WO2012026663A1 - Anticancer supplement including undecylenic acid, conjugated linoleic acid, and/or a conjugated linoleic acid isomer - Google Patents

Abstract

The present invention relates to an anticancer supplement including at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid, and a conjugated linoleic acid isomer as an active ingredient, to a composition for inhibiting peripheral nervous system disorders induced by the administration of anticancer agents, and to a method for inhibiting or improving peripheral nervous system disorders, as well as to a pharmacological, non-medicinal, and dietary compositions that include anticancer supplement. The invention further relates to a pharmacological composition including the anticancer supplement and taxol as active ingredients for the purpose of cancer treatment and to a method for the treatment of cancer, which can be effectively used for the purpose of treating cancer by enhancing the effects of anticancer activity and suppressing the side effects of anticancer agents.

Description

Anticancer adjuvant comprising undecylenic acid, conjugated linoleic acid and / or conjugated linoleic acid isomers

The present invention is an anticancer adjuvant comprising at least one fatty acid selected from the group consisting of undecylene acid, conjugated linoleic acid and conjugated linoleic acid isomers as an active ingredient, a composition for inhibiting peripheral nervous system diseases caused by administration of an anticancer agent, and inhibiting or improving peripheral nervous system diseases. How to; Pharmaceutical compositions, quasi-drug compositions, and food compositions comprising the anticancer adjuvant; It relates to a pharmaceutical composition for treating cancer and a method for treating cancer comprising the anticancer adjuvant and Taxol as an active ingredient.

Most anticancer drugs currently in use are limited due to their anticancer multidrug resistance, severe toxicity and side effects. Among the anticancer drugs, Taxol is isolated and purified from Taxus brevifolia and is widely used in the treatment of breast and ovarian cancer. Taxol has an anticancer effect by regulating the cell cycle. It selectively acts on tubulin without affecting the synthesis of DNA and RNA of cancer cells and without damaging the DNA molecule itself. By preventing the depolymerization of the polymerized tubulin, cancer cell death is stopped by stopping the growth of cancer cells in the middle of cell division.

However, Taxol has the side effect of breaking down neurites of nerve cells and causing peripheral neuropathy. In addition, when Taxol decomposes neurites and breaks the homeostasis of signal transduction in the neuromuscular junction, calcium is continuously released from the mitochondria and calcium-dependent protease calpine is continuously activated.

When p35, the substrate of calpein, is cut to p25 by activated calpain, p25 forms a complex with Cyclin-dependent kinase 5 (Cdk5) whose activity is regulated by p35. The p25 / Cdk5 complex pathologically sustains the phosphorylation activity of Cdk5, resulting in hyperphosphorylation of tau protein. The superphosphorylated tau protein produces a neurofibrillary tangle (NFT), which acts as a pathogenesis of Alzheimer's disease (Patrick G. N et al., Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration, Nature 402, 615-622, 1999). In addition, activated calpain activates caspase-3 and caspase-9, which play a key role in apoptosis. Activation of calpine / casease-3 cleaves DNA, causing apoptosis of neurons.

Therefore, there is a need for a calpine inhibitor that can not only inhibit the activity of calpine, but also reduce the side effects of anticancer agents including Taxol.

Accordingly, the present inventors have made intensive efforts to identify compounds having the activity of inhibiting calpine and simultaneously inducing the differentiation of neurites inhibited by anticancer agents. As a result, undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers are representative. When co-administered with anti-cancer drug Taxol, it was confirmed that differentiation of the neurites inhibited by Taxol was inhibited at the same time as the activity of calpine was suppressed, and the present invention was completed.

An object of the present invention is to provide an anticancer adjuvant comprising at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers.

Another object of the present invention to provide a pharmaceutical composition comprising the anticancer adjuvant.

Another object of the present invention is to provide a method for inhibiting or ameliorating peripheral nervous system diseases caused by an anticancer agent, comprising administering the pharmaceutical composition to a subject having a peripheral nervous system disease caused by an anticancer agent.

Still another object of the present invention is to provide a quasi-drug composition comprising the anticancer adjuvant.

Still another object of the present invention is to provide a food composition comprising the anticancer aid.

Another object of the present invention to provide a pharmaceutical composition for treating cancer comprising the anticancer adjuvant and Taxol as an active ingredient.

Still another object of the present invention is to provide a method for treating cancer, comprising administering the pharmaceutical composition for treating cancer to a subject having cancer.

Still another object of the present invention is to provide a cancer improving food composition comprising the anticancer aid and Taxol as an active ingredient.

Still another object of the present invention is to provide a composition for inhibiting peripheral nervous system disease caused by administration of an anticancer agent comprising at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers as an active ingredient.

As one embodiment for achieving the above object, the present invention provides an anticancer adjuvant comprising at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers.

In the present invention, conjugated linoleic acid (CLA) is a derivative of undecylenic acid (UDA), which is a positional geometric isomer of linoleic acid, which is an essential fatty acid, and traces in the ruminant's milk or muscle. Means the natural fatty acid component found.

The conjugated linoleic acid is composed of various isomers of linoleic acid having conjugated double bonds in cis or trans arrays of double bonds of octadecadienoic acid having 18 carbon atoms. isomers, and these conjugated linoleic acids may have cis or trans arrangements at positions 9 and 11 and 10 and 12, and theoretically by isomerization of linoleic acid (cis-9, cis-12 octadecadienoic acid). Sixteen structures and geometric isomers can be formed.

Preferably, the conjugated linoleic acid isomer may be, but is not limited to, cis9, trans11-conjugated linoleic acid (cis9, trans11-CLA) or trans10, cis12-conjugated linoleic acid (trans10, cis12-CLA).

In the present invention, undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers can be purchased and used commercially, or can be extracted and separated from castor ( Ricinus communis L. ).

In the present invention, cancer is a tumor or a tumor composed of undifferentiated cells that have unlimited proliferation in tissues, and the anticancer adjuvant of the present invention can be used for any type of cancer that develops in each part of the body. Can be used for the treatment of any one or more cancers selected from the group consisting of colorectal cancer, liver cancer, thyroid cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, prostate cancer, esophageal cancer, cervical cancer, colon cancer, bladder cancer, central nerve tumor and brain tumor, Preferably it can be used for the treatment of any one or more cancers selected from the group consisting of ovarian cancer, breast cancer, lung cancer and gastric cancer.

The anticancer adjuvant of the present invention can be used to increase the anticancer effect of the anticancer agent and to suppress or improve the side effects of the anticancer agent. Preferably, the side effect of the anticancer agent may be a peripheral nervous system disease caused by the anticancer agent, more preferably in Taxol. Inhibition of neurites due to neurogenesis (neurogenesis) and thereby peripheral nervous system diseases.

According to one specific embodiment of the present invention, undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers not only inhibit the activity of μ-calpain (Table 1), but also restore the inhibition of the differentiation of neurites, which is an anti-cancer side effect of Taxol. Excellent effect was shown (FIGS. 4-6). Therefore, undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers can be usefully used for the treatment of cancer as an anticancer adjuvant, and can suppress or eliminate side effects caused by anticancer agents.

The anticancer adjuvant of the present invention may be administered in combination with any kind of anticancer agent or anticancer agent to increase the anticancer effect of the anticancer agent and to suppress or improve the side effects of the anticancer agent. Preferably, the anticancer adjuvant of the present invention may be administered in combination with Taxol or Taxotere.

 As used herein, the term "inhibition" means any action that reduces the side effects of an anticancer agent by the administration of an anticancer adjuvant, and the term "improvement" in the present invention means the reduction of the side effects of an anticancer agent or the side effects of an anticancer agent by the administration of an anticancer adjuvant. It means any behavior that improves or beneficially changes the symptoms caused by cancer.

In addition, in the present invention, the term "individual" means all animals including humans who may develop or may develop cancer, and by administering the anticancer adjuvant of the present invention to a subject, cancer may be effectively treated while minimizing side effects of anticancer agents. . For example, the anticancer adjuvant of the present invention can be administered to a human suffering from cancer, including breast cancer, which is being treated with an anticancer agent, thereby effectively treating the cancer while reducing side effects of the cancer.

The route of administration of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered as intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, oral administration, intranasal administration, intrapulmonary administration, rectal administration, but is not limited thereto. Does not. In addition, the anticancer adjuvant may be administered by any device that allows the active substance to migrate to the target cell.

In another aspect, the present invention provides a pharmaceutical composition comprising an anticancer adjuvant according to the present invention.

In still another aspect, the present invention provides a method for inhibiting or ameliorating peripheral nervous system diseases caused by an anticancer agent, comprising administering the pharmaceutical composition to a subject having a peripheral nervous system disease caused by an anticancer agent.

In the present invention, the term "peripheral nervous system diseases caused by anticancer drugs" may include not only peripheral nervous system diseases caused by side effects due to the administration of anticancer drugs, but also the peripheral nervous system diseases already developed may be exacerbated by the administration of anticancer drugs.

 As used herein, the term "inhibition" means any action of reducing the side effects of an anticancer agent, in particular, peripheral nervous system diseases caused by an anticancer agent by administration of a pharmaceutical composition comprising an anticancer adjuvant, and the term "improvement" in the present invention. Anti-cancer side effects by administration of a pharmaceutical composition comprising an anticancer adjuvant means any action that improves or advantageously alters the symptoms caused by cancer due to a decrease or decrease in peripheral nervous system diseases caused by the anticancer agent.

In the present invention, the term "individual" means all animals including humans who may develop or may develop peripheral nervous system diseases caused by anticancer agents, and by administering to a subject a pharmaceutical composition comprising the anticancer adjuvant of the present invention, Anti-cancer side effects can effectively treat cancer, especially with minimal peripheral nervous system disease.

Preferably, the anticancer agent may be Taxol, and the peripheral nervous system disease may be peripheral neuropathy.

When the composition of the present invention is a pharmaceutical composition, it may include a pharmaceutically acceptable carrier. Compositions of the present invention comprising a pharmaceutically acceptable carrier may be in various oral or parenteral formulations. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants are usually used. Solid form preparations for oral administration include tablet pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, sucrose or lactose in one or more compounds. ) And gelatin. In addition to simple excipients, lubricants such as magnesium stearate, talc and the like are also used. Liquid preparations for oral administration include suspensions, solution solutions, emulsions, and syrups, and various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin, may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester 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 pharmaceutical composition of the present invention is selected from the group consisting of tablets, pills, powders, granules, capsules, suspensions, liquid solutions, emulsions, syrups, sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations and suppositories It can have any one formulation.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term “pharmaceutically effective amount” means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and an effective dose level is determined by the type of subject and its severity, age, sex, activity of the drug, drug. Sensitivity, time of administration, route of administration and rate of excretion, duration of treatment, type of cancer, consideration of concurrent anticancer agents, and other factors well known in the medical arts. However, for the desired effect, the pharmaceutical composition of the present invention is oral or parenteral route once or twice daily in an amount of 0.001 to 100 mg / kg body weight, preferably 0.01 to 50 mg / kg. It can be administered through.

The pharmaceutical composition of the present invention may be administered sequentially or simultaneously with anticancer agents known in the art, and may be administered single or multiple. In consideration of all the above factors, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and may be usually determined by the prescribing doctor.

The pharmaceutical composition of the present invention can be used in combination with methods using surgery, hormonal therapy, drug therapy and biological response modifiers for anticancer therapy.

As another aspect, the present invention provides a quasi-drug composition comprising an anticancer adjuvant according to the present invention. More specifically, the composition of the present invention can be added to the quasi-drug composition for the purpose of suppressing or improving side effects due to the administration of anticancer drugs.

When the anticancer adjuvant of the present invention is used as an quasi-drug additive, the anti-cancer adjuvant may be added as it is or used with other quasi-drugs or quasi-drug components, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the intended use.

Preferably, the quasi-drug composition of the present invention may be a disinfectant cleaner, a shower foam, a Gagreen, a wet tissue, a detergent soap, a hand wash, a humidifier filler, a mask, an ointment or a filter filler.

As another aspect, the present invention provides a food composition comprising an anticancer adjuvant according to the present invention. More specifically, the anticancer adjuvant of the present invention may be added to the food composition for the purpose of suppressing or improving the side effects caused by the administration of the anticancer agent.

The food composition of the present invention corresponds to all forms of health functional foods, nutritional supplements, nutritional supplements, pharmafood, health food, nutraceutical, designer food, food additives and the like.

When the anticancer adjuvant of the present invention is used as a food additive, the fatty acid may be added as it is or used with other food or food ingredients, and may be appropriately used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined depending on the stage of cancer progression, the type of cancer, the type of anticancer agent administered in combination, and the like.

There is no particular limitation on the type of food. Examples of the food to which the substance can be added include dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, drinks, Alcoholic beverages and vitamin complexes, and the like, may include all of the health food in the conventional sense.

In addition to the above, the food composition of the present invention includes various nutrients, vitamins, electrolytes, flavors, coloring agents, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols. And carbonation agents used in carbonated beverages. In addition, the food composition of the present invention may contain a flesh for preparing natural fruit juice, fruit juice beverage and vegetable beverage.

As another aspect, the present invention provides a pharmaceutical composition for treating cancer comprising the anticancer adjuvant and Taxol according to the present invention as an active ingredient. In order to effectively treat cancer by inhibiting or ameliorating the development of peripheral nervous system disease, which is one of the side effects of Taxol administration, the pharmaceutical composition for treating cancer according to the present invention can be used.

In still another aspect, the present invention provides a method for treating cancer, comprising administering a pharmaceutical composition for treating cancer according to the present invention to a subject having cancer.

As used herein, the term "treatment" refers to any action that improves or advantageously changes the symptoms caused by cancer by administration of the pharmaceutical composition for treating cancer of the present invention.

Preferably, the cancer may be any one or more cancers selected from the group consisting of ovarian cancer, breast cancer, stomach cancer, and lung cancer.

In the present invention, the mixing ratio of the anticancer adjuvant and Taxol is well known in the type of cancer, the age of the patient, the extent of cancer, the site of the cancer, the sex of the patient, the history of the patient and the amount of Taxol to be administered and other medical fields It can be determined according to the factors, but can usually be determined by the prescriber.

The pharmaceutical composition for treating cancer of the present invention may include a pharmaceutically acceptable carrier, as described above.

As another aspect, the present invention provides a cancer improving food composition comprising an anticancer adjuvant and Taxol according to the present invention as an active ingredient.

Specific embodiments of the cancer improving food composition of the present invention are as described in the food composition comprising an anticancer adjuvant.

As another aspect, the present invention provides a composition for inhibiting peripheral nervous system diseases caused by administration of an anticancer agent comprising at least one fatty acid selected from the group consisting of undecylene acid, conjugated linoleic acid and conjugated linoleic acid isomers as an active ingredient.

In the present invention, "peripheral nervous system disease caused by anticancer drug administration" may include not only peripheral nervous system disease caused by side effects due to anticancer drug administration, but also a peripheral nervous system disease that has already developed may be exacerbated by anticancer drug administration.

The composition for inhibiting peripheral nervous system diseases of the present invention can be used to suppress peripheral nervous system diseases caused by administration of anticancer agents, and preferably, to suppress peripheral nervous system diseases that can be caused by inhibition of neurogenesis differentiation by Taxol. Can be used.

Undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers exhibit the effect of restoring the differentiation inhibition (neurogenesis) of neurites by Taxol (Figs. 4 to 6), so that the composition for inhibiting peripheral nervous system diseases of the present invention is Taxol and By co-administration together, it can be useful for preventing or treating peripheral nervous system diseases caused by Taxol.

The peripheral nervous system diseases include all diseases caused by inhibiting the differentiation of neurites due to the administration of an anticancer agent, for example, peripheral neuropathy, diabetic peripheral neuropathy, neuromyopathy and autoimmune peripheral neuropathy. It is not limited.

The anticancer adjuvant comprising at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers according to the present invention as an active ingredient enhances the anticancer effect of the anticancer agent and at the same time inhibits the anticancer side effects. It can be useful for the treatment of

1 is a diagram showing the neuronal differentiation process of P19 cells of teratoma.

1: A is a schematic diagram of the neuronal differentiation experiment of P19 cell by NeuroD2.

FIG. 1B is a bright field image obtained by Differential Interference Contrast Microscope after transfecting NeuroD2 in a P19 cell line and incubating for 4 days, followed by immunostaining of beta III tubulin. Indicates.

1C is a fluorescence image of cells in which NeuroD2 is delivered expressing beta III tubulin.

Figure 2 is a photograph showing the neurites of P19 cells differentiated into neurons. Neuronal Profiling Bioapplication algorithm shows green and purple color along the length of neurites, and blue indicates cell body.

Figure 3 is a photograph showing that the differentiation of neurites was inhibited by the concentration-specific treatment of Taxol.

4 is a photograph showing that differentiation of neurites suppressed by Taxol occurred when undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers were treated with Taxol 10 nM.

5 is a photograph showing that differentiation of neurites suppressed by Taxol occurred when undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers were treated with Taxol 25 nM.

CLA 9Z11E and CLA 10E12Z in FIGS. 4-5 represent cis9, trans11-CLA and trans10, cis12-CLA, respectively.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples are merely to illustrate the present invention is not limited to the contents of the present invention.

Example 1 Screening of μ-calpain Inhibitors

The following experiment was performed to select compounds having μ-calpinein inhibitory activity among 6,480 compounds received from the Korea Compound Bank.

1-1. Fluorimetric μ-calpain assay

Fluorescence assays were performed in 96-well plates, and the end-point fluorescence intensity of each well was measured using a Microplate Fluorescence Reader (SPECREAmax GEMINI _EM , Molecular Divices). IC ₅₀ was measured by data graphing software TableCurve 2D (Systat software Inc.). Fluorescence intensity was expressed in RFU (Relative fluorescence unit).

For the measurement of μ-calpein activity, see Stifun Mittoo et al. (Stifun Mittoo et al., Synthesis and evaluation of fluorescent probes for the detection of calpain activity, Analytical Biochemistry, Aug 15; 319 (2), 234-8, 2003). Fluorescence-based probes were used to measure the activity of μ-calpine, and the principle of fluorescence resonance energy transfer (FRET) was used. The substrate is based on the calpain cleavage site of p35, which is based on the [2-Abz] -Ser-Thr-Phe-Ala-Gln-Pro-3-nitrotyrosine] -NH2 linking the donor and the recipient on both sides. It was used (hereinafter referred to as pep2). μ-calcane cleaves between phenylalanine and alanine in pep2. The assay uses a reaction buffer (50 mM Tris-HCl, 50 mM NaCl, 1 mM EDTA, 5 mM β-mercaptoethanol; pH 7.5) at a final volume of 100 μl, 100 μM pep2, 2.5 mM CaCl ₂ , 5.25 units / ml Calpine (Calbiochem, Germany) purified from human erythrocytes was used. Substrate, μ-calpein, and the compound to be tested are added in order, and finally, CaCl ₂ is added, followed by incubation at room temperature for 30 minutes, followed by fluorescence intensity at 320 nm excitation (ex) and 420 nm emission (em). The change was measured. As a positive control, MDL28170 (sigma, USA), which is known as a calpine inhibitor, was used.

1-2. Fluorimetric Cat-B & Cat-L Assays

Along with the μ-calpane assay, compounds were inhibited by Cat-B and Cat-L activity with reference to Dominic Cuerrier et al. (Dominic Cuerrier et al., Development of calpain-specific inactivators by screening of positional-). scanning epoxide libraries, JBC papers in press, Jan 11, 1-18, 2007). Essays were performed at a final volume of 100 μl. Cat-B reaction buffer [50 mM sodium acetate, 2 mM dithiothreitol (DTT), 2 mM ethylenediaminetetraacetic acid (EDTA); pH 5.5] and a 20 μM substrate, 1.5 nM Cat-B (Calbiochem, Germany), 4 nM Cat-L (Calbiochem, using a Cat-L reaction buffer (200 mM sodium acetate, 4 mM EDTA, 8 mM DTT; pH 5.5)). Germany). Substrates were Z-RR-AMC, a Cat-B specific substrate, and Z-FR-AMC, a Cat-L substrate. Kadepsin (Cathepsin) was previously reacted for 30 minutes at 37 ° C. in a buffer and then treated with the substrate and the compound to be tested, shaken for 10 minutes at room temperature, and then incubated at 37 ° C. for 30 minutes. Fluorescence intensity changes were measured at 360 nm (ex) and 450 nm (em) wavelengths. Cat-B was used as a positive control CA-074 (sigma, USA), Cat-L was used Z-FF-FMK (sigma, USA).

1-3. Screening of Undecylenic Acid and Conjugated Linoleic Acid to Inhibit μ-Calpine Activity

The fluorescence assay measurement results are shown in Table 1 below.

Table 1

As shown in Table 1, undecylenic acid (Undaylenic acid, UDA), its derivative conjugated linoleic acid (CLA) and conjugated linoleic acid isomers (10t12c CLA, 9c11t CLA) inhibitory activity against μ-calcane You can see this excellent (Table 1).

Specifically, conjugated linoleic acid (IC ₅₀ = 2.14 μM) selectively inhibited calpine at a concentration about 2 times lower than undecylene acid (IC ₅₀ = 5.37 μM). In addition, the conjugated linoleic acid isomers 10t12c CLA (IC ₅₀ = 2.24 μM) and 9c11t CLA (IC ₅₀ = 5.52 μM) also selectively inhibited calpine. Among other undecylenic acid derivatives, lauric acid inhibited Cat-B activity by about 60% at 100 μM, and arachidonic acid was concentration-independent at 100 μM. 98% inhibition of Cat-B activity. Gamma-linoleic acid had no calpine inhibitory effect, but inhibited Cat-B and Cat-L activity at IC ₅₀ values of 8.08 μM and 3.78 μM, respectively. Since the substrate contained a cleavage site of p35, it was found that these compounds inhibited the calpein overactivation resulting in cleavage of p35 to p25.

Example 2 Confirmation of the Restorative Effect of Undecylenic Acid, Conjugated Linoleic Acid, and Conjugated Linoleic Acid Isomers on Inhibition of Neurites Differentiation by Taxol

As confirmed in Example 1, in order to determine whether the undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers having μ-calcine inhibitory activity can restore differentiation of neurites inhibited by Taxol, Was performed.

2-1. Experiment method

P19 cells, an embryonic carcinoma, were grown in DMEM (Hyclone laboratories Inc, USA) and 10% FBS (Hyclone laboratories Inc, USA), 1% penicillin. Cells were maintained at 37 ° C., 5% CO ₂ environment. The medium was changed every two to three days, and the subculture was 1: 4 to 1: 8. In order to differentiate P19 cells into neurons, neuroD2, a neuronal transcription factor, was transfected and cultured for 4 days. In this case, in order to identify differentiated neurons, beta III tubulin (beta III tubulin) specifically expressing only neurons (Neuron) was immunostained to measure the degree of differentiation of neurons (see FIG. 1). P19 cells differentiated into neurons were treated with Taxol, Undecylenic Acid (UDA), Conjugated Linoleic Acid (CLA), Conjugated Linoleic Acid Isomer, or DMSO (Control), and images were acquired using Cellmics, an image analyzer. Then, the length (differentiation degree) of the neurites was measured by a Neuronal Profiling Bioapplication algorithm. At this time, it is divided into green or purple according to the length of the neurites, and numerical results can be obtained (see FIG. 2).

2-2. Experiment result

<2-2-1> Inhibition of neurites differentiation following Taxol treatment

According to the experimental method of Example 2-1, the result of treating Taxol to P19 cells by concentration is shown in FIG. 3. As a result, the differentiation of neurites was suppressed in the Taxol treatment group compared to the DMSO treatment group as a control group, and it was confirmed that the differentiation of the neurites was remarkably suppressed especially when the Taxol treatment was 10 nM or more (see FIG. 3).

<2-2-2> Neurites Differentiation Effect of Taxol 10 nM and UDA, CLA or CLA Isomer Simultaneously

According to the experimental method of Example 2-1, the result of treatment of Taxol 10 nM and undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers (9Z11E, 10E12Z) with 10 μM or 20 μM, respectively, was carried out according to the experimental method of Example 2-1. . As a result, when 10 μM or 20 μM of undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers were treated, it was confirmed that differentiation of neurites suppressed by Taxol occurred. In particular, when treated with undecylenic acid or conjugated linoleic acid 9Z11E, it was confirmed that differentiation of neurites inhibited by Taxol occurred remarkably (see FIG. 4).

<2-2-3> Neurites Differentiation Effect of Taxol 25 nM and UDA, CLA or CLA Isomers Simultaneously

According to the experimental method of Example 2-1, P19 cells were treated with Taxol 25 nM, undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers (9Z11E, 10E12Z) at 10 μM or 20 μM, respectively. . As a result, when 10 μM or 20 μM of undecylenic acid, conjugated linoleic acid or conjugated linoleic acid isomers were treated, it was confirmed that differentiation of neurites suppressed by Taxol occurred. In particular, when treated with undecylenic acid or conjugated linoleic acid 9Z11E, it was confirmed that differentiation of neurites suppressed by Taxol occurred remarkably (see FIG. 5).

Claims (18)

1. An anticancer adjuvant comprising at least one fatty acid selected from the group consisting of undecylenic acid, conjugated linoleic acid and conjugated linoleic acid isomers.
2. The anticancer adjuvant of claim 1, wherein the conjugated linoleic acid isomer is cis9, trans11-conjugated linoleic acid (cis9, trans11-CLA) or trans10, cis12-conjugated linoleic acid (trans10, cis12-CLA).
3. The anticancer adjuvant of claim 1, wherein the anticancer adjuvant inhibits or ameliorates peripheral nervous system diseases caused by the anticancer agent.
4. The anticancer adjuvant of claim 3, wherein the anticancer agent is Taxol.
5. The anticancer adjuvant of claim 1, wherein the anticancer adjuvant is for treating or ameliorating any one or more cancers selected from the group consisting of ovarian cancer, breast cancer, gastric cancer, and lung cancer.
6. A pharmaceutical composition comprising an anticancer adjuvant according to claim 1.
7. A method of inhibiting or ameliorating peripheral nervous system diseases caused by an anticancer agent, comprising administering the pharmaceutical composition of claim 6 to a subject having a peripheral nervous system disease caused by an anticancer agent.
8. 8. The method of claim 7, wherein the anticancer agent is Taxol.
9. 8. The method of claim 7, wherein the peripheral nervous system disease is peripheral neuropathy.
10. Quasi-drug composition comprising an anticancer adjuvant according to claim 1.
11. Food composition comprising an anticancer adjuvant according to claim 1.
12. A pharmaceutical composition for treating cancer, comprising the anticancer adjuvant and taxol according to claim 1 as an active ingredient.
13. A cancer treatment method comprising administering the pharmaceutical composition for treating cancer of claim 12 to a subject having cancer.
14. The method of claim 13, wherein the cancer is one or more cancers selected from the group consisting of ovarian cancer, breast cancer, gastric cancer, and lung cancer.
15. A cancer improving food composition comprising the anticancer aid and taxol according to claim 1 as an active ingredient.
16. A composition for inhibiting peripheral nervous system diseases caused by administration of an anticancer agent comprising at least one fatty acid selected from the group consisting of undecylene acid, conjugated linoleic acid and conjugated linoleic acid isomers as an active ingredient.
17. The composition of claim 16, wherein the anticancer agent is Taxol.
18. The composition of claim 16, wherein the peripheral nervous system disease is peripheral neuropathy.

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