dichloroacetic acid) 및 락테이트(Lactate) 중 선택된 2종의 화합물이 Ca, Zn, Mg 및 Fe로부터 선택되는 1종의 금속이온과 결합된 이온화합물을 유효성분으로 포함하는 암 관련 피로 예방 또는 개선용 약학 조성물.
- 아스코빅산(Ascorbic acid), 다이클로로아세트산(Dichloroacetic acid) 및 락테이트(Lactate) 중 선택된 2종의 화합물이 Ca, Zn, Mg 및 Fe로부터 선택되는 1종의 금속이온과 결합된 이온화합물을 유효성분으로 포함하는 암 개선용 식품 조성물.
- 제13항에 있어서,상기 식품 조성물은 과자, 음료, 주류, 발효식품, 통조림, 우유가공식품, 육류가공식품 또는 국수가공식품의 형태인 건강기능성 식품으로 제조되는 것인 식품 조성물.
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CN201980054305.1A CN112584830B (zh) | 2018-08-22 | 2019-08-19 | 包含结合到金属离子中的离子化合物的肿瘤治疗用药学组合物 |
JP2021534100A JP7112791B2 (ja) | 2018-08-22 | 2019-08-19 | 金属イオンに結合されたイオン化合物を含む癌治療用薬学組成物 |
EP19850999.4A EP3842042A4 (en) | 2018-08-22 | 2019-08-19 | PHARMACEUTICAL COMPOSITION WITH A METAL ION-BONDED IONIC COMPOUND FOR THE TREATMENT OF CANCER |
BR112021003078-6A BR112021003078A2 (pt) | 2018-08-22 | 2019-08-19 | composições farmacêuticas que compreendem um composto iônico que tem um íon metálico ligado ao mesmo e composição alimentar para tratamento de câncer |
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BR112021003078A2 (pt) | 2021-05-11 |
AU2019324286B2 (en) | 2023-02-02 |
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