KR101643347B1 - A composition comprising auraptene for preventing or treating renal cell carcinoma - Google Patents
A composition comprising auraptene for preventing or treating renal cell carcinoma Download PDFInfo
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- KR101643347B1 KR101643347B1 KR1020150041452A KR20150041452A KR101643347B1 KR 101643347 B1 KR101643347 B1 KR 101643347B1 KR 1020150041452 A KR1020150041452 A KR 1020150041452A KR 20150041452 A KR20150041452 A KR 20150041452A KR 101643347 B1 KR101643347 B1 KR 101643347B1
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Abstract
Description
The present invention relates to a composition for the prophylaxis or treatment of renal cancer, including auretans. The present invention also relates to a composition for inhibiting renal cancer cell metastasis comprising aurotensin.
Renal cell carcinoma usually refers to renal cell carcinoma arising from parenchyma (composed of water and cortex), the part of the kidney where cells that urinate are gathered. It accounts for 3% of adult cancers in the United States, about 32,000 patients per year, and about 12,000 deaths from renal cell carcinoma. The incidence of kidney cancer is increasing every year in the world. In Korea, it occurs mainly in the elderly people in the 60s and 70s. The cancer rate is 2.0% in males and 10% in females. Respectively.
For the treatment of renal cancer, if the tumor is not metastasized to other organs, extensive resection of the kidney and its surrounding normal tissues may be performed. If the tumor is not large, surgery may be performed using laparoscopy. In the case of metastasis only, the tumor is removed. Other therapies include immunotherapy, hormone therapy, chemotherapy, and radiation therapy, but the therapeutic effect is not so great. So far, there is no definitive treatment for surgery other than surgical surgery. It's a problem.
On the other hand, hypoxia in cancer, especially in solid cancer, is a common phenomenon. Since solid cancer cells are generally adapted to hypoxic conditions through various genetic changes, cancer cells become more malignant as well as resistant to anticancer drugs. In addition, hypoxia is known to be a major causative agent in over 70% of all cancers in humans (Bos, R. et al., 2003; Hockel, M. et al., 2001; Kung, AL et al. , 2000; Maltepe, E. et al., 1997).
Hypoxia inducible factor-1 (HIF-1) is the most important factor that regulates the adaptation of cancer cells under hypoxic conditions. In order to respond appropriately to changes in external oxygen concentration, HIF- (Semenza, GL, 2003), which is a transcription factor that maintains intracellular homeostasis. Among them, HIF-1α has basix helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) structure and under conditions of hypoxic condition or genetic defect, the expression of HIF- Is known to activate HIF-1? Dependent signaling to induce tumor cell proliferation and promote angiogenesis, as well as to promote resistance to cancer drugs and cancer cell metastasis (reference figure 1). Thus, HIF-1 plays an important role in the growth, proliferation and malignancy of solid tumors, and therefore research on anticancer agents targeted therewith is very active (Rapisarda, A. et al., 2002; Semenza G. L., 2003).
[Reference Figure 1]
Auraptene is a kind of coumarin compounds and has been isolated from citrus fruits and has anticancer activity, antioxidant activity, anti-inflammatory activity, peroxisome proliferator-activated receptor agonist activity, antimicrobial activity, antiplatelet activity, Physiological activity such as mania activity is known.
In addition, prior art related to auraptene includes anticancer effects by inhibiting HIF-1 signaling in cancer cells (Li, J. et al., 2013), effects on colon cancer (Epifano, F. et al. , 2013), the inhibitory effect of melanoma cancer cells on lung metastasis (Tanaka, T. et al., 2000; Barthomeuf, C. et al., 2008), the effect of inhibiting cancer metastasis (US Patent Application Publication No. 2009/0118361, 2009 (Razorenova, OV et al., 2014) have been reported. However, it is not yet known that the effect of a selective anti-cancer activity of aureten on kidney cancer cells to be.
Therefore, the inventors of the present invention have found that by using auraptene, a citrus extract known as mitochondrial inhibitor, selectively induces hypoxia inducible factor-1α (HIF-1α), which is a major regulator of cancer metabolism and metastasis And confirming the preventive or therapeutic effect of renal cancer, thereby completing the present invention.
It is an object of the present invention to provide a composition for the prevention or treatment of renal cancer including auabutin or a composition for inhibiting the transfer of kidney cancer cells.
The present invention relates to a composition for preventing or treating kidney cancer comprising auraptene of the following formula (1).
[Chemical Formula 1]
The aureptin has an effect of inhibiting hypoxia inducible factor-1 alpha (HIF-1 alpha).
The present invention also relates to a composition for inhibiting metastasis of kidney cancer cells comprising auraptene of Formula 1 above.
In another aspect, the present invention relates to a health functional food for preventing or ameliorating renal cancer including auraptene of Formula 1 above.
Hereinafter, the present invention will be described in detail.
The present invention relates to a composition for the prophylaxis or treatment of renal cancer, including auretans, and can preferably be used by selectively inhibiting hypoxia inducible factor-1 ?.
The present invention also relates to a composition for inhibiting the metastasis of kidney cancer cells, comprising auabacten, and more preferably to a composition for inhibiting metastasis of kidney cancer cells.
On the other hand, the aurotensin of the present invention can be synthesized according to a conventional method in the art, and can also be made into a pharmaceutically acceptable salt.
The present invention also provides a pharmaceutical composition for preventing or treating renal cancer including aurabutene, wherein the pharmaceutical composition containing the aurotensin is administered in the form of powders, granules, tablets, capsules, suspensions, Emulsions, syrups, aerosols and the like, external preparations, suppositories, and sterilized injection solutions. Examples of carriers, excipients and diluents that can be contained in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain at least one excipient such as starch, calcium carbonate, sucrose or lactose , Gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, and syrups. In addition to water and liquid paraffin, simple diluents commonly used, various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. Examples of the suppository base include witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin and the like.
The dosage of the pharmaceutical composition comprising the aurotensin of the present invention will vary depending on the age, sex, body weight, the particular disease or condition to be treated, the severity of the disease or condition, the route of administration, and the judgment of the prescriber. Dosage determinations based on these factors are within the level of ordinary skill in the art and generally the dosage ranges from 0.01 mg / kg / day to approximately 2000 mg / kg / day. A more preferable dosage is 1 mg / kg / day to 500 mg / kg / day. The administration may be carried out once a day or divided into several times. The dose is not intended to limit the scope of the invention in any way.
The pharmaceutical composition comprising the aurotensin of the present invention can be administered to mammals such as rats, livestock, humans, and the like in a variety of routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine dural or intracerebral injection. Since the auroptenes of the present invention have little toxicity and side effects, they can be safely used for prolonged use for preventive purposes.
The present invention also provides a health functional food for preventing or ameliorating renal cancer, comprising aobactan and a pharmaceutically acceptable food-aid additive. The aurobutene may be added to the health functional food of the present invention in an amount of 0.001 to 100% by weight. The health functional food of the present invention includes forms such as tablets, capsules, pills, and liquid preparations. Examples of the foods to which the auropten can be added in the present invention include various foods, beverages, gums, tea, vitamins And combinations thereof.
The present invention relates to a composition for the prophylaxis or treatment of renal cancer including auretane, wherein the aureptan is excellent in an effect of selectively inhibiting hypoxia inducible factor-1 alpha in renal cancer cells and of inhibiting the mobility of kidney cancer cells, A composition for preventing or treating cancer and a composition for inhibiting the transfer of kidney cancer cells.
FIG. 1 shows the measurement results of oxygen consumption (FIG. 1A) and cell growth (FIG. 1B) showing that the aureptin of the present invention inhibits the process and mitochondrial metabolism but does not affect cell growth.
Figure 2 shows the Western blot results showing that the aureptenes of the present invention are selective for kidney cancer cells (Figure 2A) and have an effect of inhibiting HIF-1 alpha protein expression in dependence of treatment concentration (Figure 2B) and time (Figure 2C) to be.
Fig. 3 shows immunofluorescence staining results showing that the aureptin of the present invention has an effect of inhibiting the expression of HIF-1 alpha protein.
FIG. 4 shows the effect (FIG. 4A) of inhibiting the migration of renal cancer cells in a concentration-dependent manner and the graph of FIG. 4B (FIG. 4B).
Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.
≪ Example 1: Oxygen Consumption Rate and Cell Growth Confirmation of Auraptene >
Oxygen consumption rate (OCR) and cell growth were measured to confirm that the aureptenes of the present invention inhibited the process and mitochondrial metabolism but did not affect cell growth.
To measure the oxygen consumption rate, RCC4 (Renal cell carcinoma 4) was dispensed into a 24-well OCR plate at a concentration of 5 × 10 3 cells / well, and then DMSO (control group) or 10 μM augarptene (Sigma-Aldrich, USA) And cultured for 24 hours. Thereafter, 2 μg / ml of mitochondrial ATP synthase inhibitor oligomycin (Sigma-Aldrich, USA), mitochondrial uncoupler CCCP (carbonyl cyanide 3-chlorophenylhydrazone, Sigma-Aldrich, , USA) and 2 μM of mitochondrial complex I inhibitor (rotenone, Sigma-Aldrich, USA) were sequentially added, and the oxygen consumption rate was measured with an XF24 analyzer (seahorse, MA, USA) Respectively.
Also, MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) assays were performed to measure cell growth in RCC4 cells of auretane. First, RCC4 cells were cultured in RPMI 1640 supplemented with 10% [v / v] FBS (fetal bovine serum, Gibco, Rockville, MD, USA) and 1% [v / v] penicillin / streptomycin (100 U / mg, Sigma-Aldrich Co., USA ) And Dulbecco's modified Eagle's medium supplemented with 100 μg / ml of G418 (Sigma-Aldrich, USA) were added to each well of a 96-well microtiter plate, to the group treated with the group, and from 25 to 100μM and incubated for 6 to 24 hours under the condition that 37 ℃, atmospheric humidity is maintained with 5% CO 2 which is not treated. Thereafter, the medium was removed, and a serum-free medium containing the MTT solution was added thereto. After the reaction was carried out for 1 hour, the prepared formazan crystals were dissolved in DMSO and the resulting mixture was centrifuged at 570 nm And the absorbance was measured in Fig. 1B.
Referring to the results shown in FIG. 1, the aureptin of the present invention shows a significant effect of mitochondrial respiration of RCC4 cells. However, since cancer cells prefer metabolism via the corresponding process rather than mitochondrial respiration, cell growth is not affected regardless of the concentration of the aurotensin of the present invention, and thus it can be confirmed that there is no cytotoxicity.
<Example 2> Confirmation of inhibitory effect of HIF-1α protein expression>
Western blot and immunofluorescence staining were carried out to confirm the effect of the present invention on the expression of HIF-1 alpha protein.
Example 2-1. Confirmation of inhibitory effect of HIF-1α protein expression - Western blot
(Human breast cancer, ATCC, MD, USA) were used for the measurement of protein expression using Western blot, and each MEFs (Murine embryonic fibroblasts, Cefobio, Korea), HepG2 (human hepatic carcinoma, ATCC, ) And RCC4 (ECACC, Salisbury, UK) cells were placed in each medium according to the following conditions and incubated at 37 ° C in 5% CO 2 and 21% O 2 Lt; / RTI >
* Media conditions of each cell
MEFs: DMEM + 15% [v / v] FBS;
HepG2: DMEM + 10% [v / v] FBS + 1% [v / v] penicillin / streptomycin (100 U / mg);
MCF-7: DMEM + 10% [v / v] FBS + 1% [v / v] penicillin / streptomycin (100 U / mg);
RCC4: DMEM + 10% [v / v] FBS + 1% [v / v] penicillin / streptomycin (100 U / mg) + 100 g / ml G418.
The cultured cells were incubated with RIPA buffer (50 mM Tris-HCl pH 7.5, 150 mM NaCl, 1% [v / v] Nonidet (pH 7.5) containing protease inhibitor cocktail (Roche, Switzerland) (SDS-PAGE) (sodium dodecyl sulfate-polyacrylamide gel electrophoresis), followed by electrophoresis (SDS-PAGE) And transferred to a nitrocellulose membrane (Pall corporation, USA). (Novus biologicals, USA), anti-rabbit beta-actin (Santa Cruz biotechnology, USA), anti-α-tubulin (Sigma-Aldrich) primary antibody and HRP (Amersham biosciences, England) using a horseradish peroxidase-anti-mouse IgG (Pierce biotechnology, USA) or anti-rabbit IgG (Calbiochem, USA) as a secondary antibody and an ECL system 2A-2C.
Referring to FIG. 2, the aureptin of the present invention shows an effect (FIG. 2A) of reducing the expression of HIF-1α selectively expressed only in renal cancer cells (RCC4), unlike MEFs, HepG2 and MCF-7 cells. In addition, the effect of decreasing HIF-1.alpha. Protein expression depending on the treatment concentration (FIG. 2B) and time (FIG. 2C) of the aureptin was shown to be excellent, and it was confirmed that the effect as a composition for preventing or treating renal cancer was excellent.
Example 2-2. Identification of the inhibitory effect of HIF-1α protein expression - Immunofluorescent staining
For immunofluorescence staining, RCC4 cells were treated with a solution of ethanol and nitric acid on a cover slip. Thereafter, the cells were treated with 100 μM augaraben for 24 hours, fixed with 4% [v / v] paraformaldehyde at room temperature for 15 minutes, and then suspended in 0.25% [v / v] triton triton X-100 for 10 minutes. An anti-mouse HIF-1α antibody (BD Transduction, USA) in which the cells were dissolved in PBS was added and reacted at 4 ° C for 16 hours. Then, the cells were washed with PBS, and an anti-mouse (conjugated with Alexa Fluor 488) secondary antibody diluted in PBS was added. After reacting at room temperature for 1 hour, the cells were reacted with DAPI (4 ', 6-diamidino- HIF-1.alpha. and DAPI were observed with a LSM 510 META microscope (Carl Zeiss AG, Jena, Germany) for 5 minutes at room temperature.
3 shows that the aureptin of the present invention has an effect of reducing the expression of HIF-1α selectively expressed only in the kidney cancer cells, and thus is excellent as a composition for preventing or treating renal cancer.
≪ Example 3: Confirmation of the inhibitory effect of auretane on kidney cancer cell mobility &
In order to confirm the effect of the present invention on the mobility of renal cancer cells, a wound healing assay was performed.
The layer of RCC4 cells (ECACC, Salisbury, UK) was scratched with a pipette tip followed by washing with a medium, followed by 24 h of the group not treated with augaractin and the group treated with 50 to 100 μM auroptene . Thereafter, the horizontal distance of the scraped space was measured to confirm the mobility of the remaining cells except for the scratched portion, which is shown in FIGS. 4A and 4B.
Referring to FIG. 4, it can be confirmed that the aureptin of the present invention has an effect of inhibiting the mobility of kidney cancer cells in a concentration-dependent manner, and thus is excellent as a composition for inhibiting renal cancer cell metastasis.
< Example 4. Toxicity test>
Example 4-1. Acute toxicity
The present experiment was conducted to investigate the toxicity to the animal body in an acute (within 24 hours) when the aurotensin of the present invention was ingested in a short period of time and to determine the mortality rate. Twenty ICR mice were prepared, and 10 mice were assigned to each group. In the control group, 30% PEG-400 alone was administered, and the experimental group was orally administered with the aurobutene of the present invention at a concentration of 1.0 g / kg. After 24 hours of administration, the respective mortality rates were examined. As a result, both the control group and the test group administered with the aureptin survived.
Example 4-2. Organ organs toxicity test in experimental group and control group
The long-term toxicity test was carried out on C57BL / 6J mice to investigate the effects of the present invention on the organs (tissues) of the animals. The test group administered with 1.0 g / kg of the aureptenes of the present invention and the control animals (Glutamate-pyruvate transferase) and BUN (blood urea nitrogen) in the blood were measured by Select E (vital scientific NV, Netherland). As a result, GPT, which is known to be related to hepatotoxicity, and BUN, which is known to be related to renal toxicity, showed no significant difference compared to the control group. In addition, liver and kidney were cut from each animal and histological observation was performed with an optical microscope through a conventional tissue section production process, but no abnormal abnormalities were observed.
≪ Formulation Example 1 >
Formulation Example 1-1. Manufacture of tablets
200 g of augaraben of the present invention was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicic acid. To this mixture was added a 10% gelatin solution, which was pulverized and passed through a 14-mesh sieve. This was dried, and a mixture obtained by adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate was made into tablets.
Formulation Example 1-2. Injection preparation
1 g of the present invention, 0.6 g of sodium chloride and 0.1 g of ascorbic acid were dissolved in distilled water to make 100 ml. This solution was placed in a bottle and sterilized by heating at 20 DEG C for 30 minutes.
< Formulation example 2. Food Manufacturing>
Formulation Example 2-1. Manufacture of cooking seasonings
The aurobutene of the present invention was added to the cooking seasoning at 1% by weight to prepare a cooking sauce for health promotion.
Formulation Example 2-2. Manufacture of flour food products
The bread of the present invention was added to wheat flour at 0.1% by weight, and bread, cake, cookies, crackers and noodles were prepared to prepare a food for health promotion.
Preparation Example 2-3. Manufacture of soups and gravies
The health supplement soup and the juice were prepared by adding the aurobutene of the present invention to the soup and juice at 0.1 wt%.
Formulation Example 2-4. Manufacture of dairy products
The aurobutene of the present invention was added to milk in an amount of 0.1 wt%, and various dairy products such as butter and ice cream were prepared using the milk.
Formulation Example 2-5. Vegetable juice manufacturing
0.5 g of Aureoben of the present invention was added to 1,000 ml of tomato juice or carrot juice to prepare health promotion vegetable juice.
Formulation example 2-6. Fruit juice Produce
0.1 g of Aureaben of the present invention was added to 1,000 ml of apple juice or grape juice to prepare fruit juice for health promotion.
Claims (8)
[Chemical Formula 1]
Wherein said aureptin inhibits hypoxia-inducible factor-1 alpha (HIK-1 alpha).
[Chemical Formula 1]
Wherein said aureptin inhibits hypoxia-inducible factor-1 alpha (HIK-1 alpha).
[Chemical Formula 1]
Wherein said aureptin inhibits hypoxia-inducible factor-1 alpha (HIK-1 alpha).
[Chemical Formula 1]
Wherein said aureptin inhibits hypoxia-inducible factor-1 alpha (HIK-1 alpha).
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Citations (3)
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| JP2004131432A (en) * | 2002-10-11 | 2004-04-30 | Kumamoto Technology & Industry Foundation | Malignancy inhibitor |
| US20080119417A1 (en) * | 2005-01-21 | 2008-05-22 | Arkray, Inc. | Metabolic Syndrome-Improving Agent and Medicine, Supplement, Functional Food and Food Additive Containing the Same |
| US20090118361A1 (en) * | 2006-05-17 | 2009-05-07 | Arkray, Inc. | Suppressor of expression of mcp-1, and ameliorating agent for inflammatory disease, pharmaceutical, supplement, food, beverage or food additive using the suppressor |
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2015
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Patent Citations (3)
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| JP2004131432A (en) * | 2002-10-11 | 2004-04-30 | Kumamoto Technology & Industry Foundation | Malignancy inhibitor |
| US20080119417A1 (en) * | 2005-01-21 | 2008-05-22 | Arkray, Inc. | Metabolic Syndrome-Improving Agent and Medicine, Supplement, Functional Food and Food Additive Containing the Same |
| US20090118361A1 (en) * | 2006-05-17 | 2009-05-07 | Arkray, Inc. | Suppressor of expression of mcp-1, and ameliorating agent for inflammatory disease, pharmaceutical, supplement, food, beverage or food additive using the suppressor |
Non-Patent Citations (12)
| Title |
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| Barthomeuf, C. et al., Umbelliprenin from Ferula szowitsiana inhibits the growth of human M4Beu metastatic pigmented malignant melanoma cells through cell-cycle arrest in G1 and induction of caspase-dependent apoptosis, Phytomedicine, 15(12), 103-111, 2008. |
| Bos, R. et al., Levels of hypoxia-inducible factor-1alpha independently predict prognosis in patients with lymph node negative breast carcinoma, Cancer, 97(6), 1573-1581, 2003. |
| Epifano, F. et al., Auraptene and its effects on the re-emergence of colon cancer stem cells, Phytother. Res., 27(5), 784-786, 2013. |
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