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WO2018021618A1 - Inhibiteur de croissance de cellules souches cancéreuses, contenant du cis-3-hexénal. - Google Patents

Inhibiteur de croissance de cellules souches cancéreuses, contenant du cis-3-hexénal. Download PDF

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Publication number
WO2018021618A1
WO2018021618A1 PCT/KR2016/011209 KR2016011209W WO2018021618A1 WO 2018021618 A1 WO2018021618 A1 WO 2018021618A1 KR 2016011209 W KR2016011209 W KR 2016011209W WO 2018021618 A1 WO2018021618 A1 WO 2018021618A1
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cancer
composition
hexenal
cis
cells
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Korean (ko)
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이동선
고상운
최학선
김지향
김수림
정동기
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    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
    • A24D3/06—Use of materials for tobacco smoke filters
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
    • A24D3/06—Use of materials for tobacco smoke filters
    • A24D3/08—Use of materials for tobacco smoke filters of organic materials as carrier or major constituent
    • A—HUMAN NECESSITIES
    • A24—TOBACCO; CIGARS; CIGARETTES; SIMULATED SMOKING DEVICES; SMOKERS' REQUISITES
    • A24D—CIGARS; CIGARETTES; TOBACCO SMOKE FILTERS; MOUTHPIECES FOR CIGARS OR CIGARETTES; MANUFACTURE OF TOBACCO SMOKE FILTERS OR MOUTHPIECES
    • A24D3/00—Tobacco smoke filters, e.g. filter-tips, filtering inserts; Filters specially adapted for simulated smoking devices; Mouthpieces for cigars or cigarettes
    • A24D3/06—Use of materials for tobacco smoke filters
    • A24D3/14—Use of materials for tobacco smoke filters of organic materials as additive
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L9/00—Disinfection, sterilisation or deodorisation of air
    • A61L9/015—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone
    • A61L9/04—Disinfection, sterilisation or deodorisation of air using gaseous or vaporous substances, e.g. ozone using substances evaporated in the air without heating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q13/00—Formulations or additives for perfume preparations

Definitions

  • the present invention comprises cis-3-hexenal or a pharmaceutically acceptable salt thereof as an active ingredient, a composition for inhibiting cancer stem cell growth, perfume composition, inhibiting metastasis of cancer comprising the composition, or treating cancer or It relates to a prophylactic pharmaceutical composition, food composition and the like.
  • Cancer stem cells were first identified in myeloid leukemia and then in various solid cancers, including breast, brain, colon, ovary, pancreatic, and prostate cancers.
  • the cancer stem cells are also called tumor-initiating cells and cancer stem-like cells. It has also been shown that various cancer types, including breast cancer, originate from cancer stem cells (CSCs), a subpopulation of tumors. Such populations are known to cause changes in tumor volume through self-renewal and differentiation. Wnt (wingless), Shh (Sonic hedgehog), Stat3, NF- ⁇ B, Wnt / ⁇ -catenin, TGF- ⁇ and Notch signaling pathways are known to be critical for self-renewal of CSCs.
  • CSCs cancer stem cells
  • Wnt wingless
  • Shh Sonic hedgehog
  • Stat3 NF- ⁇ B
  • Wnt / ⁇ -catenin Wnt / ⁇ -catenin
  • TGF- ⁇ and Notch signaling pathways are known to be critical for self-renewal of CSCs.
  • Cancer stem cells exhibit drug resistance and radiation resistance to chemotherapy and radiation therapy and cause cancer to recur and metastasize.
  • targeted therapies for cancer stem cells are essential for the treatment of cancer.
  • Cancer stem cells are known to express certain proteins, including Oct4, C-myc, Nanog, and Aldehyde dehydrogenase-1 (ALDH).
  • the ALDH is an enzyme that oxidizes toxic aldehydes, and its enzymatic activity is widely used as a CSC (cancer stem cells) marker of leukemia, head and neck, bladder, bone, colon, liver, lung, pancreas, prostate, thyroid and cervical cancer. have.
  • ALDH is known as a therapeutic target for cancer stem cells.
  • Stat3 (Signal transducers and activators of transcription 3) is mainly activated in CSCs, and mammosphere formation is associated with the JAK1-STAT3 pathway.
  • Secreted IL-6 activates the JAK1-STAT3 pathway and increases expression of the Oct4 gene.
  • the IL-6 / JAK1 / STAT3 signaling pathway is known to be important for the conversion of NSCCs (Non-CSCs) to CSCs. Blocking the STAT3 signaling pathway is known to inhibit the growth of breast cancer cell-derived CD44 + / CD24- stem cell-like cells.
  • Nuclear factor- ⁇ B (NF- ⁇ B) transcription factor is structurally (constantly) activated in tumor cells, including colon, breast and liver cancer, and regulated by the I ⁇ B kinase (IKK) complex.
  • IKK I ⁇ B kinase
  • Pyrrolidinedithiocarbamate (PDTC) an inhibitor of NF- ⁇ B, is known to inhibit breast cancer stem-like cells.
  • the breast cancer stem cells are known to be identified by the expression of biomarkers such as CD44 high / CD24 low , ESA + (epithelial specific antigen) and ALDH. Chemotherapy is known to increase the proportion of cancer cells expressing CD44 + / CD24- and mammosphere formation. CSCs overexpress specific ABC transporters to protect CSCs from toxins. ABC pumps are used to separate side populations (SP) and can be classified by ABCG2 transporter-specific Hoechst 33342 dyes. Because breast CSCs produce low levels of reactive oxygen species (ROS) compared to tumor cells, breast cancer stem-likes cells are radiation resistant.
  • ROS reactive oxygen species
  • CSCs are known to have less DNA damage than non-stem cancer cells (Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M, Joshua B, Kaplan MJ, Wapnir I, Dirbas FM, Somlo G, Garberoglio C, et al.Association of reactive oxygen species levels and radioresistance in cancer stem cells.Nature. 2009; 458 (7239): 780-783).
  • the breast cancer cell line MCF-7 is known to have a subset of cells with similar capacity to stem cells that can grow in oval form without apoptosis without attachment in vitro. Artificially creating a non-basement condition by floating culture, the cells with stem cell properties are attached to each other to form a spherical cell mass, which is called a neurosphere. Applying this concept to human breast stem cells is the "mammosphere". Mammoth Fair contains eight times more progenitor cells than normal human breast cells, and can be passaged continuously. After several passages, 100% of the cells grow into bi-potent precursors.
  • Mammoth is capable of differentiating into mammary gland epitherlial cells, ductal epithelial cells, and alveolar epitherlial cells, which are adult breast cells. It is observed to form a complex functional breast structure while forming a three-dimensional structure. Mammoth fair is one of the most characteristic characteristics of stem cells is capable of self-proliferation, so that a large number of mammo pairs or breast stem cells can be obtained from a single mammo pair. In addition, compared with hematopoietic stem cells, neural stem cells, embryonic stem cells, etc., many expression genes were confirmed to overlap, and mammospheres were reported to be actual breast stem cells. The standard method for analyzing the self-renewal ability of cancer stem cells is to analyze the implantation in vivo and the mammosphere formation in vitro.
  • cells having stem cell properties may be attached to each other to form spherical cell masses in various cancer cell lines including breast cancer cells as well as lung cancer, which is called a tumorsphere.
  • the two pairs refers to tumor cells developed by the proliferation of one cancer stem cell or cancer progenitor cell.
  • Lung cancer is the leading cause of cancer-related deaths worldwide, and is classified into two major subtypes: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • NSCLC non-small cell lung cancer
  • the non-small cell lung cancer (NSCLC) is divided into three subtypes, adenocarcinoma, squamous cell carcinoma and large cell carcinoma.
  • Smoking is a major risk factor for lung cancer.
  • Lung cancer can be treated with chemotherapy and radiation but becomes resistant.
  • the 5-year survival rate of lung cancer is low, and the 1-year survival rate of small cell lung cancer is 40%, and the 5-year survival rate is 5% or less.
  • cancer stem cells have chemical resistance and radiation resistance to chemotherapy and radiotherapy to eradicate bulk tumors, resulting in cancer recurrence and metastasis.
  • treatment targeting CSC is essential for the treatment of lung cancer.
  • cancer stem cells To date, studies on cancer stem cells have many limitations, and the role of cancer stem cells in the formation and maintenance of tumors is not clear. In order to efficiently perform treatments targeting cancer stem cells without damaging normal stem cells, knowledge and understanding of molecular biological characteristics and its regulatory pathways that are important for the maintenance and regulation of cancer stem cells are required.
  • An object of the present invention is to provide a composition for inhibiting cancer stem cell growth comprising a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for inhibiting metastasis of cancer, or treating or preventing cancer, comprising the composition for inhibiting cancer stem cell growth.
  • Another object of the present invention is to provide a food composition for metastasis, cancer improvement, or prevention of cancer, comprising the composition for inhibiting cancer stem cell growth.
  • Another object of the present invention is to provide a fragrance composition for inhibiting growth of cancer stem cells, which comprises a volatile compound represented by the formula (1).
  • Another object of the present invention is to provide a method of inhibiting the growth of cancer stem cells, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for inhibiting cancer metastasis, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a method for preventing or treating cancer, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting the growth of cancer stem cells.
  • Another object of the present invention is to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting cancer metastasis.
  • Still another object of the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of cancer.
  • Cis-3-hexenal of the present invention inhibits the growth of breast and lung cancer cells and inhibits the formation of stem cells of breast and lung cancer.
  • it inhibited the expression of self-renewing genes such as Nanog, C-myc, Oct4, and CD44, which are known to be characteristically expressed in lung cancer stem cells, and produced IL-6, which is known to be involved in the mammoth formation of breast cancer stem cells.
  • IL-6 which is known to be involved in the mammoth formation of breast cancer stem cells.
  • STAT3 signaling pathway inhibited the production of IL-8, which is known to be involved in the tumorous formation of lung cancer stem cells, and confirmed that it inhibits the NF- ⁇ B signaling pathway.
  • the compound inhibits the growth of cancer stem cells, such as breast cancer and lung cancer, and the growth of these cancers, and can be used for the treatment of cancers such as breast cancer and lung cancer.
  • Figure 1 shows that cis-3-hexenal inhibits various cancer features in breast cancer cell lines.
  • Figure 1 (A and B) shows the chemical structure of cis-3-hexenal and the viability of cis-3-hexenal for MCF-7 and MDA-MB-231 cells. MCF-7 and MDA-MB-231 cells were treated with increasing concentrations of cis-3-hexenal for 48 hours. The anti-proliferative effect of cis-3-hexenal was determined by MTS analysis.
  • C, D shows the effect of cis-3-hexenal on cell death of breast cancer cells.
  • MDA-MB-231 and MCF-7 cells were treated with cis-3-hexenal for 24 hours and killed cells were analyzed by FACS using the Annexin V-PI staining kit.
  • Fig. 2 (A) shows the effect of cis-3-hexenal on cell death of breast cancer cells.
  • MCF-7 and MDA-MB-231 cells were treated with cis-3-hexenal for 24 hours and killed cells were analyzed by FACS using the Annexin V-PI staining kit.
  • FIG. 2 (B) shows the effect of cis-3-hexenal on the migration potential of human breast cancer cells. Wound healing of MDA-MB-231 cells was taken at 0 and 18 hours, depending on whether cis-3-hexenal was treated.
  • FIG. 2 (C) shows the effect of cis-3-hexenal on colony formation in human breast cancer cells.
  • the dissociated 1000 MDA-MB-231 cells were seeded in 6-well plates and treated for 7 days at the indicated concentrations of cis-3-hexenal and DMSO. Representative images of colonies were recorded. Data shown represent mean ⁇ SD of three independent experiments. * p ⁇ 0.05 vs. DMSO-treated control.
  • FIG. 3 shows the effect of cis-3-hexenal on tumor growth in xenograft models.
  • Three million cells were injected into the mammary fat pad of immunodeficient NOD-SCID female nude mice.
  • (B and C) show the effect of cis-3-hexenal on the weight of the tumor. Tumor weights were measured after treatment.
  • MCF-7 and MDA-MB-231 cells were incubated under mammoth pairing conditions for 7 days.
  • (A) shows the effect of cis-3-hexenal on MCF-7 cell-derived mammoth pair formation.
  • Primary mammoth pairs were incubated with cis-3-hexenal (10 and 20 ⁇ M) or DMSO.
  • (B) shows the effect of cis-3-hexenal on the formation of mammoth pair derived from MDA-MB-231 cells.
  • the mammo pair was incubated with cis-3-hexenal (25 ⁇ M) or DMSO.
  • FIG. B shows the effect of cis-3-hexenal on ALDH positive cell populations.
  • MDA-MB-231 cells were treated with cis-3-hexenal (25 ⁇ M) or DMSO for 2 days, followed by ALDEFLUOR analysis and FACS analysis.
  • the top panel shows ALDH positive cells treated with DEAB, an ALDH inhibitor as a negative control, and the bottom panel shows ALDH positive cells untreated with DEAB.
  • ALDH positive populations are marked in boxes.
  • (A) shows the effect of cis-3-hexenal on the STAT3 signaling pathway in mammoth pairs.
  • Nuclear protein expression and activation of STAT3 and NF-kB were measured in mammoth pairs with antibodies to pSTAT3, STAT3, P65 and Lamin B.
  • Cis-3-hexenal reduced the level of nuclear pSTAT3 protein in mammoths.
  • Lane 1 probe alone; Lane 2: probe + nuclear extract; Lane 3: probe + cis-3-hexenal treated nuclear extract; Lane 4: self competition; Lane 5: nuclear extract incubated with mutant STAT3 probe.
  • the cis-3-hexenal reduced DNA / STAT3 interactions in mammoth nuclear lysates.
  • (B) shows the effect of cis-3-hexenal on mammosphere growth.
  • the cis-3-hexenal inhibited mammosphere growth.
  • the cis-3-hexenal and DMSO treated mammoth pairs were dissociated into single cells for 2 days and plated in 6 cm dishes with the same cell number. After 24 hours of plating, cells were counted. On days 2 and 3, cells were counted and plotted to mean value.
  • the data represent the mean ⁇ SD of three independent experiments. * p ⁇ 0.05 vs. DMSO-treated control.
  • C Models of Stat3 signaling and formation of CSCs by IL-6 are shown.
  • Activated pStat3 forms a dimer.
  • the dimerized pStat3 migrates to the nucleus and binds to the promoter of the IL-6 gene, producing IL-6.
  • the secreted IL-6 can convert non-cancerous stem cells (NSCCs) into cancer stem cells (CSCs) and regulate the dynamic equilibrium of NSCCs to CSCs.
  • NSCCs non-cancerous stem cells
  • CSCs cancer stem cells
  • Cis-3-hexenal deregulates dynamic equilibrium from NSCCs to CSCs through deregulation of IL-6 and dephosphorylation of STAT3.
  • Figure 8 shows that cis-3-hexenal inhibits various cancer features in lung cancer cell lines.
  • Figure 8 (A, B) shows the chemical structure of cis-3-hexenal and the viability of cis-3-hexenal for A549 lung cancer cells. A549 cells were treated with increasing concentrations of cis-3-hexenal for 48 hours. The anti-proliferative effect of cis-3-hexenal was determined by MTS analysis.
  • FIG. 8 (C) shows the effect of cis-3-hexenal on cell death of lung cancer cells.
  • A549 cells were treated with cis-3-hexenal for 24 hours and killed cells were analyzed by FACS using the Annexin V-PI staining kit.
  • FIG. 8 Apoptotic cells were analyzed by fluorescence staining, and nuclei were stained with Hoechst 33258 (enlarged, x100) in lung cancer.
  • 9A shows the effect of cis-3-hexenal on the migration potential of human lung cancer cells. Wound healing of A549 cells was taken at 0 and 18 hours, depending on whether cis-3-hexenal was treated.
  • FIG. 9 (B) shows the effect of cis-3-hexenal on colony formation in human lung cancer cells.
  • the dissociated 1000 A549 cells were seeded in 6-well plates and treated with cis-3-hexenal and DMSO at the indicated concentrations for 7 days. Representative images of colonies were recorded. Data shown represent mean ⁇ SD of three independent experiments. * p ⁇ 0.05 vs. DMSO-treated control.
  • FIG. 10 shows the effect of cis-3-hexenal on tumor growth in xenograft models implanted with lung cancer cells. Five million cells were injected into the tail vein of immunodeficient NOD-SCID male nude mice.
  • FIG. 11 shows the effect of cis-3-hexenal on tumor growth in xenograft models implanted with lung cancer cells. Three million cells were injected into the skin of immunodeficient NOD-SCID male nude mice.
  • (A) The effect of cis-3-hexenal on tumor growth in immunodeficient nude mice producing A549 cells.
  • the drug dosage used is 10 mg / kg.
  • (B) shows the effect of cis-3-hexenal on tumor weight. Tumor weights were measured after treatment.
  • (C) Tumor volume was measured twice a week using a caliper and calculated as (width 2 ⁇ length) / 2. Tumor growth curves were monitored during the experiment. P ⁇ 0.05 compared to control. Representative images were captured at the 7th week of treatment and the results were shown in vehicle treated controls, cis-3-hexenal treated mice.
  • Figure 12 shows the effect of cis-3-hexenal on tomuspher formation.
  • A549 cells were incubated for 7 days under tomuspher forming conditions.
  • (A) shows the effect of cis-3-hexenal on A549 cell-derived tomuspher formation.
  • Primary tomuspares were incubated with cis-3-hexenal (0.1, 0.2, 0.3 and 0.4 mM) or DMSO.
  • FIG. 13 shows the effect of cis-3-hexenal on ALDH positive cell populations.
  • A549 cells were treated with cis-3-hexenal (0.4 mM) or water for 2 days, followed by ALDEFLUOR analysis and FACS analysis.
  • the top panel shows ALDH positive cells treated with DEAB, an ALDH inhibitor, and the bottom panel shows ALDH positive cells untreated with DEAB.
  • ALDH positive populations are marked in boxes.
  • Nanog, C-myc, Oct4 and CD44 genes were determined by real-time PCR (RT-PCR) using CSC marker specific primers in cis-3-hexenal and DMSO-treated tomerspares. It was analyzed using. ⁇ -actin was used as an internal control.
  • Figure 15 shows the effect of cis-3-hexenal on NF-kB signaling pathway and extracellular IL-8 protein levels in Too's Pair.
  • (B) Human inflammatory cytokine analysis of cis-3-hexenal or DMSO treated tumors.
  • the inflammatory cytokines were measured using a BD cytometric bead array (CBA) human inflammatory cytokines kit.
  • CBA analysis was performed using IL-6, IL-8, IL-10, IL-12, IL-1 ⁇ , and TNF antibodies.
  • the present inventors are candidates for inhibition of cancer stem cells, which are plant-derived volatile organic compounds (VOCs), jasmonate, salicylic acid, cinnamic acid, hexanal , Octaneol, ⁇ -citronellol, and rose oxide were screened, among which only leaf aldehyde cis-3-hexenal was found. It was confirmed to selectively inhibit the cells.
  • VOCs plant-derived volatile organic compounds
  • Cis-3-hexenal known as ( Z ) -3-hexenal, is a major volatile compound present in ripe tomatoes, which selectively inhibits the STAT3 signaling pathway in mammoth cells compared to MCF-7 bulk cells.
  • cis-3-hexenal inhibits the growth of cancer stem cells including breast cancer and lung cancer by targeting CSCs, confirming that the cis-3-hexenal can be used for treating cancers including breast cancer and lung cancer, and completed the present invention.
  • the present invention provides a composition for inhibiting cancer stem cell growth comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound may be derived from a plant, which is a colorless volatile compound present in ripe tomatoes with fragrances when cutting green grass or leaves, and is present in a small amount in most plants, and serves to attract insects. .
  • the compound is cis-3-hexenal, and the compound has volatility.
  • cancer generally refers to or describes the physiological state of a mammal that is characterized by unregulated cell growth.
  • Cancer refers to a condition in which a problem occurs in the regulation of normal division, differentiation and death of cells, abnormally proliferating and invading surrounding tissues and organs to form agglomerates and destroy or modify existing structures.
  • the term "cancer stem cell” is an undifferentiated cell having the ability to differentiate into various cancer cells
  • the cancer includes colorectal cancer and colorectal cancer, breast cancer, cervical cancer, cervical cancer, ovarian cancer, including colon cancer and rectal cancer Cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, gastric cancer, lung cancer, pancreatic cancer, liver cancer, esophageal cancer, small intestine cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, neutrophil Jenkin's disease, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, head cancer, neck cancer, skin melanoma, intraocular melanoma, endocrine gland cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma , Urethral cancer, penile cancer, central nervous system (CN)
  • breast cancer stem cell refers to an undifferentiated cell having the ability to differentiate into breast cancer cells.
  • lung cancer stem cell refers to an undifferentiated cell having the ability to differentiate into lung cancer cells.
  • breast cancer stem cell growth inhibition is meant to include breast cancer stem cell maintenance (maintenance) inhibition, breast cancer stem cell malignance (inhibition), breast cancer stem cell migration and breast cancer stem cell invasive activity (invasive) inhibition.
  • lung cancer stem cell maintenance maintenance
  • lung cancer stem cell malignance inhibition
  • lung cancer stem cell migration inhibition
  • lung cancer stem cell invasive activity inhibition
  • the primary mammosphere (mammosphere) derived from MCF-7 and MDA-MB-231 cells Cis-3-hexenal was treated, and as a result, cis-3-hexenal was found to inhibit the formation of primary mammoths derived from breast cancer cell lines, specifically, breast cancer cells MCF-7 and MDA. Not only did the number of mammo pairs derived from -MB-231 cells decrease by 40-90%, but the size of mammo pairs also decreased (Figs. 4A and 4B). Accordingly, it was confirmed that the compound of the present invention can inhibit the formation of mammospheres or inhibit the growth of mammospheres.
  • cis-3-hexenal to determine whether cis-3-hexenal can inhibit the growth of lung cancer stem cells, cis-3- is added to a primary spheresphere derived from A549 cells. Hexenal was treated, and as a result, cis-3-hexenal was found to inhibit the formation of primary tumourspare derived from lung cancer cell line, and specifically, the number of tumor spares derived from lung cancer cells A549 cells was 50 Not only was confirmed to decrease to ⁇ 90%, it was also confirmed that the size of the Tooth Spare reduced (Fig. 12A).
  • the compound of the present invention inhibits the formation of mammosphere (mammosphere) derived from breast cancer, (ii) inhibits the proliferation of mammosphere derived from breast cancer, or (iii) a tumer derived from lung cancer Inhibits the formation of tumorspheres, or (iv) inhibits the proliferation of tumors from lung cancer.
  • the lung cancer stem cells may express one or more self-renewal genes selected from Nanog, C-myc, Oct4, and CD44.
  • cis-3-hexenal inhibited the expression of self-renewing genes such as Nanog, C-myc, Oct4, and CD44, which are known to be characteristically expressed in lung cancer stem cells (FIG. 14A).
  • Inhibition of the production of IL-6, known to be involved in mammosphere formation of stem cells (FIG. 7A), was confirmed to inhibit the STAT3 signaling pathway (FIG. 6B). Accordingly, it was confirmed that the compound can inhibit the growth of breast cancer stem cells.
  • the lung cancer stem cells inhibited the production of IL-8, which is known to be involved in the formation of tumorous pairs (FIG. 15C), and confirmed that the NF- ⁇ B signaling pathway was inhibited (FIG. 15A). . Accordingly, it was confirmed that the compound can inhibit the growth of lung cancer stem cells.
  • composition of the present invention can be used as a pharmaceutical composition or food composition.
  • composition of the present invention when utilized as a pharmaceutical composition, it may include the compound or a pharmaceutically acceptable salt thereof.
  • the term "pharmaceutically acceptable salts” refers to all salts that retain the desired biological and / or physiological activity of the compound and exhibit minimal unwanted toxicological effects. Salts prepared according to conventional methods in the art, which methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from pharmacologically or physiologically acceptable inorganic and organic acids and bases.
  • salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines; Substituted amines, including naturally occurring substituted amines; And isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, Hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, and / or N-ethylpiperi Salts of cyclic amines, including dean. Also included are other carboxylic
  • salts derived from inorganic acids include hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids are acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid , But may include, but is not limited to, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and / or salicylic acid.
  • the pharmaceutical composition may include a pharmaceutically acceptable carrier or additive.
  • pharmaceutically acceptable means that the subject of application (prescription) is not toxic as long as it is adaptable without inhibiting the activity of the active ingredient.
  • carrier is defined as a compound that facilitates the addition of the compound into cells or tissues.
  • the cis-3-hexenal of the present invention may be administered alone or in admixture with any convenient carrier and the like, and such dosage forms may be single or repeated dose formulations.
  • the pharmaceutical composition may be a solid formulation or a liquid formulation.
  • Solid preparations include, but are not limited to, powders, granules, tablets, capsules, suppositories, and the like.
  • Solid form preparations may include, but are not limited to, carriers, flavoring agents, binders, preservatives, disintegrants, lubricants, fillers, and the like.
  • Liquid formulations include, but are not limited to, solutions such as water, propylene glycol solutions, suspensions, emulsions, and the like, and may be prepared by adding suitable colorants, flavors, stabilizers, viscosity agents, and the like.
  • powders may be prepared by simply mixing cis-3-hexenal, the active ingredient of the present invention, with a suitable pharmaceutically acceptable carrier such as lactose, starch, microcrystalline cellulose.
  • Granules are cis-3-hexenal of the present invention; Suitable carriers, pharmaceutically acceptable; And a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone, hydroxypropyl cellulose, and the like, and then wet granulation using a solvent such as water, ethanol, isopropanol, or dry granulation using compression.
  • a suitable pharmaceutically acceptable binder such as polyvinylpyrrolidone, hydroxypropyl cellulose, and the like, and then wet granulation using a solvent such as water, ethanol, isopropanol, or dry granulation using compression.
  • a suitable pharmaceutically acceptable lubricant such as magnesium stearate
  • Cis-3-hexenal of the present invention is oral, injectable (eg, intramuscular, intraperitoneal, intravenous, infusion, subcutaneous, implants), inhalants, depending on the condition and condition of the subject to be treated. , Nasal, vaginal, rectal, sublingual, transdermal, topical, etc., but is not limited thereto. It may be formulated into a suitable dosage unit dosage form comprising a pharmaceutically acceptable carrier, excipient, vehicle, conventionally used and nontoxic, depending on the route of administration.
  • the pharmaceutical composition of the present invention may be administered daily from about 0.0001 mg / kg to about 10 g / kg, and may be administered in a daily dosage of about 0.001 mg / kg to about 1 g / kg.
  • the dosage may vary depending on the degree of purification of the mixture, the condition of the patient (age, sex, weight, etc.), the severity of the condition being treated, and the like. If desired, the total daily dose may be divided several times a day for convenience.
  • the content of cis-3-hexenal in the composition can be appropriately adjusted to an effective amount capable of exhibiting anti-inflammatory activity according to the symptoms of the disease, the progress of symptoms, the condition of the patient,
  • the amount of cis-3-hexenal may be 0.0001% by weight or more, specifically 0.001% by weight or more, 80% by weight or less, specifically 50% by weight or less, based on the total weight of the total composition. It is not.
  • the compound of the present invention was confirmed to inhibit the growth (proliferation) of breast cancer cell-derived mammoth, it can be used as a food composition for inhibiting breast cancer stem cell growth.
  • the compound was confirmed to inhibit the growth (proliferation) of lung cancer cell-derived Tumors pair, can be used as a food composition for inhibiting lung cancer stem cell growth.
  • composition of the present invention when used as a food composition, it may include an acceptable food supplement additive, and may further include suitable carriers, excipients and diluents commonly used in the preparation of food.
  • the food means a natural product or a processed product containing one or more nutrients, and specifically, means a state in which it can be directly eaten through a certain degree of processing.
  • the foods include various foods, beverages, gums, teas, vitamin complexes, and functional foods.
  • the food of the present invention includes special nutritional products (e.g., prepared oils, infants, baby food, etc.), processed meat products, fish products, tofu, jelly, noodles (e.g., ramen, noodles, etc.), health supplements, seasoned foods ( For example, soy sauce, miso, red pepper paste, mixed soy sauce), sauces, confectionery (e.g.
  • snacks dairy products (e.g. fermented milk, cheese, etc.), other processed foods, kimchi, pickles (various kimchi, pickles, etc.), beverages ( Examples include, but are not limited to, fruits, vegetable drinks, soy milk, fermented beverages, ice cream, etc., natural seasonings (eg, ramen soup, etc.), vitamin complexes, alcoholic beverages, alcoholic beverages, and other dietary supplements.
  • the functional food, beverages, food additives or beverage additives may be prepared by a conventional manufacturing method.
  • the term "functional food” refers to the control of biological defense rhythm, disease prevention and recovery of food groups or food compositions that have added value to the food by using physical, biochemical, or biotechnological techniques to act and express the function of the food for a specific purpose. It means a food that is designed and processed to fully express the body control function related to the living body, specifically, it may be a health functional food.
  • the term "health functional food” refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and pills using raw materials or ingredients having useful functions for the human body.
  • the term “function” means obtaining a useful effect for health purposes such as nutrient control or physiological action on the structure and function of the human body.
  • the health functional food of the present invention can be prepared by a method commonly used in the art, and the preparation can be prepared by adding raw materials and ingredients commonly added in the art.
  • the formulation of the health functional food can also be prepared without limitation as long as the formulation is recognized as a health functional food.
  • Food composition of the present invention can be prepared in various forms of formulation, unlike the general medicine has the advantage that there is no side effect that can occur when taking a long-term use of the drug as a raw material, and excellent portability, the present invention Dietary supplements are available as supplements to enhance the effects of breast and lung cancer stem cell growth inhibition.
  • the functional food may include a food-acceptable food supplement additive, and may further include appropriate carriers, excipients and diluents commonly used in the manufacture of functional foods.
  • the amount of cis-3-hexenal may be at least 0.00001% by weight, specifically at least 0.1% by weight of the total weight of the food composition, at most 80% by weight, specifically at most 50% by weight, more specifically 40 wt% or less, and when the food is a beverage, based on 100 ml of the total volume of the food, 0.001 g or more, specifically 0.01 g or more, 50 g or less, specifically 10 g or less, more specifically 2 g or less It may be included in the ratio of, but is not limited thereto.
  • the food composition of the present invention may include sweeteners, flavoring agents, bioactive ingredients, minerals, etc. in addition to the active ingredients.
  • Sweeteners may be used in amounts that give the food a suitable sweet taste, and may be natural or synthetic.
  • a natural sweetener is used.
  • natural sweeteners include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose and maltose.
  • Flavoring agents can be used to enhance the taste or aroma, both natural and synthetic. It is the case of using a natural thing specifically ,. In addition to flavors, the use of natural ones can be combined with nutritional purposes.
  • the natural flavor may be obtained from apples, lemons, citrus fruits, grapes, strawberries, peaches, and the like, or may be obtained from green tea leaves, round leaves, jujube leaves, cinnamon, chrysanthemum leaves, jasmine and the like. Moreover, what was obtained from ginseng (red ginseng), bamboo shoots, aloe vera, ginkgo, etc. can be used. Natural flavors can be liquid concentrates or solid extracts. In some cases, synthetic flavoring agents may be used, and synthetic flavoring agents may include esters, alcohols, aldehydes, terpenes, and the like.
  • catechins such as catechin, epicatechin, gallocatechin, epigallocatechin, vitamins such as retinol, ascorbic acid, tocopherol, calciferol, thiamine, riboflavin, and the like can be used.
  • mineral calcium, magnesium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium, zinc and the like can be used.
  • the food composition of the present invention may contain a preservative, an emulsifier, an acidulant, a thickener, and the like, in addition to the sweetening agent.
  • preservatives, emulsifiers and the like are preferably added and used in very small amounts as long as the use to which they are added can be achieved. By trace amounts it is meant numerically in the range of 0.0005% to about 0.5% by weight based on the total weight of the food composition.
  • preservatives include sodium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, EDTA (ethylenediaminetetraacetic acid), and the like.
  • Emulsifiers that can be used include acacia gum, carboxymethylcellulose, xanthan gum, pectin and the like.
  • acidulants examples include lead acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, phosphoric acid, and the like. Such acidulant may be added so that the food composition is at an appropriate acidity for the purpose of inhibiting the growth of microorganisms in addition to the purpose of enhancing taste.
  • Thickeners that can be used include suspending implements, sedimenters, gel formers, swelling agents and the like.
  • the present invention provides a pharmaceutical composition for inhibiting metastasis of cancer, or preventing or treating cancer, comprising the composition for inhibiting cancer stem cell growth.
  • the cancer is classified into primary cancer existing at the site of occurrence and metastatic cancer that has spread from the site of development to other parts of the body.
  • the metastasis of the cancer refers to a state in which a malignant tumor has spread to other tissues away from the organ. Cancer cells are formed by spreading through the blood circulation or lymph circulation, usually by blood circulation to other organs and then growing into new tumors. Cancer cells, on the other hand, are formed by moving directly to neighboring tissues.
  • the metastasis of the cancer is the proliferation of cancer cells by invasion where cancer cells move directly into and penetrate neighboring tissues, and cancer cells move through the bloodstream to form new tumors in organs that are not physically adjacent to the primary cancer. It includes all metastasis.
  • the cancer metastasis the movement of cells is essential. Therefore, it is obvious that inhibiting the migration of cancer cells is the primary method of preventing cancer metastasis.
  • the cancer is not limited thereto, but may be breast cancer or lung cancer.
  • the terms "cancer”, “cancer stem cells”, “cancer stem cell growth inhibition”, “pharmaceutical composition” is as described above.
  • the composition of the present invention when cis-3-hexenal was treated in MCF-7 cell line and MDA-MB-231 cell line, growth of breast cancer cell lines was inhibited (FIGS. 1A and 1B). Accordingly, the composition of the present invention can be used as a pharmaceutical composition for the treatment or prevention of breast cancer. In addition, it was confirmed that the cis-3-hexenal inhibits the migration and colony formation of MDA-MB-231 cells in a concentration-dependent manner (FIGS. 2B and 2C). Accordingly, the composition of the present invention can suppress cancer metastasis by inhibiting the movement of cancer cells.
  • the pharmaceutical composition comprising cis-3-hexenal may be used as a pharmaceutical composition for inhibiting metastasis of breast cancer as well as for treating or preventing breast cancer.
  • the composition of the present invention can be used as a pharmaceutical composition for the treatment or prevention of lung cancer.
  • the cis-3-hexenal inhibits the migration and colony formation of A549 cells (FIGS. 9A and 9B).
  • the pharmaceutical composition comprising cis-3-hexenal may be used as a pharmaceutical composition for inhibiting metastasis of lung cancer, as well as for treating or preventing lung cancer.
  • cis-3-hexenal inhibitors reduced the population expressing ESA + / CD44 high / CD24 low in breast cancer cells (FIG. 5A) and confirmed that the percentage of ALDH positive breast cancer cells was reduced. (FIG. 5B). Accordingly, the composition of the present invention can inhibit the growth of breast cancer cells expressing ESA + / CD44 high / CD24 low and can inhibit the growth of aldehyde dehydrogenase (ALDH) positive breast cancer cells.
  • ALDH aldehyde dehydrogenase
  • the composition of the present invention can inhibit the growth of aldehyde dehydrogenase (ALDH) positive lung cancer cells.
  • the present invention provides a food composition for cancer metastasis or cancer improvement or prevention, comprising the composition for inhibiting cancer stem cell growth.
  • the cancer may be breast cancer or lung cancer, but is not limited thereto.
  • cancer in the present invention, the terms "cancer”, “cancer stem cell”, “cancer stem cell growth inhibition”, “transition”, “food composition” are as described above.
  • the present invention provides a fragrance composition for inhibiting growth of cancer stem cells, comprising a volatile compound represented by the following Formula 1.
  • the cancer may be breast cancer or lung cancer, but is not limited thereto.
  • the compound is characterized in that cis-3-hexenal.
  • volatile means a property of the components of low-boiling substances in liquid or solid evaporate or sublimate at room temperature, and the higher the vapor pressure of the material, the more volatility becomes. Molecules fall off the surface of liquids or solids. Low boiling liquid fuels, gasoline, organic solvents, aromatic compounds including benzene are highly volatile.
  • fragrance means a substance that smells. It has a fragrance and enters the nose with intake to reach the nostrils, which stimulates the sense of smell and gives pleasure. It is divided into natural and synthetic fragrances of essential oils extracted from animals and plants. Synthetic fragrances may be synthesized and steered from other raw materials for synthesizing the same components as those of natural fragrances, and those having similar aroma as natural fragrances. In addition, it is a highly aromatic organic substance added to add fragrance to household goods such as cosmetics and food products, and they have excellent volatility at room temperature.
  • CSCs breast cancer stem cells
  • the volatile compound represented by Formula 1 of the present invention can inhibit the growth of stem cells of breast cancer and lung cancer by the fragrance evaporated from the volatile compounds, bar stem growth of breast cancer and lung cancer It can be used as a fragrance composition that can be.
  • the present invention provides a pharmaceutical composition comprising the perfume composition.
  • the cis-3-hexenal is a pharmaceutical composition that can inhibit the growth of breast cancer and lung cancer stem cells by the fragrance evaporated into a volatile compound, the growth of breast cancer and lung cancer stem cells Available.
  • the present invention provides an external preparation for skin, comprising the perfume composition.
  • the cis-3-hexenal can suppress the growth of stem cells of breast cancer and lung cancer by the fragrance evaporated into a volatile compound
  • an external skin agent that can inhibit the growth of stem cells of breast cancer and lung cancer Can be used as Examples of the external preparation for skin according to the present invention include, but are not limited to, ointments, lotions, soluble burns, suspensions, emulsions, creams, gels, sprays, powders, warnings, patches or water pastes. It may be formulated to any of the bases well known in the art.
  • the external preparation for skin according to the present invention may contain the perfume composition in an amount of 0.01 to 20% by weight based on the total weight of the composition.
  • the present invention provides a food composition comprising the perfume composition.
  • the perfume composition of the present invention can be used as a food composition, the description of the term "food composition” is as described above.
  • the present invention provides a cosmetic composition comprising the perfume composition.
  • the cosmetic composition of the present invention may include other ingredients known in the art to be added to the cosmetic composition in addition to the perfume composition described above. Since the cosmetic composition of the present invention is basically applied to the skin, it can be provided with reference to the cosmetic composition in the art, for example, solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, It may be formulated as a surfactant-containing cleansing, oil, powder foundation, emulsion foundation, wax foundation and spray, and the like, but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, nutrition lotion, nutrition cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.
  • the formulation of the present invention is a paste, cream or gel, animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components.
  • animal oils, vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide may be used as carrier components.
  • animal oils vegetable oils, waxes, paraffins, starches, trachants, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicas, talc or zinc oxide
  • cellulose derivatives polyethylene glycols
  • silicones bentonites
  • silicas talc or zinc oxide
  • lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used, in particular in the case of a spray, additionally chlorofluorohydrocarbon, propane Propellant such as butane or dimethyl ether.
  • a solvent, solubilizer or emulsifier is used as the carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 Fatty acid esters of, 3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan.
  • liquid carrier diluents such as water, ethanol or propylene glycol
  • suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Crystalline cellulose, aluminum metahydroxy, bentonite, tracant and the like can be used.
  • the carrier component is an aliphatic alcohol sulfate, an aliphatic alcohol ether sulfate, a sulfosuccinic acid monoester, an isethionate, an imidazolinium derivative, a methyltaurate, a sarcosinate, a fatty acid amide.
  • Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters and the like can be used.
  • the present invention can provide a perfume composition comprising the perfume composition. That is, the perfume composition of the present invention can be added to the perfume composition.
  • the fragrance composition of the present invention may comprise from 0.001 to 30% by weight, preferably from 1 to 30% by weight, more preferably from 1 to 10% by weight of the perfume composition.
  • the fragrance composition is added in less than 0.001% by weight of the total composition, the fragrance is very low, it is difficult to taste the fragrance, and when added in excess of 30% by weight, the fragrance is too strong for use as a perfume.
  • the composition can be added as it is or mixed with any ingredient useful for a flavor or perfume composition.
  • they may be mixed with one or more of a wide range of natural, synthetic, synthetic chemicals, natural fragrances, flavoring substances, flavors or natural extracts used in the field of fragrances.
  • the fragrance composition may contain one or more ingredients or excipients commonly used with flavoring and fragrances, for example carrier materials, thickening agents, flavor enhancers and other auxiliaries commonly known and used in the art. Can be.
  • the fragrance composition of the present invention may provide a gelled or solidified composition for use in volatile fragrances, or may provide a liquid composition for use in sprayed fragrances.
  • the present invention provides an additive for a humidifier including the perfume composition.
  • fragrance composition of the present invention is volatile, it can be used as an active ingredient of an additive for a humidifier.
  • the present invention provides a cigarette filter comprising the perfume composition.
  • the fragrance composition of the present invention is volatile, it can be used when manufacturing a cigarette filter.
  • the present invention provides an electronic cigarette comprising the perfume composition.
  • the fragrance composition of the present invention is volatile, it can be used in the production of electronic cigarette.
  • the fragrance composition of the present invention may be applied to an atomizer or an electronic cigarette to be vaporized or made into a particulate state to be inhalable.
  • Electronic cigarette or atomizer refers to an electronic device that vaporizes or particulates a fragrance or inhalable component added to a solvent such as propylene glycol, vegetable glycerin or water.
  • Vaporization means that the liquid component becomes a gas, for example, by Joule resistance heat according to the power supply.
  • And to be in the particulate state means atomizing the liquid by the nozzle structure or by using ultrasonic waves.
  • the electronic cigarette makes the perfume composition inhalable by vaporization and the atomizer is inhalable by making it into particulate form using a nozzle structure or ultrasonic waves.
  • the fragrance composition can be made in an inhalable state in a variety of ways.
  • the present invention provides a personal care product comprising the perfume composition.
  • the personal care products of the present invention include hair products such as shampoos, rinses, treatments, hair essences, etc. without departing from the object of the present invention; Oral products such as toothpaste and gargle; Skin cleaners such as body washes, body gels, soaps, cleansing creams, cleansing foams, cleansing water and cleansing oils; Perfumes, and the like.
  • the present invention provides a home care product comprising the perfume composition.
  • the home care products of the present invention include, but are not limited to, detergents such as liquid detergents, dish detergents, laundry detergents, and bathroom detergents within the scope of not impairing the object of the present invention.
  • detergents such as liquid detergents, dish detergents, laundry detergents, and bathroom detergents within the scope of not impairing the object of the present invention.
  • pigments, fungicides, antioxidants, preservatives, moisturizers, thickeners, inorganic salts, synthetic polymer materials and the like can be further added.
  • the present invention provides a method for inhibiting the growth of cancer stem cells, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the term "individual” means all animals including humans having cancer metastases or having cancer. Mammals, birds, and the like, including cattle, pigs, sheep, chickens, dogs, humans, and the like, wherein the growth of cancer stem cells is inhibited by the volatile compounds of the present invention. Include.
  • the compound represented by the formula (1) of the present invention is volatile, by administering the compound to the subject, it is also possible to suppress the growth of stem cells of cancer by the volatilization of the compound.
  • Another object of the present invention is to provide a method for inhibiting cancer metastasis, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a method for treating or preventing cancer, comprising administering to a subject a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a use of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting the growth of cancer stem cells.
  • Another object of the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for inhibiting cancer metastasis.
  • Still another object of the present invention is to provide a use of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the prevention or treatment of cancer.
  • 6-, 24-well culture plates containing very low adherent cluster plates were obtained from Corning (Tewksbury, MA, USA).
  • Aromatic compounds, including cis-3-hexenal, were purchased from Sigma-Aldrich Co. (St. Louis, Mo., USA).
  • Cell viability was measured using CellTiter 96® aqueous one solution cell proliferation assay kit (Promega, Madison, Wis., USA).
  • the ALDEFLUOR TM Kit was purchased from STEMCELL Technologies Inc (Vancouver, BC, Canada). Chemicals such as doxorubicin are described, for example, in Sigma-Aldrich Co. (St. Louis, MO, USA).
  • MCF-7 Human breast cancer cells, were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA). MCF-7 cells contain Dulbecco's Modified Essential Medium (DMEM; Hyclone, Logan, UT, USA) containing 10% fetal bovine serum (FBS; Hyclone), 100 U / ml penicillin, and 100 ⁇ g / ml streptomycin (Hyclone). Incubated at. The MCF-7 cells were maintained at 37 ° C. in a humidified incubator containing 5% CO 2 . Cells were plated at a density of 1 ⁇ 10 6 cells in a 10 cm culture dish.
  • DMEM Dulbecco's Modified Essential Medium
  • FBS fetal bovine serum
  • Hyclone fetal bovine serum
  • single cell suspended MCF-7 cells were 3.5-4 per well in ultra-low attachment 6-well plates containing 2 ml of complete MammoCult TM medium (StemCell Technologies, Vancouver, BC, Canada). Inoculated at a cell number of 10 4 .
  • the complete MammoCult TM medium was supplemented with 4 ⁇ g / ml heparin, 0.48 ⁇ g / ml hydrocortisone, 100 U / ml penicillin and 100 ⁇ g / ml streptomycin.
  • the cells were cultured in 37 ° C., 5% CO 2 incubator for 7 days.
  • Human lung cancer cells were cultured under the same culture conditions as the breast cancer cells of Example 2-1.
  • single cell suspended A549 cells were 5 ⁇ 10 4 per well in ultra-low attachment 6-well plates containing 2 ml of Cancer Stem Premeium medium (ProMab Biotechnologies Inc, Richmond, CA, USA). Inoculated with a cell number of. The cells were incubated for 7 days at 37 ° C., 5% CO 2 incubator.
  • the cell culture plates were placed in a scanner (Epson Perfection V700 PHOTO, Epson Korea, Co, Seoul, Korea) to obtain 8-bit gray scale images of mammo pairs.
  • images were obtained using a NICE software program and downloaded from ftp://ftp.nist.gov/pub/physics/mlclarke/NICE.
  • the desired number of rows and columns e.g., 2 x 3 for 6-well plates and 4x6 for 24-well plates
  • was chosen to generate ROIs and the elliptical setting of the NICE program
  • individual ROIs were defined by moving and scaling the provided ROI shape.
  • the background signal of the image was negated using a threshold algorithm, and the selected image was automatically counted.
  • the mammosphere formation assay determined the formation efficiency (MFE,%) of mammo pairs corresponding to the number of mammo pairs per well / total number of plated cells per well x100.
  • Example 3-1 Lung cancer tumour pairs were counted in the same manner as in Example 3-1, and the tumour pair formation assay was based on the number of tumour pairs per well / total number of plated cells per well x100. ) was determined.
  • MCF-7 cells were measured using a CellTiter 96® aqueous one solution cell proliferation kit.
  • MCF-7 cells were cultured in 96-well plates in the presence of 50 ⁇ M, 100 ⁇ M, 200 ⁇ M, 400 ⁇ M and 1000 ⁇ M cis-3-hexenal for 48 hours. Absorbance was determined at 490 nm using a 96-well plate reader (Dynex Revelation, Dynex Ltd., Billingshurst, UK) according to the manufacturer's protocol. Each data was determined by measuring three sets.
  • Example 4-1 except that A549 cells were used as lung cancer cells, and cis-3-hexenal was treated at concentrations of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 and 1 mM. The same procedure was followed.
  • Cancer cells were cultured in 6-well plates and cultured for 24 hours with cis-3-hexenal 20, 30, and 100 ⁇ M for breast cancer, with cis-3-hexen 0.4 mM or DMSO for lung cancer. It was. Bistained with PI and FITC-Annexin V according to manufacturer's instructions. The samples were analyzed by flow cytometry (Accuri C6, BD, San Diego, CA, USA).
  • MDA-MB-231 cells were treated with cis-3-hexenal 30 and 100 ⁇ M, or A549 cells at cis-3-hexen 0.4 mM for 24 hours, and cells were treated with Hoechst 33258 solution (10 mg / ml). Incubated at 37 °C for 30 minutes. The cells were then observed under a fluorescence microscope.
  • MDA-MB-231 or A549 cells were seeded at low density in 6-well plates and treated with different cis-3-hexenal concentrations in DMEM medium. After 24 hours the medium was replaced with fresh medium and incubated for 7 days of growth. Grown colonies were counted.
  • MDA-MB-231 or A549 cells were seeded in 6-well plates and grown to 90% confluency. Using a sterile white micro pipette tip, the cell layer was scratched. After washing with DMEM medium, breast or lung cancer was treated with cis-3-hexenal or DMSO. At 16 hours, wounded areas were photographed with a 40x optical microscope.
  • CD44 and CD24 in MCF-7 cells were measured by FACS analysis. After isolation and harvesting cells using 1 ⁇ Trypsin / EDTA, one million cells were suspended and FITC-bound anti-human CD44 and PE-bound anti-human CD24 antibodies (BD Pharmingen, San Diego, CA, USA) ) And incubated at 4 ° C. for 30 minutes. The cells were then washed three times with 1 ⁇ PBS and analyzed by flow cytometry (Accu C6, BD, San Diego, Calif., USA).
  • transcripts were measured with a One Step SYBR PrimeScript RT-PCR kit (Takara, Tokyo, Japan) using SYBR Green as a double stranded DNA specific dye.
  • One-step RT-PCR reactions were performed for 1 ⁇ g total RNA, 10 ⁇ l 2X
  • One Step SYBR RT-PCR Buffer IV 1 ⁇ l PrimeScript 1 step Enzyme Mix II, CD44, NANOG, OCT4, C-myc, ⁇ -actin It was performed at a final volume of 20 ⁇ l per reaction, including 10 ⁇ M of PCR forward primer, and PCR reverse primer.
  • the forward and reverse primers are as follows.
  • CD44 forward primer AGAAGGTGTGGGCAGAAGAA (SEQ ID NO: 1)
  • CD44 reverse primer AAATGCACCATTTCCTGAGA (SEQ ID NO: 2)
  • NANOG forward primer ATGCCTCACACGGAGACTGT (SEQ ID NO: 3),
  • NANOG reverse primer AAGTGGGTTGTTTGCCTTTG (SEQ ID NO: 4),
  • OCT4 forward primer AGCAAAACCCGGAGGAGT (SEQ ID NO: 5),
  • OCT4 reverse primer CCACATCGGCCTGTGTATATC (SEQ ID NO: 6),
  • C-myc forward primer AATGAAAAGGCCCCCAAGGTAGTTATCC (SEQ ID NO: 7),
  • C-myc reverse primer GTCGTTTCCGCAACAAGTCCTCTTC (SEQ ID NO: 8),
  • ⁇ -actin forward primer TGTTACCAACTGGGACGACA (SEQ ID NO: 9),
  • ⁇ -actin reverse primer GGGGTGTTGAAGGTCTCAAA (SEQ ID NO: 10).
  • the relative expression level of mRNA of the target gene was calculated using the comparative CT method. At least three independent PCR procedures were performed following statistical analysis. PCR products were normalized to the ⁇ -actin gene as an internal control.
  • the ALDEFLUOR assay system provides a novel approach to the identification, evaluation and isolation of CSCs based on the activity of aldehyde dehydrogenase (ALDH).
  • Active reagent BODIPY-aminoacetaldehyde was added to breast cancer cells or lung cancer cells and converted to fluorescence BODIPY-aminoacetate by aldehyde dehydrogenase (ALDH).
  • Diethylaminobenzaldehyde (DEAB), an ALDH inhibitor was used as a negative control.
  • MCF-7 cells or A549 cells were treated with 50 ⁇ M or 0.4 mM cis-3-hexenal for 24 hours, and the proportion of ALDH positive cells was analyzed by ALDEFLUOR assay.
  • ALDH positive and negative cells were sorted using flow cytometry (Accuri C6, BD, San Diego, CA, USA).
  • Cis-3-hexenal treated samples were separated on 10% SDS-PAGE and transferred to a polyvinylidene difluoride membrane (Millipore, Bedford, Mass., USA). The membrane was blocked in PBS-Tween 20 (0.1%, v / v) containing 5% skim milk powder at room temperature for 30 minutes. The blots were incubated overnight at 4 ° C. with blocking solutions containing primary antibodies. Primary antibodies used were as follows: Stat3, p65, Lamin B, and phospho-Stat3 (Cell Signaling, Beverly, MA, USA). ⁇ -actin (Santa Cruz Biotechnology) was used as a loading control.
  • the blots were incubated with horseradish peroxidase-bound secondary antibody and photosensitized with a chemiluminescence detection kit (Santa Cruz Biotechnology).
  • Inflammatory cytokines were measured using a BD cytometric bead array (CBA) human inflammatory cytokines kit, according to the manufacturer's instructions (BD, San Diego, CA, USA).
  • CBA BD cytometric bead array
  • the mixed capture beads were vortexed and 50 ⁇ l beads were added to the assay tube.
  • 50 ⁇ l of human inflammatory cytokine standard and incubated tomuspher solution were added to the assay tube and the cytokine PE solution was mixed. After 3 hours, the mixed solution was washed and analyzed by flow cytometry (Accuri C6, BD, San Diego, CA, USA).
  • Example 16 Elecrrophoretic mobility shift assays (EMSA)
  • EMSA was detected using Lightshift's chemiluminscet EMSA kit (Thermoscientific, IL, USA) according to the manufacturer's instructions.
  • the biotin-top and bottom probs of the Stat3 probe (5'-CTTCATTTCCCGGAAATCCCTA-Biotin3 ', SEQ ID NO: 11 and 5'-TAGGGATTTCCGGGAAATGAAG-Biotin3', SEQ ID NO: 12) were annealed and the double-stranded oligonucleotides were terminally labeled with biotin.
  • Biotin-labeled DNA probes were incubated with cis-3-hexenal treated nuclear proteins in a final volume of 20 ⁇ L EMSA buffer containing 1 ⁇ g / ⁇ L poly [dI-dC]) at room temperature for 20 minutes.
  • the reaction mixture was electrophoresed on 4% polyacrylamide unmodified gel in 0.5 ⁇ TBE (45 mM Tris borate and 1 mM EDTA) at 4 ° C. and visualized using a chemiluminescent nucleic acid detection kit (Thermoscientific, IL, USA) It was.
  • Example 17-1 Immunodeficiency NOD- Producing Breast Cancer Cells SCID ( BALB Of cSIc (nu / nu)) chemotherapy in female nude mice
  • NOD-SCID (BALB / cSIc (nu / nu)) female nude mice producing a total of 24 breast cancer cells were divided into four groups. Six mice as negative controls did not receive chemotherapy. Tumor volume of control mice was measured every 3 days and calculated using the formula (width ⁇ length 2 ) / 2. The other six nude mice received the test drug using the infusion process at the optimal dose of 10 mg / kg / day. Another six nude mice were positive control and received 10 mg / kg / day of doxorubicin daily in the tail vein. The last group remaining was used as non-tumor group without treatment.
  • Example 17-2 Immunodeficiency NOD- Producing Lung Cancer Cells SCID ( BALB Of cSIc (nu / nu)) Chemotherapy in male nude mice
  • NOD-SCID (BALB / cSIc (nu / nu) male nude mice, producing a total of 18 lung cancers, were divided into three groups: 18 mice received lung cells injected into the tail vein. The other group received cis-hexenal and vapor-cis-hexenal chemotherapy Volumes of control mouse tumors were measured every 3 days and calculated using the formula (width ⁇ length 2 ) / 2. Nude mice received the test drug prior to anticancer therapy using an infusion process at an optimized dose of 10 mg / kg / day The last group remaining was used as tumor group without steam-cis-hexenal treatment.
  • Example 17-3 Immunodeficiency NOD- Producing Lung Cancer Cells SCID ( BALB Of cSIc (nu / nu)) Chemotherapy in male nude mice
  • NOD-SCID (BALB / cSIc (nu / nu) male nude mice, producing a total of 18 lung cancers, were divided into three groups: 18 mice received lung cells injected subcutaneously. The other groups received cis-hexenal and vapor-cis-hexenal chemotherapy Volumes of control mouse tumors were measured every 3 days and calculated using the formula (width ⁇ length 2 ) / 2. Nude mice were administered prodrug anticancer therapy using an infusion process at an optimized dose of 10 mg / kg / day The last group remaining was steam-cis- for 40 minutes under saturated cis-hexenal vapor. Used as hexenal treated tumor group.
  • caspase 3/7 fluorescence was performed in MDA-MB-231 cells. As a result, it was confirmed that the caspase 3/7 activity was induced at 50 ⁇ M and 100 ⁇ M of cis-3-hexenal. (FIG. 1E).
  • cis-3-hexenal treatment confirmed the formation of apoptotic bodies in MCF-7 and MDA-MB-231 cells (FIG. 2A).
  • cis-3-hexenal inhibited the migration and colony formation of MDA-MB-231 cells (FIGS. 2B and 2C). These results indicate that cis-3-hexenal effectively inhibits various cancer features (proliferation, migration, cell death and colony formation).
  • Cis-3-hexenal was confirmed in FIG. 1 to inhibit the proliferation of breast cancer cells in vitro.
  • Tumor volume in the cis-3-hexenal group was smaller than that in the cis-3-hexenal-treated control group, and the tumor volume was smaller than that of the positive control group doxorubicin (FIGS. 3A and 3D).
  • the tumor weight in the cis-3-hexenal treatment group was smaller than that of the control without the cis-3-hexenal treatment (FIGS. 3B and 3C).
  • the body weight of the mice in the cis-3-hexenal treated group was similar to the control (FIG. 3A).
  • MCF-7 cells were treated with cis-3-hexenal for 24 hours, and the effects of the cis-3-hexenal inhibitors were investigated in subpopulations expressing ESA + / CD44 high / CD24 low in breast cancer cells. As a result, the cis-3-hexenal inhibitor reduced the population expressing ESA + / CD44 + high / CD24-low in breast cancer cells (FIG. 5A).
  • MCF-7 cells were treated with cis-3-hexenal for 24 hours and ALDEFLUOR assay was performed to investigate the effect of cis-3-hexenal inhibitors on the proportion of ALDH positive breast cancer cells. As a result, it was confirmed that cis-3-hexenal reduced the proportion of ALDH positive breast cancer cells (FIG. 5B).
  • IL-6 has been known to play an important role in mammoth pair formation (Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, Ceccarelli C, Santini D, Paterini P, Marcu KB, Chieco P and Bonafe M.
  • IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland.J Clin Invest. 2007; 117 (12): 3988-4002).
  • Western blot was performed in a mammosphere culture using IL-6 antibody.
  • Experimental Example 8 Sheath -3- Hexenal Induces cell death of human lung cancer cells and inhibits proliferation.
  • FIG. 8C the number of lung cancer cells (annexin V +) killed in A549 cells was confirmed to increase by treatment with cis-3-hexenal 0.4 mM.
  • fluorescence analysis of caspase 3/7 was performed in A549 cells, and as a result, it was confirmed that the caspase 3/7 activity was induced at cis-3-hexenal 0.4 mM (FIG. 8D).
  • cis-3-hexenal treatment confirmed the formation of apoptotic bodies (FIG. 8E).
  • cis-3-hexenal inhibited the migration and colony formation of A549 cells (FIGS. 9A and 9B).
  • Cis-3-hexenal was confirmed in FIG. 8 to inhibit the proliferation of lung cancer cells in vitro.
  • lung cancer cells were administered to the tail vein to determine whether cis-3-hexenal and vapor-cis-3-hexenal inhibit tumor induction in a xenograft tumor model.
  • the tumor volume of the cis-3-hexenal and vapor-cis-3-hexenal administration groups was smaller than that of the control group (FIGS. 10A and 10F).
  • the tumor weights of the cis-3-hexenal and vapor-cis-3-hexenal treatment groups were smaller than those of the control group (FIG. 10D).
  • mice in the cis-3-hexenal and vapor-cis-3-hexenal treated groups were similar to the control (FIG. 10A). These results indicate that cis-3-hexenal effectively inhibits tumor development in xenograft models.
  • tumor volume was lower in the cis-3-hexeal treated group and the vapor-cis-3-hexenal treated group than in the cis-3-hexenal treated group (FIG. 11C).
  • tumor weight was lower in the cis-3-hexeal treated group and the vapor-cis-3-hexenal treated group than in the cis-3-hexenal treated group (FIG. 11B).
  • mice in the cis-3-hexenal treatment group and the vapor-cis-3-hexenal treatment group were similar to the control group (FIG. 11A). These results indicate that cis-3-hexenal effectively inhibits tumor development in xenograft models.
  • A549 cells were treated with cis-3-hexenal for 24 hours, and ALDEFLUOR assay was performed to investigate the effect of cis-3-hexenal inhibitors on the proportion of ALDH positive lung cancer cells. As a result, it was confirmed that cis-3-hexenal reduced the proportion of ALDH positive lung cancer cells (FIG. 13).
  • cis-3-hexenal inhibits the expression of the self regenerative gene
  • self regenerative gene expression was examined by real-time PCR (RT-PCR).
  • RT-PCR real-time PCR
  • cis-3-hexenal reduced the expression of self-renewing genes such as nanog, c-myc, oct4, and CD44 in lung cancer cells (FIG. 14A).
  • cis-3-hexenal was treated with cis-3-hexenal in order to confirm whether cis-3-hexenal inhibits the growth of two-mersarea, and the number of cells of the two-in-one pairs was counted.
  • cis-3-hexenal induced apoptosis of tumormers, and the number of cells observed in cis-3-hexenal-treated tomerspar was small. From these results, it was found that cis-3-hexenal greatly reduced the growth of Too's pair (FIG. 14B).
  • cis-3-hexenal To investigate the cell function of cis-3-hexenal, the STAT3 and NF-kB pathways were investigated in cimurs derived from A549 cells under cis-3-hexenal treatment. As a result, cis-3-hexenal reduced the amount of nuclear p65 protein compared to the control. However, cis-3-hexenal did not reduce the level of phosphorylated STAT3 protein in the nucleus (FIG. 15A).
  • IL-8 has been known to play an important role in the formation of tumuspair (Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M, Wicinski J, Cabaud O, Charafe-Jauffret E, Birnbaum D, Guan JL, Dontu G and Wicha MS.CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts.J Clin Invest. 2010; 120 (2): 485-497).
  • an inflammatory cytokine profiling assay was performed using a flow cytometer.
  • cis-3-hexenal treatment reduced the production level of secreted IL-8.
  • the internal control used a cis-3-hexenal untreated A549 Tomuspair culture.
  • the cis-3-hexenal of the present invention not only inhibits the proliferation of breast cancer and lung cancer, but also inhibits the growth of stem cells of breast cancer and lung cancer, thereby confirming that breast cancer and lung cancer and their stem cells It can be seen that it can be used for growth inhibition of.

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Abstract

La présente invention porte sur un composé aromatique destiné à inhiber la croissance de cellules souches cancéreuses. Il contient du cis-3-hexénal, ou un sel pharmacologiquement comparable de celui-ci, un composé pharmaceutique et alimentaire destinée à inhiber les métastases, traiter ou prévenir le cancer. Le cis-3-hexénal supprime la croissance des cellules mammaires et colorectales, et inhibe la formation de leur cellules souches. Le cis-3-hexénal inhibe l'expression de gènes d'auto-renouvellement, tels que le Nanog, C-myc, Oct4 et CD44, qui sont exprimés dans les cellules souches du cancer du sein. Ils inhibent la production d'IL-6, qui est impliquée dans la formation de mammosphères de cellules souches du cancer du sein et qui inhibent la voie de signalisation de STAT3. Le cis-3-hexénal inhibe la production d'IL-8, impliquée dans la formation de tumeurs de cellules souches du cancer du poumon, et la voie de signalisation du NF-κB. Par conséquent, le composé inhibe la croissance de cellules souches du cancer du sein et du poumon, et peut donc être utilisé comme traitement pour inhiber la croissance de ces cancers.
PCT/KR2016/011209 2016-07-29 2016-10-06 Inhibiteur de croissance de cellules souches cancéreuses, contenant du cis-3-hexénal. Ceased WO2018021618A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004182699A (ja) * 2002-12-06 2004-07-02 Soda Aromatic Co Ltd 抗菌剤およびそれを含有する香粧品並びに微生物の増殖抑制方法
KR20090114747A (ko) * 2008-04-30 2009-11-04 (주)아모레퍼시픽 더덕의 향취를 재현한 향료 조성물 및 이를 함유하는 피부외용제 조성물
JP2014155483A (ja) * 2013-01-17 2014-08-28 Sapporo Breweries Ltd ビールテイスト飲料及びその製造方法
JP2015165822A (ja) * 2015-06-29 2015-09-24 日本デルモンテ株式会社 ブレンドトマトジュース及びその製造方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004182699A (ja) * 2002-12-06 2004-07-02 Soda Aromatic Co Ltd 抗菌剤およびそれを含有する香粧品並びに微生物の増殖抑制方法
KR20090114747A (ko) * 2008-04-30 2009-11-04 (주)아모레퍼시픽 더덕의 향취를 재현한 향료 조성물 및 이를 함유하는 피부외용제 조성물
JP2014155483A (ja) * 2013-01-17 2014-08-28 Sapporo Breweries Ltd ビールテイスト飲料及びその製造方法
JP2015165822A (ja) * 2015-06-29 2015-09-24 日本デルモンテ株式会社 ブレンドトマトジュース及びその製造方法

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