KR101926021B1 - Pharmaceutical composition comprising extract of Telectadium dongnaiense for preventing or treating colon cancer - Google Patents
Pharmaceutical composition comprising extract of Telectadium dongnaiense for preventing or treating colon cancer Download PDFInfo
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- KR101926021B1 KR101926021B1 KR1020170076747A KR20170076747A KR101926021B1 KR 101926021 B1 KR101926021 B1 KR 101926021B1 KR 1020170076747 A KR1020170076747 A KR 1020170076747A KR 20170076747 A KR20170076747 A KR 20170076747A KR 101926021 B1 KR101926021 B1 KR 101926021B1
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- wnt
- colon cancer
- present
- catenin
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Abstract
본원은 텔렉타디엄 동나이엔스(Telectadium dongnaiense) 추출물을 유효성분으로 포함하는 대장암 예방 및 치료용 약학조성물, 및 건강기능식품에 관한 것으로, 상기 추출물은 Wnt/β-카테닌 신호전달계를 표적으로 하여 Wnt 신호전달계의 이상으로 인한 암의 치료 또는 항암 보조제로 유용하게 사용될 수 있다. The company is located in Telectadium The present invention relates to a pharmaceutical composition for prevention and treatment of colorectal cancer, which comprises an extract of dongnaiense as an active ingredient, and a health functional food. The extract is characterized by treating Wnt / β-catenin signal transduction system to treat cancer caused by abnormality of Wnt signal transduction system Or as anticancer adjuvants.
Description
본 발명은 텔렉타디엄 동나이엔스 추출물을 유효성분으로 하는 대장암 예방 및 치료용 조성물에 관한 것이다.The present invention relates to a composition for prevention and treatment of colorectal cancer, comprising telekteridium dongaense extract as an active ingredient.
있을 것으로 여겨진다 (Clevers H et al (2006) Cell 127:469-480; Mlodzik M (2002) Trends Genet 18:564-571; Huelsken J et al (2001) 11:547-553; MacDonald BT et al (2009) Dev Cell 17:9-26; Fearnhead NS (2001) Mol Genet 10:721-733; Klaus A et al (2008) Nat Rev Cancer 8:387-398; Barker N et al (2006) Nat Rev Drug Discov 5:997-1014). (2002) Trends Genet 18: 564-571; Huelsken J et al (2001) 11: 547-553; MacDonald BT et al (2009) Barker N et al. (2006) Nat Rev Drug Discov 5 (1997); Nat Rev Cancer 8: 387-398; Dev Cell 17: 9-26; Fearnhead NS (2001) Mol Genet 10: 721-733; Klause et al : 997-1014).
대한민국 공개특허공보 제2015-0037024호는 가중나무 추출물을 유효성분으로 하는 암질환의 치료 또는 예방용 조성물에 관한 것으로 가중나무 추출물을 포함하는 Wnt/β-카테닌 신호전달체계를 억제하는 대장암 치료 또는 예방용 조성물을 개시한다. Korean Patent Laid-Open Publication No. 2015-0037024 relates to a composition for treating or preventing a cancerous disease using an extract of a weight tree as an active ingredient, which comprises a treatment for colorectal cancer inhibiting a Wnt /? -Catenin signaling system comprising a weighted tree extract or A composition for prevention is disclosed.
대한민국 공개특허공보 제2015-0037024호 (2015년 4월 8일 공개)는 가중나무 추출물을 유효성분으로 하는 Wnt 신호전달 경로를 억제하는 암질환 치료 또는 예방용 조성물을 개시한다. Korean Patent Laid-Open Publication No. 2015-0037024 (published on April 8, 2015) discloses a composition for the treatment or prevention of cancer diseases that inhibits the Wnt signaling pathway containing the weighted tree extract as an active ingredient.
대장암 예방 또는 치료에 사용하기 위하여서는 Wnt/β-카테닌 신호전달체계를 억제하여야 하므로 상기 가중나무 추출물 이외의 Wnt/β-카테닌 경로를 표적으로 하는 다양한 천연유래 물질 기반의 치료제의 개발이 필요하다. It is necessary to inhibit the Wnt / beta -catenin signaling system for use in the prevention or treatment of colorectal cancer, and thus it is necessary to develop various natural-based therapeutic agents targeting Wnt /? - catenin pathway other than the above- .
본원은 텔렉타디엄 동나이엔스 추출물을 유효성분으로 하는 대장암 예방 및 치료용 조성물을 제공하고자 한다.The present invention provides a composition for prevention and treatment of colorectal cancer, which comprises Telekterthide dongaense extract as an active ingredient.
한 양태에서 본원은 텔렉타디엄 동나이엔스(Telectadium dongnaiense)의 추출물을 유효성분으로 포함하는 대장암 예방 및 치료용 약학조성물을 제공한다. In one embodiment, the present invention is directed to Telectadium The present invention also provides a pharmaceutical composition for preventing and treating colon cancer, which comprises an extract of dongnaiense as an active ingredient.
본원에 따른 추출물은 특히 유기용매에서 효과적으로 추출된다. 이러한 유기용매는 예를 들면 매는 탄소수 1 내지 4의 저급 알콜, 클로로포름, 아세톤, 프로필렌글리콜, 초산에틸, 부틸렌글리콜, 및 에테르로 구성된 군으로부터 선택된 하나 또는 그 이상의 혼합 용매이나, 이로 제한하는 것은 아니다. Extracts according to the present invention are particularly efficiently extracted in organic solvents. Such organic solvents include, for example, but are not limited to, one or more mixed solvents selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, chloroform, acetone, propylene glycol, ethyl acetate, butylene glycol, .
일 구현예에서는 특히 유기용매로서 클로로포름, 아세톤, 및 탄소수 1 내지 4의 저급 알콜, 특히 메탄올이 10~1 : 1~10 : 1~10(v/v)의 비로 혼합된 혼합용매가 사용된다. In one embodiment, a mixed solvent in which chloroform, acetone, and a lower alcohol having 1 to 4 carbon atoms, in particular methanol, at a ratio of 10: 1 to 10: 1 to 10 (v / v) is used as the organic solvent.
본원에 따른 추출물은 Wnt/β-카테닌 신호전달체계 또는 경로를 억제하여 대장암 세포의 증식을 효과적으로 억제할 수 있으며, Wnt/β-카테닌 신호전달체계에 관여하는 다양한 전사인자에 미치는 효과를 검증하였다. 본원에 따른 대장암은 특히 Wnt/β-카테닌 신호전달체계가 과활성화 된 대장암이다. Wnt/β-카테닌 신호전달체계가 과활성화 여부는 본원 실시예를 포함하는 본원 명세서에 기재된 사항 및 본원 명세서에 기재된 문헌을 참조하여, 예를 들면 Wnt/β-카테닌 신호전달체계를 구성하는 구성인자의 유전자 및 단백질 발현을 측정, 또는 유전자 및 단백질의 변이를 측정하고, 이 것을 적절한 대조군 예를 들면 정상 대장 세포에서의 대응하는 측정값과 비교하여 판단할 수 있을 것이다. The extract according to the present invention can effectively inhibit the proliferation of colorectal cancer cells by inhibiting the Wnt /? -Catenin signaling pathway or pathway, and has demonstrated the effect on various transcription factors involved in the Wnt /? -Catenin signaling system . Colorectal cancer according to the present invention is a colon cancer which is hyperactivated, in particular the Wnt /? - catenin signaling system. Whether or not the Wnt / 3-catenin signaling system is overactivated can be determined by comparing the components described in the present specification including the present example embodiments and the documents described in the present specification with, for example, the constituent factors constituting the Wnt / Or by measuring the gene and protein variation, and comparing the gene and protein variation to a corresponding control, for example, a corresponding measurement in normal colon cells.
이에 다른 양태에서 본원은 또한 상술한 바와 같은 텔렉타디엄 동나이엔스 추출물을 유효성분으로 포함하는 세포의 Wnt/β-카테닌 신호전달체계를 억제하는 Wnt 표적 항암제 또는 항암보조제를 제공한다. 이로 제한하는 것은 아니나 Wnt 표적 항암제는 Wnt/β-카테닌 신호전달체계에 관여하는 하나 이상의 분자의 활성 등을 조절하여 궁극적으로 Wnt/β-카테닌 신호전달체계에 의해 영향을 받는, 암세포의 증식과 같은 생물학적 효과를 조절하는 것이다. In another aspect, the present invention also provides a Wnt target anticancer agent or anticancer adjuvant that inhibits the Wnt / beta -catenin signaling system of cells comprising the telecadapterium dnaeins extract as an active ingredient as described above. But are not limited to, the Wnt target anticancer drug may modulate the activity of one or more molecules involved in the Wnt / beta -catenin signaling pathway, such as the proliferation of cancer cells that are ultimately affected by the Wnt / It controls the biological effects.
본원에 따른 Wnt 표적 항암제 또는 항암보조제는 특히 Wnt/β-카테닌 신호전달체계의 이상과 높은 관련성이 있는 대장암 세포의 증식 억제에 유용하게 사용될 수 있다. The Wnt target anticancer agent or anticancer adjuvant according to the present invention can be usefully used for inhibiting the proliferation of colon cancer cells, which is highly related to the abnormality of the Wnt /? - catenin signaling system.
다른 양태에서 본원은 또한 상술한 바와 같은 본원에 따른 텔렉타디엄 동나이엔스 추출물을 포함하는, 대장암 예방 및 개선용 건강기능식품을 제공한다.In another aspect, the present invention also provides a health functional food for preventing and / or improving colorectal cancer, comprising telecitabine Dongnaeans extract according to the present invention as described above.
본 발명의 텔렉타디엄 동나이엔스(Telectadium dongnaiense)의 추출물을 포함하는 대장암 예방 또는 치료용 약학 조성물 및 건강기능식품은 Wnt/β-카테닌 신호전달 경로를 억제하는 작용기전을 가지며, 암 특히 대장암에 대한 항암효능을 지니므로, 대장암 예방 및 치료, 또는 기존항암제에 보조제로서 유용하게 사용될 수 있다. The Teldadium of the present invention The present invention relates to a pharmaceutical composition for prevention or treatment of colorectal cancer, which comprises an extract of dongnaiense and a health functional food, which has an action mechanism for inhibiting the Wnt /? -catenin signaling pathway and has anticancer activity against cancer, Prophylactic and therapeutic, or as an adjuvant to existing anticancer agents.
도 1은 본 발명의 텔렉타디엄 동나이엔스 추출물의 사람 신장세포주에서의 TCF/LEF 전사저해 활성에 대한 분석을 나타낸 것이다. 이러한 결과는 Wnt 신호가 과발현 되어 β-카테닌이 증가하면 핵 내에서 β-카테닌-TCF/LEF 복합체 형성 후 발암유전자의 전사를 촉진하기 때문에 본원에 따른 추출물은 TCF/LEF의 전사활성을 저해하여 Wnt 신호가 과발현 되어 있는 암의 치료에 유용하게 사용될 수 있음을 나타내는 것이다.
도 2는 본 발명의 텔렉타디엄 동나이엔스 추출물의 24시간 처리시의 대장암세포에 대한 세포독성을 나타낸 것이다. 이러한 결과는 본원에 따른 텔렉타디엄 동나이엔스 추출물의 대장암 세포주에 대한 50% 생존율에 대하여 IC50 값이 1.5μg/㎖로, 대장암 세포의 사멸에 효과적임을 나타내는 것이다.
도 3은 본 발명의 텔렉타디엄 동나이엔스 추출물의 24시간 처리시의 대장암세포에 대한 TCF/LEF 전사분석에서 저해활성을 나타낸 것이다. 이는 본원에 따른 추출물이 Wnt 신호가 과발현 되어 있는 대장암 치료에 유용하게 사용될 수 있음을 나타내는 것이다.
도 4는 대장암 세포주에서 텔렉타디엄 동나이엔스 추출물에 의한 Wnt/β-카테닌 신호전달의 하위조절자인 c-Myc, Cyclin D1 및 Survivin 유전자발현에 미치는 영향을 나타낸 것이다. 이는 본원에 따른 텔렉타디엄 동나이엔스 추출물은 Wnt/β-카테닌 신호전달체계를 억제를 통해 대장암의 증식을 억제하는 것을 나타낸다.
도 5는 대장암 세포주(HCT116)에서 텔렉타디엄 동나이엔스 추출물에 의한 Wnt/β-카테닌 신호전달의 하위조절자인 c-Myc, Cyclin D1 및 Survivin 단백질발현에 미치는 농도 의존적 영향을 나타낸 것이다. 이는 본원에 따른 텔렉타디엄 동나이엔스 추출물은 Wnt/β-카테닌 신호전달체계를 억제를 통해 대장암의 증식을 억제하는 것을 나타낸다. FIG. 1 shows the analysis of the inhibitory activity of TCF / LEF on human renal cell line of telecitabine Dong-Naiens extract of the present invention. These results suggest that the increase of β-catenin by overexpression of Wnt signals promotes the transcription of the oncogenic gene after formation of β-catenin-TCF / LEF complex in the nucleus. Therefore, the extract according to the present invention inhibits the transcription activity of TCF / Which is useful for the treatment of cancer in which the signal is overexpressed.
Fig. 2 shows the cytotoxicity of the telecitabine Dongnaeans extract of the present invention to colon cancer cells treated for 24 hours. These results indicate that the telecitabine Dongnaeans extract according to the present invention has an IC 50 value of 1.5 μg / ml against the colon cancer cell line at a 50% survival rate and is effective in killing colon cancer cells.
Fig. 3 shows the inhibitory activity in the TCF / LEF transcriptional analysis of colon cancer cells at 24 hours treatment of the telecitabine Dongnaeans extract of the present invention. This indicates that the extract according to the present invention can be useful for the treatment of colon cancer in which the Wnt signal is overexpressed.
Figure 4 shows the effect of telekteridium dnaeinens extract on the expression of c-Myc, Cyclin D1 and Survivin genes, sub-regulators of Wnt / beta -catenin signaling in colorectal cancer cell lines. This indicates that the telecitabine Dongnaeans extract according to the present invention inhibits the proliferation of colon cancer through inhibition of the Wnt /? -Catenin signaling system.
FIG. 5 shows the concentration-dependent effects on the expression of c-Myc, Cyclin D1 and Survivin proteins, sub-regulators of Wnt /? -Catenin signaling by telecitabine Dongnaeans extract in colon cancer cell line (HCT116). This indicates that the telecitabine Dongnaeans extract according to the present invention inhibits the proliferation of colon cancer through inhibition of the Wnt /? -Catenin signaling system.
본 발명은 텔렉타디엄 동나이엔스(Telectadium dongnaiense)의 추출물이 Wnt/β-카테닌 신호전달 경로를 억제하는 작용기전을 가지며, 암 특히 대장암에 대한 항암효능을 가진다는 발견에 근거한 것이다.The present invention relates to the use of Telectadium dongnaiense extract has an action mechanism that inhibits the Wnt / β-catenin signal transduction pathway and has anticancer efficacy against cancer, especially colon cancer.
Wnt/β-카테닌 신호전달경로의 조절이상은 초기단계의 대장암화에 있어 매우 중요한 역할을 담당하는데, Wnt는 GSK3β의 활성을 억제하여 APC의 인산화를 감소시킴으로 결과적으로 β-카테닌의 세포내 양을 증가시키고 Wnt에 의해 β-카테닌이 증가하면 β-카테닌은 전사인자인 TCF/LEF의 복합체 즉 β-카테닌-TCF/LEF 복합체가 핵으로 가서 발암유전자의 전사를 촉진하는 것으로 추정된다. 본 발명자는 11,000 여종의 전 세계 4대 권역으로부터 입수한 해외식물을 스크리닝하였으며, 그 결과 상기 텔렉타디엄 동나이엔스 추출물이 Wnt/β-카테닌 신호전달계의 활성화를 저해하며, 특히 TCF/LEF 전사저해활성, 및 c-Myc, Cyclin D1 및 Survivin 유전자발현 억제활성을 가지며, 상기 Wnt/β-카테닌 신호전달체계 억제를 통한 대장암의 증식 억제활성을 가진다는 사실을 밝혔다. Regulation of the Wnt / β-catenin signaling pathway plays a crucial role in the early stages of colon cancer. Wnt inhibits the activity of GSK3β and reduces the phosphorylation of APC, resulting in the intracellular level of β-catenin Β-catenin is thought to promote the transcription of the oncogenic gene by going to the nucleus, ie, the β-catenin-TCF / LEF complex, a transcription factor, TCF / LEF, when β-catenin is increased by Wnt. The present inventors screened foreign plants obtained from the 4 major regions of 11,000 species and found that the telecitabine Dongnaeans extract inhibited the activation of the Wnt / β-catenin signaling system, and in particular inhibited TCF / LEF transcription Activity, and c-Myc, cyclin D1 and Survivin gene expression inhibitory activity and inhibited the proliferation of colon cancer by inhibiting the Wnt / β-catenin signaling pathway.
따라서 한 양태에서 본원은 텔렉타디엄 동나이엔스 추출물을 유효성분으로 함유하는 대장암 예방 및 치료용 약학조성물에 관한 것이다.Accordingly, in one aspect, the present invention relates to a pharmaceutical composition for preventing and treating colon cancer, which comprises telekteridium Dong Naiens extract as an active ingredient.
본원에 따른 추출물의 제조에 사용되는 식물 텔렉타디엄 동나이엔스는 박주과리과에 속하는 베트남의 동나이(Dongnai) 지방이 원산지인 식물이다. 상기 텔렉타디엄 동나이엔스는 텔렉타디엄 동나이엔스의 꽃, 가지, 줄기, 잎, 미성숙열매, 또는 열매를 포함한 지상부, 뿌리줄기, 또는 뿌리, 보다 바람직하게는, 지상부, 뿌리줄기, 또는 뿌리, 보다 더 바람직하게는 지상부를 사용할 수 있다. 본원의 일 구현예에서 텔렉타디엄 동나이엔스의 지상부를 사용하나, 이에 제한되지 않는다.The plant Teletastim Dongnaiens used in the preparation of the extract according to the present invention is a plant originating from the Dongnai province of Vietnam belonging to the genus Phalaenopsis. The telecetradem Dongnaiens is a plant of the genus Telekterthium dongaensis, including a flower, branch, stem, leaf, immature fruit or fruit, including root, rootstock or root, more preferably ground, rootstock or root , And more preferably, the ground portion can be used. In one embodiment herein, the terrestrial portion of teletardim Dong Naiens is used, but is not limited thereto.
텔렉타디엄 동나이엔스의 Wnt/β-카테닌 신호전달 경로를 타겟으로 하는 암질환 연구는 어떠한 보고도 된 바 없는 것으로 본 발명에서 개시된다.There is no disclosure in the present invention of a cancer disease study targeting the Wnt / beta -catenin signaling pathway of telecitabine Dong Naiens.
본원의 추출물은 통상의 식물 추출물의 공지된 일반적 제조방법을 사용하여 제조될 수 있으며, 특별히 제한되지 않는다. 예를 들면, 초음파 추출법, 환류 냉각 추출법, 열수 추출법 또는 후술하는 추출용매로 하여 공지의 방법에 의해 제조하는 방법일 수 있다(예를 들어 Nomura T. Phenolic compounds of the mulberry tree and related plants. In: Progress in the Chemistry of Organic Natural Products (Herz W, Grisebach H, Kirby GW, Tamm Ch, eds.), vol. 53. Springe:Vienna, 1988;87-201).The extract of the present invention can be produced by using a common general production method of a conventional plant extract, and is not particularly limited. For example, it may be an ultrasonic extraction method, a reflux cooling extraction method, a hot water extraction method, or a method of preparing by the known method as an extraction solvent to be described later (for example, Nomura T. Phenolic compounds of the mulberry tree and related plants. Progress in the Chemistry of Organic Natural Products (Herz W, Grisebach H, Kirby GW, Tamm Ch, eds.), 53. Springe: Vienna, 1988, 87-201).
예를 들면 본 발명의 텔렉타디엄 동나이엔스 추출물은 하기와 같이 제조될 수 있다. 건조된 텔렉타디엄 동나이엔스를 세척 및 세절 후 정제수를 포함한 메탄올, 에탄올, 부탄올, 프로판올 및 이소프로판올 등을 포함하는 탄소수 1 내지 4의 저급 알콜, 클로로포름, 아세톤, 프로필렌글리콜, 초산에틸, 부틸렌글리콜, 및 에테르로 구성된 군으로부터 선택된 하나 또는 그 이상의 혼합 용매, 바람직하게는, 클로로포름, 아세톤, 메탄올 또는 이의 혼합용매, 보다 바람직하게는, 클로로포름, 아세톤, 및 메탄올의 10-1:1-10:1-10(v/v) 혼합비, 보다 더 바람직하게는, 클로로포름, 아세톤, 및 메탄올의 5-1:1-5:1-5(v/v) 혼합비의 혼합용매를 수회 섞을 수 있다. For example, the telecitabine Dongnaiens extract of the present invention can be prepared as follows. The dried telecitabine Dong Naiens is washed and subdivided into a lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, butanol, propanol and isopropanol, including chloroform, acetone, propylene glycol, ethyl acetate,
추출물 제조온도는 4 내지 150℃일 수 있으나, 이에 한정되지는 않으며 30℃ 내지 150℃, 바람직하게는 50℃ 내지 100℃의 온도에서 추출할 수 있다.The extract preparation temperature may be 4 to 150 ° C, but is not limited thereto and can be extracted at a temperature of 30 ° C to 150 ° C, preferably 50 ° C to 100 ° C.
추출시간은 특별히 한정되지는 않으나 10분 내지 30일 일 수 있으며, 바람직하게는 30분 내지 48시간, 더욱 바람직하게는 1시간 내지 12시간일 수 있으며, 통상의 초음파 추출법, 열수 추출법, 상온 추출법 또는 환류추출법, 바람직하게는 초음파 추출법을 약 1 내지 20회, 바람직하게는 2 내지 10회 반복 수행할 수 있다. 상기 방법으로 제조된 본 발명의 텔렉타디엄 동나이엔스 추출물은 이후 감압 여과 또는/및 동결건조하여 용매를 제거할 수 있다.The extraction time is not particularly limited, but may be 10 minutes to 30 days, preferably 30 minutes to 48 hours, more preferably 1 hour to 12 hours, and may be determined by conventional ultrasonic extraction, hot water extraction, The reflux extraction method, preferably the ultrasonic extraction method, may be repeatedly performed about 1 to 20 times, preferably 2 to 10 times. The telecitabine Dongnaiens extract of the present invention prepared by the above method can then be subjected to vacuum filtration and / or lyophilization to remove the solvent.
일 구현예에서 본원에 따른 텔렉타디엄 동나이엔스 추출물은 유기용매 추출물이다. 상기 유기용매는 메탄올, 에탄올, 부탄올, 프로판올 및 이소프로판올 등을 포함하는 탄소수 1 내지 4의 저급 알콜, 클로로포름, 아세톤, 프로필렌글리콜, 초산에틸, 부틸렌글리콜, 및 에테르로 구성된 군으로부터 선택된 하나 또는 그 이상의 혼합 용매, 바람직하게는, 클로로포름, 아세톤, 메탄올 또는 이의 혼합용매, 보다 바람직하게는, 클로로포름, 아세톤, 및 메탄올의 10-1:1-10:1-10(v/v) 혼합비, 보다 더 바람직하게는, 클로로포름, 아세톤, 및 메탄올의 5-1:1-5:1-5(v/v) 혼합비의 혼합용매이다. 본원의 일 구현예에서 상기 혼합용매는 클로로포름, 아세톤 및 메탄이 1:1:1(v/v)의 혼합비로 사용된다.In one embodiment, the telecitabine Dongnaiens extract according to the present invention is an organic solvent extract. The organic solvent may be one or more selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, butanol, propanol and isopropanol, chloroform, acetone, propylene glycol, ethyl acetate, butylene glycol, More preferably 10-1: 1-10: 1-10 (v / v) mixing ratio of chloroform, acetone, methanol or a mixed solvent thereof, more preferably chloroform, acetone, and methanol, Is a mixed solvent of chloroform, acetone, and methanol in a mixing ratio of 5-1: 1-5: 1-5 (v / v). In one embodiment of the invention, the mixed solvent is used in a mixing ratio of 1: 1: 1 (v / v) of chloroform, acetone, and methane.
본원에 따른 텔렉타디엄 동나이엔스 추출물은 Wnt/β-카테닌 신호전달 체계를 억제함으로써 대장암 증식을 억제할 수 있다. The telecitabine Dongnaiens extract according to the present invention can inhibit colon cancer growth by inhibiting the Wnt /? -Catenin signaling system.
본원에서 사용된 용어 "치료" 란 질환, 또는 질환으로 인한 증상 또는 상태의 억제, 제거, 경감, 완화, 개선, 및/또는 예방을 포함하는 개념이다.The term " treatment " as used herein is a concept involving inhibiting, eliminating, alleviating, ameliorating, and / or preventing a disease or condition or condition due to a disease.
본원의 조성물은 대장암의 치료 또는 예방을 위하여 단독으로, 또는 다른 통상적인 화학 요법 또는 방사 요법과 함께 이용될 수도 있다. 통상적이 화학요법에 사용되는 항암제로는 엽산유도체(methotrexate), 퓨린유도체(6-mercaptopurine, 6-thioguanine), 피리미딘유도체(5-fluorouracil, cytarabine) 등의 대사길항제(antimetabolites); 니트로겐 머스타드계 화합물(chlorambucil,cyclophosphamide), 에틸렌이민계 화합물(thiotepa), 알킬설포네이트계 화합물(busulfan), 니트로소우레아계화합물(carmustine), 트리아젠계 화합물(dacarbazine) 등의 알킬화제(alkylating agent); 악티노마이신 D(actinomycin D), 독소루비신, 블레오마이신, 미토마이신과 같은 항암성항암제, 빈크리스틴, 빈블라스틴과 같은 식물알칼로이드, 탁산환을 포함하는 유사분열 저해제인 탁소이드 등의 유사분열억제제(antimitotic drugs); 또는 부신피질호르몬이나 프로게스테론과 같은 호르몬제; 시스플라틴 같은 백금함유 화합물 등이 포함될 수 있다.The compositions herein may be used alone or in combination with other conventional chemotherapy or radiotherapy for the treatment or prevention of colorectal cancer. Anticancer agents commonly used in chemotherapy include antimetabolites such as methotrexate, 6-mercaptopurine, 6-thioguanine, and 5-fluorouracil and cytarabine; An alkylating agent such as a chlorambucil, a cyclophosphamide, an ethylene imine compound, an alkyl sulfonate compound, a carnustine compound or a dacarbazine compound, ); Antitumor agents such as actinomycin D, doxorubicin, bleomycin and mitomycin, plant alkaloids such as vincristine and vinblastine, and mitotic inhibitors such as taxoid, a mitotic inhibitor containing a taxane ring antimitotic drugs); Hormones such as corticosteroids or progesterone; Platinum-containing compounds such as cisplatin, and the like.
본원의 조성물은 상기 언급한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 제조할 수 있다. 약제학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올, 리포좀 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있으며, 표적 기관에 특이적으로 작용할 수 있도록 표적 기관 특이적 항체 또는 기타 리간드를 상기 담체와 결합시켜 사용할 수 있다. 더 나아가 당해 기술분야의 적정한 방법으로 또는 레밍턴의 문헌(Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제형화할 수 있다.In addition to the above-mentioned active ingredients, the composition of the present invention may further comprise at least one pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be a mixture of saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, liposome and one or more of these components. Other conventional additives such as buffers, bacteriostats and the like may be added. In addition, it can be formulated into injection formulations, pills, capsules, granules or tablets such as aqueous solutions, suspensions, emulsions and the like by additionally adding diluents, dispersants, surfactants, binders and lubricants, Specific antibody or other ligand can be used in combination with the carrier. Can further be suitably formulated according to the respective disease or ingredient according to the appropriate method in the art or using the methods disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA have.
본원의 조성물의 투여방법은 특별히 이에 제한되는 것은 아니며, 공지된 투여방법을 적용할 수 있으며, 목적하는 방법에 따라 비경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 적용)하거나 경구 투여할 수 있으며, 신속한 치료효과를 얻기 위해서는 정맥내 주사에 의한 투여가 바람직하다. 투여량은 투여대상체의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.01 ~ 1,000㎎/일이며, 바람직하게는 0.01 ~ 500㎎/일이며, 하루 일회 내지 수회에 나누어 투여할 수 있다. 일 구현예에서 단위 제형당 상기 추출물 또는 항암보조제 및 항암제의 1일 용량 또는 이의 1/2, 1/3 또는 1/4의 용량이 함유되도록 하며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 하루 1 내지 6회 분할 투여할 수도 있다.The method of administration of the composition of the present invention is not particularly limited thereto, and a known administration method can be applied, and parenteral administration (for example, intravenous, subcutaneous, intraperitoneal or topical application) In order to obtain a rapid therapeutic effect, administration by intravenous injection is preferable. The dose may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the subject to be administered, and is generally 0.01 to 1,000 mg / day on the basis of an adult patient weighing 70 kg, Day is 0.01 to 500 mg / day, and can be administered once or divided into several times a day. In one embodiment, the daily dose of the extract or the anti-cancer adjuvant and the anticancer drug or a half, 1/3 or 1/4 thereof is contained per unit dosage form. It may be administered in one to six divided doses.
본원의 텔렉타디엄 동나이엔스 유기용매 추출물은 Wnt 신호전달체계를 억제하는 효능을 가진다. 구체적으로는 β-카테닌이 도입된 HEK293 세포주 및 사람 대장암 세포주에서 TCF/LEF 루시퍼라아제 활성을 저해하고, β-카테닌 표적 유전자인 c-Myc, Cyclin D1 및 Survivin 유전자 발현의 감소시킴으로써 Wnt 신호전달체계를 억제한다.The telecentadim Dong Naiens organic solvent extract of the present invention has an effect of inhibiting the Wnt signaling system. Specifically, it inhibits TCF / LEF luciferase activity in HEK293 cell line and human colon cancer cell line into which β-catenin is introduced, and decreases the expression of c-Myc, Cyclin D1 and Survivin gene of β-catenin, Suppresses the system.
이에 다른 양태에서 본원은 텔렉타디엄 동나이엔스의 유기용매 추출물이 Wnt/β-카테닌 신호전달체계를 억제하는 것인, 텔렉타디엄 동나이엔스의 유기용매 추출물을 함유하는 Wnt 표적 항암제, 특히 Wnt 표적 대장암 항암제에 관한 것이다.In another embodiment herein, the present invention provides a Wnt-targeted anticancer agent, particularly a Wnt antagonist, comprising an organic solvent extract of telecitabine Dong-Naien, wherein the organic solvent extract of telecitabine Dong-Naiens inhibits the Wnt / And to a colon cancer anticancer agent.
본 발명의 텔렉타디엄 동나이엔스의 유기용매 추출물은 상기한 바와 같다.The organic solvent extract of telecitabine Dongnaiens of the present invention is as described above.
상기 표적항암제는 발암 과정의 특정 표적인자만 선택적으로 공격하는 치료제를 말하며, 본원의 표적항암제는 대장암 발암 과정에 관여하는 Wnt/β-카테닌 신호전달체계를 표적으로 하는 Wnt 표적 항암제이다.The target anticancer agent refers to a therapeutic agent selectively attacking only specific target factors of the carcinogenesis process. The target anticancer agent is a Wnt target anticancer agent targeting the Wnt /? -Catenin signaling system involved in the colon cancer carcinogenesis process.
본 발명의 상기 추출물은 Wnt 신호전달 저해효능을 가지므로 암세포에 대한 항암보조제로 사용될 수 있다.Since the extract of the present invention has a Wnt signaling inhibitory effect, it can be used as an anti-cancer adjuvant for cancer cells.
이에 또다른 양태에서 본원은 텔렉타디엄 동나이엔스의 유기용매 추출물이 Wnt/β-카테닌 신호전달체계를 억제하는 것인, 텔렉타디엄 동나이엔스의 유기용매 추출물을 함유하는 Wnt 표적 항암보조제에 관한 것이다.Accordingly, in another embodiment, the present invention provides a Wnt-targeted anticancer adjuvant comprising an organic solvent extract of telecitabine Dongnaiens, wherein the organic solvent extract of telecitabine Dongnaiens inhibits the Wnt / .
본 발명의 텔렉타디엄 동나이엔스의 유기용매 추출물은 상기한 바와 같다. The organic solvent extract of telecitabine Dongnaiens of the present invention is as described above.
본 발명의 항암보조제는 Wnt/β-카테닌 신호전달체계를 표적으로 하는 것으로, 항암제의 항암효과는 증대시키고, 항암제의 부작용을 억제하거나 개선시키기 위하여 사용할 수 있다.The anticancer adjuvant of the present invention targets the Wnt / beta -catenin signal transduction system and can be used to increase the anticancer effect of the anticancer agent and to suppress or improve the side effect of the anticancer agent.
본 발명에서 상기 "억제"는 항암보조제의 투여에 의해 항암제의 부작용을 감소시키는 모든 행위를 의미하며, 본 발명에서 용어, "개선"이란 항암보조제의 투여에 의한 항암제 부작용의 감소 또는 항암제 부작용의 감소로 인한 암에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term " improvement " in the present invention means reduction in side effects of the anticancer drug by administration of the anticancer adjuvant or reduction of side effects of the anticancer drug in the present invention. Means any action that improves or alters the symptoms caused by cancer.
또한, 본 발명에서 상기 "개체"란 암이 발병하였거나 발병할 수 있는 인간을 포함한 모든 동물을 의미하고, 본 발명의 항암보조제를 개체에게 투여함으로써, 항암제 부작용을 최소화하면서 효과적으로 암을 치료할 수 있다. 예를 들어, 본 발명의 항암보조제를 항암제를 투여받고 있는 대장암을 앓고 있는 인간에게 투여하여 항암 부작용을 감소시키면서 효율적으로 암을 치료할 수 있다.In the present invention, the term " individual " means all animals including humans who have developed or developed cancer. By administering the anticancer adjuvant of the present invention to a subject, cancer can be effectively treated while minimizing side effects of the anticancer drug. For example, the anticancer adjuvant of the present invention can be administered to a human suffering from colon cancer receiving the anticancer agent, thereby effectively treating the cancer while reducing the anticancer side effect.
본 발명의 상기 표적항암제 또는 항암보조제의 허용가능한 담체, 제형, 투여방법 및 투여량은 상기 약학조성물에 기재된 바와 같다. Acceptable carriers, formulations, administration methods and doses of the target anticancer agent or anticancer agent of the present invention are as described in the above pharmaceutical composition.
또한 본 발명의 조성물은 식품, 특히 기능성 식품 조성물로 제조될 수 있다. 이에 본 발명은 텔렉타디엄 동나이엔스의 유기용매 추출물을 함유하는, 대장암 예방 및 개선용 건강기능식품에 관한 것이다.In addition, the composition of the present invention can be manufactured into foods, especially functional food compositions. Accordingly, the present invention relates to a health functional food for prevention and improvement of colorectal cancer, which contains an organic solvent extract of telecitabine Dong Naiens.
본 발명의 텔렉타디엄 동나이엔스의 유기용매 추출물은 상기한 바와 같다.The organic solvent extract of telecitabine Dongnaiens of the present invention is as described above.
본 발명의 추출물을 포함하는 건강기능식품은 대장암의 예방 및 개선을 위한 약제, 식품 및 음료 등에 다양하게 이용될 수 있다. 본 발명의 화합물을 첨가할 수 있는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.The health functional food containing the extract of the present invention can be used variously for medicines, foods and beverages for prevention and improvement of colon cancer. Examples of foods to which the compound of the present invention can be added include various foods, beverages, gums, tea, vitamin complexes, health supplements and the like, and they can be used in powder, granule, tablet, have.
본 발명의 기능성 식품 조성물은 식품제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분으로서의 상기 추출물 이외에 향미제 또는 천연 탄수화물을 추가 성분으로서 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함한다. 향미제로서 천연 향미제(예컨대, 타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다. 식품에 대한 용이한 접근성을 고려한다면, 본 발명의 건강기능식품은 암의 치료 또는 예방에 매우 유용하다.The functional food composition of the present invention includes components that are ordinarily added during the manufacture of food, and includes, for example, proteins, carbohydrates, fats, nutrients, and seasonings. For example, in the case of a preparation made of a drink, a flavoring agent or a natural carbohydrate may be added as an additional ingredient in addition to the above-mentioned extract as an active ingredient. For example, natural carbohydrates include monosaccharides (e.g., glucose, fructose, etc.); Disaccharides (e.g., maltose, sucrose, etc.); oligosaccharide; Polysaccharides (e.g., dextrin, cyclodextrin and the like); And sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.). Synthetic flavors (e.g., saccharin, aspartame, etc.) can be used as flavorings, and natural flavoring agents (e.g., tau martin, stevia extract (for example, rebaudioside A and glycyrrhizin) and the like) Considering the easy accessibility to food, the health functional food of the present invention is very useful for the treatment or prevention of cancer.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 조성물들은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 그렇게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0 내지 약 20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above-mentioned composition, the composition of the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, coloring agents and intermediates (cheese, chocolate etc.), pectic acid and its salts, Salts, organic acids, protective colloid thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compositions of the present invention may contain flesh for the production of natural fruit juices and fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not so critical, but is generally selected in the range of 0 to about 20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 조성물은, 조성물 총 중량에 대하여 상기 화합물을 0.01 내지 99% 중량으로 포함한다. 그러나 상기와 같은 조성은 반드시 이에 한정되는 것은 아니고, 환자의 상태 및 질환의 종류 및 진행 정도에 따라 변할 수 있다.The composition of the present invention contains 0.01 to 99% by weight of the compound, based on the total weight of the composition. However, the composition is not limited thereto, and may vary depending on the condition of the patient, the type of disease, and the progress of the disease.
이하, 본 발명의 이해를 돕기 위해서 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐 본 발명이 하기의 실시예에 한정되는 것은 아니다.Hereinafter, embodiments are provided to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited to the following examples.
실시예 Example
실시예Example 1. One. 텔렉타디엄Telekta 동나이엔스Dong Naiens (( TelectadiumTelectadium dongnaiensedongnaiense Pierre ex Costantin) 추출물의 제조 Preparation of Pierre ex Costantin) Extract
텔렉타디엄 동나이엔스(베트남 원산지)는 꽃, 가지, 줄기, 잎, 미성숙열매, 열매를 포함하는 지상부; 뿌리줄기; 및 뿌리를 채취하고 선택된 하나 이상의 검정된 공시재료를 세척한 후 절단하여 사용하였다.Teletastadium Dong Naiens (origin of Vietnam) is a ground-top section containing flowers, branches, stems, leaves, immature fruit, and fruit; Rootstock; And roots were harvested and one or more of the assay materials selected were washed and cut and used.
시료인 건조된 텔렉타디엄 동나이엔스의 지상부; 뿌리줄기; 및 뿌리 각 1㎏에 10L의 클로로포름 : 아세톤 : 메탄올 (1:1:1, v/v)로 초음파 추출기 장치(SDN-900H, SD-ULTRASONIC CO. LTD)를 이용, 수욕상에서 3시간씩 3회 추출하였다. 추출물을 여과한 다음 감압 농축한 후에 동결 건조하여 갈색의 텔렉타디엄 동나이엔스 (Telectadium dongnaiense Pierre ex Costantin) 지상부 추출물; 뿌리줄기 추출물; 및 뿌리 추출물을 각각 수득하였으며, -20℃에 보관하며 이하 실험예 분석을 위하여 지상부 추출물을 시료로 사용하였다.Above ground of the dried teletardim Dong Naiens sample; Rootstock; (SDN-900H, SD-ULTRASONIC CO. LTD) with 10 L of chloroform: acetone: methanol (1: 1: 1, v / v) And extracted. The extract was filtered, concentrated under reduced pressure, and then lyophilized to obtain brown ground extract of Tlectadium dongnaiense Pierre ex Costantin; Rootstock extract; And root extracts were obtained, respectively, and stored at -20 ° C. For the analysis of the experimental examples, the above-ground extract was used as a sample.
실시예Example 2. 2. 텔렉타디엄Telekta 동나이엔스Dong Naiens 지상부 추출물의 β- The β- 카테닌이Catenin 도입된 HEK293 세포주에서의 In the introduced HEK293 cell line TCFTCF // LEFLEF 루시퍼라아제Luciferase 활성 저해 효과 확인 Identify active inhibitory effects
몇몇의 암 세포주, 특히 대장암에서 Wnt 신호전달 관련 단백질들의 변이에 의해 β-카테닌의 발현이 과활성화 되어있음이 알려져 있기 때문에 β-카테닌의 작용을 저해할 수 있는 물질을 발견하는 것은 의미 있는 일이라 여겨지며, 텔렉타디엄 동나이엔스 추출물이 이러한 효과를 나타내는지 확인하기 위해 HEK293 세포에 β-카테닌을 도입하여 이를 과활성화 시킨 후 텔렉타디엄 동나이엔스 추출물에 의해 억제되는지를 평가하였다. 종래 문헌(Kang YJ et al (2012) Mol Pharm 82:168-177)의 방법을 일부 변형하여 실험하였다.Since it is known that the expression of β-catenin is hyperactivated by the mutation of Wnt signaling-related proteins in some cancer cell lines, especially in colorectal cancer, it is meaningful to find a substance that can inhibit the action of β-catenin In order to confirm whether telekteridium Dong Naiens extract showed this effect, β-catenin was introduced into HEK293 cells and overactivated and then evaluated for inhibition by telecitabine Dong-Naiens extract. (Kang YJ et al (2012) Mol Pharm 82: 168-177).
상기 실시예 1의 텔렉타디엄 동나이엔스 추출물이 β-카테닌이 결합하는 전사 인자인 TCF/LEF (T-cell factor/lymphoid enhancer factor)의 전사활성 조절과 관련이 있는지를 확인하기 위하여, HEK293 세포 (Human Embryonic Kidney cell; ATCC, USA)에 TCF4 및 pcDNA β-카테닌 그리고 TCF 결합 부위를 포함하는 plasmid (TOPFlash)를 일시적으로 트랜스팩션(transfection) 시킨 후 텔렉타디엄 동나이엔스 추출물이 TCF의 전사활성증가에 따른 루시퍼라아제 활성에 어떠한 영향을 미치는지를 다음과 같이 시험하였다.In order to confirm whether the telecitabine Dongnaeans extract of Example 1 was involved in the transcriptional regulation of TCF / LEF, a transcription factor to which β-catenin binds, HEK293 cells (TOPFlash) containing TCF4 and pcDNA beta -catenin and TCF binding site was transfected into Human Embryonic Kidney Cell (ATCC, USA), and then telecitabine Dongnaiens extract was transfected with TCF On the activity of luciferase was examined as follows.
HEK293 세포를 10% FBS가 포함된 DMEM 배지 (#12800-017, Gibco)로 48 웰 플레이트에 웰 당 1.5 ⅹ 104 가 되도록 조절하여 37℃, 5% CO2 조건에서 24시간을 배양하고 루시퍼라아제가 붙어 있는 TRE 결합부위를 가지고 있는 플라스미드 100ng, TCF4 플라스미드 8ng, β-카테닌 20ng과 각 DNA 총 합의 1/20 량의 pRL-SV40 벡터 (E2231, Promega)와 리포펙타민 2000 (#11668-019, Invitrogen)을 Opti-MEM (31985-070, Gibco)에서 혼합하여 24시간 동안 트랜스팩션 시킨 후, 10% FBS가 포함된 DMEM 배지에 미리 희석해 둔 텔렉타디엄 동나이엔스 추출물 (5, 10, 20 μg/ml)을 처리하고 24시간 배양한 후 상등액을 모두 제거하고 1X Passive Lysis Buffer (E194A, Promega)에 현탁하여 15분간 섞어준 후 Dual Luciferase Kit (E1910, Promega)을 이용하여 Luminometer (Cetro LB 960, Berthold사, Germany)로 luciferase activity를 측정하고, 트랜스팩션 효율은 pRL-SV40 루시퍼라제 활성으로 보정하였다.HEK293 cells were adjusted to 1.5 × 10 4 per well in DMEM medium (# 12800-017, Gibco) containing 10% FBS and cultured for 24 hours at 37 ° C. and 5% CO 2 . 100 ng of a plasmid with a TRE binding site with an azide, 8 ng of a TCF4 plasmid, 20 ng of beta -catenin, 1/20 of a pRL-SV40 vector (E2231, Promega) and lipofectamine 2000 (# 11668-019 , Invitrogen) were mixed in Opti-MEM (31985-070, Gibco) and transfected for 24 hours. Then, telekteridium dongaense extract (5, 10, After incubation for 24 hours, the supernatant was removed and suspended in 1 × Passive Lysis Buffer (E194A, Promega). The cells were mixed for 15 minutes and then diluted with a Luminometer (Cetro LB 960, Berthold, Germany), and the transfection efficiency was measured using pRL-SV40 Lucy Lt; / RTI > activity.
실험결과는 표 1 및 도 1에 제시된 바와 같이, HEK293 세포에 TCF4, pcDNA β-카테닌, TOPFlash를 함께 도입하면, TOPFlash 단독 혹은 TOPFlash와 TCF4 plasmid를 함께 도입한 대조군에 비하여 luciferase activity가 증가하게 된다. HEK293세포에 TCF4, pcDNA β-카테닌를 함께 도입한 상태에서 텔렉타디엄 동나이엔스 추출물을 처리하면 증가되었던 TCF/LEF luciferase activity가 도 1에 제시된 바와 같이, 텔렉타디엄 동나이엔스 추출물을 1, 2.5, 5 μg/ml 첨가하고 TCF/LEF 전사활성을 분석한 결과, 통계적으로 유의성을 가지며 (**P<0.01) 농도의존적으로 전사 저해활성을 나타냈으며, 자세하게는 텔렉타디엄 동나이엔스 추출물을 1μg/㎖ 첨가시 35.2%, 2.5μg/㎖ 첨가시 55.6%, 5μg/㎖ 첨가시 73.4%, TCF/LEF 전사저해활성을 나타냈다. 상기 결과로부터 텔렉타디엄 동나이엔스 추출물의 전사저해활성 IC50는 2.1μg/㎖로 탁월한 저해활성을 나타냈다. 또한 텔렉타디엄 동나이엔스 추출물 이용하여 TCF 결합 부위가 변이(mutation)된 plasmid (FOPFlash)를 트랜스팩션 시킨 경우에는 TCF4, pcDNA β-카테닌을 함께 도입하여도 루시퍼라제 활성에 영향이 없는 것으로 나타났다. 이러한 결과는 Wnt 신호가 과발현 되어 β-카테닌이 증가하면 핵 내에서 β-카테닌-TCF/LEF 복합체 형성 후 발암유전자의 전사를 촉진하기 때문에 본원에 따른 추출물은 TCF/LEF의 전사활성을 저해하여 Wnt 신호가 과발현 되어 있는 암의 치료에 유용하게 사용될 수 있음을 나타내는 것이다. As shown in Table 1 and FIG. 1, when TCF4, pcDNA beta -catenin, and TOPFlash were introduced into HEK293 cells, luciferase activity was increased compared to the control group in which TOPFlash alone or TOPFlash and TCF4 plasmids were introduced together. TCF / LEF luciferase activity increased when telecitabine Dongnaeans extract was treated with HEK293 cells in the presence of TCF4 and pcDNA β-catenin, , And 5 μg / ml, and the TCF / LEF transcriptional activity was statistically significant (** P <0.01). As a result, the content of telecitabine Dong-naiens extract was 1 μg / ㎖, and TCF / LEF transcriptional inhibitory activity was 55.6% at the addition of 2.5 .mu.g / ml and 73.4% at the addition of 5 .mu.g / ml. From the above results, the transcriptional inhibitory activity IC 50 of telecitabine DongNaiens extract showed an excellent inhibitory activity of 2.1 μg / ml. In addition, when plasmid (FOPFlash) mutated with TCF binding site was transfected using telecitabine Dongnaeans extract, the addition of TCF4 and pcDNA β-catenin did not affect luciferase activity. These results suggest that the increase of β-catenin by overexpression of Wnt signals promotes the transcription of the oncogenic gene after formation of β-catenin-TCF / LEF complex in the nucleus. Therefore, the extract according to the present invention inhibits the transcription activity of TCF / Which is useful for the treatment of cancer in which the signal is overexpressed.
[표 1][Table 1]
실시예Example 3. 시험관 내에서 3. In vitro 텔렉타디엄Telekta 동나이엔스Dong Naiens 지상부 추출물의 사람 Person of above-ground extract 대장암세포에 대한 성장 억제Growth inhibition against colorectal cancer cells 효능 확인 Check efficacy
상기 실시예 1에서 얻은 시료의 시험관내에서의 사람 대장암세포 등에 대한 성장 억제 효능을 확인하기 위하여 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Lee SK et al (2008) Chem Biol Interact 115:215-28).In order to confirm the growth inhibitory effect of the sample obtained in Example 1 on human colorectal cancer cells and the like in vitro, experiments were conducted as described below (Lee SK et al (2008) Chem Biol Interact 115 : 215-28).
사람 대장암 세포주 HCT116은 한국 세포주 은행 (CCL-247, ATCC, USA)에서 분양 받았다.Human colon cancer cell line HCT116 was distributed from Korean Cell Line Bank (CCL-247, ATCC, USA).
본 발명에 이용된 사람의 대장암세포주를 10% FBS, 1% PSF 등을 함유한 RPMI배지에서 계대 배양하였다. 96-웰 플레이트의 각 웰에 10% DMSO에 녹아있는 시료 10㎕와 상기 세포현탁액 190㎕ (5 x 104 cells/ml) 넣고 3일간 배양하였다. 적어도 16웰에 상기 세포현탁액 190㎕를 넣고 30분간 배양하여 실험 전의 음성대조(zero-day control)로 사용하였다. 배양한 세포를 10% TCA (trichloroacetic acid)로 고정시킨 후 SRB 용액 (S9012, Sigma)으로 염색하고, 10 mM 트리스 베이스(Tris-base)로 염색액을 용해시킨 다음 515 nm에서 흡광도를 측정하였다. 10% DMSO에서 배양한 경우를 대조군으로 하여 각 시험 물질처리에 따른 세포 생존율을 하기 수학식 1을 이용하여 측정하였다.Human colon cancer cells used in the present invention were subcultured in an RPMI medium containing 10% FBS, 1% PSF and the like. To each well of a 96-well plate, 10 μl of a sample dissolved in 10% DMSO and 190 μl (5 × 10 4 cells / ml) of the cell suspension were added and cultured for 3 days. 190 μl of the cell suspension was added to at least 16 wells and incubated for 30 minutes, and used as a zero-day control before the experiment. The cultured cells were fixed with 10% TCA (trichloroacetic acid), stained with SRB solution (S9012, Sigma), dissolved in 10 mM Tris base, and then absorbed at 515 nm. 10% DMSO was used as a control, and the cell survival rate according to the treatment of each test substance was measured using the following equation (1).
[수학식 1][Equation 1]
% 생존율 = {OD(sample) - OD(0-day))/ (OD(10% DMSO) - OD(0-day)} X 100 % Survival rate = OD (0-day) / OD (10% DMSO) -OD (0-day)}
시료를 처리하지 않은 대조군을 100%로 하였을 때 시료 처리군의 값을 대조군에 대한 백분율로 나타내었으며, 각 시험물질 처리는 이중 혹은 삼중 시험의 평균값 ± SEM으로 구하여 그 결과를 하기 표 2 및 도 2에 나타내었다.When the control group without the sample was taken as 100%, the value of the sample treatment group was expressed as a percentage of the control group, and the treatment of each test substance was a mean value ± SEM of the double or triple test. Respectively.
자세하게는 도 2에 나타난 바와 같이, 텔렉타디엄 동나이엔스 추출물을 1, 2, 4, 8 μg/ml 첨가하고 사람 대장암 세포주에 대한 세포독성을 평가한 결과, 통계적으로 유의성을 가지며 (**P<0.01) 농도 의존적으로 세포독성을 나타냈으며, 자세하게는 텔렉타디엄 동나이엔스 추출물을 1μg/㎖ 첨가시 12.4%, 2μg/㎖ 첨가시 83.5%, 4μg/㎖ 첨가시 92.4%, 8μg/㎖ 첨가시 97.2%, 세포독성을 각각 나타냈다. 상기 결과로부터 텔렉타디엄 동나이엔스 추출물의 HCT116 세포주에 대한 50% 생존율에 대한 시험 물질의 농도인 IC50는 1.5μg/㎖로 탁월한 세포독성을 나타냈다.In detail, as shown in FIG. 2, the cytotoxicity of telecitabine DongNaiens extract to 1, 2, 4, and 8 μg / ml of human colon cancer cell line was statistically significant (** P <0.01). In detail, when 1 μg / ml of telecetradem Dongnaiens extract was added, the concentration was 12.4%, 83.5% when 2 μg / ml was added, 92.4% and 8 μg / ml when 4 μg / And 97.2% when added, respectively. From the above results, IC 50 , the concentration of the test substance for 50% survival rate of HCT116 cell line of telecitabine Dongnaeens extract, showed excellent cytotoxicity at 1.5 μg / ml.
[표 2][Table 2]
실시예Example 4. 사람 대장암 세포주에서 4. In human colon cancer cell lines 텔렉타디엄Telekta 동나이엔스Dong Naiens 지상부 추출물의의 Above-ground extract TCFTCF // LEFLEF luciferaseluciferase 활성 저해효능 확인 Identify active inhibition efficacy
과활성화된 β-카테닌의 작용을 저해한다는 실시예 2의 결과를 바탕으로, Wnt 신호전달 관련 단백질인 GSK3β 및 β-카테닌 자체에 유전자 변이가 있어 β-카테닌이 과발현 되어있는 것으로 알려진 HCT116 대장암 세포주에서 TCF/LEF luciferase 활성도를 평가하였다.Based on the results of Example 2, which inhibits the action of activated β-catenin, the HCT116 colon cancer cell line, which is known to overexpress β-catenin due to gene mutation in GSK3β and β-catenin itself, And the activity of TCF / LEF luciferase was evaluated.
사람 대장암 세포주 HCT 116 (5 X 103 cells/mL) 세포를 10% FBS가 포함된 RPMI 1640 배지 (#31800-022, Gibco)로 48-well plate 각 well에 300μL씩 넣고 37℃, 5% CO2 조건에서 배양하였다. 24시간 후 TOPflash (β-카테닌/TCF reporter plasmids) (#21-170, upstate biotechnology) 100ng, pRL-SV40 reporter plasmids (E2231, Promega) 5ng을 Opti-MEM (#31985-070, Gibco)에 희석한 뒤 lipofectamine 2000 (#11668-019, invitrogen)을 이용하여 트랜스팩션 시켰다. 24시간 후 배지에 미리 희석한 텔렉타디엄 동나이엔스 추출물 시료를 처리한 다음 배양기에서 다시 24시간 동안 배양하였다. Well 내의 배지를 모두 제거하고, 1X passive lysis buffer (E194A, Promega)를 이용하여 세포를 lysis 시켰다. 10μl의 세포 lysate를 흰색의 96 well plate로 옮긴 후 dual luciferase reporter assay system (E1910, Promega)을 이용하여 luciferase activity를 확인하였고, Renilla luciferase activity로 보정하여, 그 결과를 하기 표 3 및 도 3에 나타내었다.Human colonic cancer cell line HCT 116 (5 × 10 3 cells / mL) was added to each well of a 48-well plate with RPMI 1640 medium (# 31800-022, Gibco) containing 10% CO 2 conditions. After 24 hours, 5 ng of TOPflash (β-catenin / TCF reporter plasmids) (# 21-170, upstate biotechnology) and 5 ng of pRL-SV40 reporter plasmids (E2231, Promega) were diluted in Opti-MEM (# 31985-070, Gibco) Followed by transfection using lipofectamine 2000 (# 11668-019, invitrogen). 24 hours later, the medium was pretreated with telekteridium Dong Naiens extract, and then cultured for 24 hours in an incubator. Cells were lysed using 1X passive lysis buffer (E194A, Promega). 10 μl of the cell lysate was transferred to a white 96-well plate and the luciferase activity was confirmed using a dual luciferase reporter assay system (E1910, Promega). The result was corrected by Renilla luciferase activity and the results are shown in Table 3 and FIG. 3 .
도 3에 나타난 바와 같이, 텔렉타디엄 동나이엔스 추출물을 1, 2.5, 5 μg/ml 첨가하고 사람 대장암 세포주에서 TCF/LEF luciferase 활성도 저해효능 평가한 결과, 통계적으로 유의성을 가지며 (*P<0.05) 농도의존적으로 TCF/LEF 전사저해활성을 나타냈으며 자세하게는 텔렉타디엄 동나이엔스 추출물을 1.0μg/㎖ 첨가시 27.5%, 2.5μg/㎖ 첨가시 37.7%, 5μg/㎖ 첨가시 49.7%, 전사 활성을 저해하였다. 상기 결과로부터 텔렉타디엄 동나이엔스 추출물은 대장암 세포주에서 탁월한 TCF/LEF 전사 저해활성을 가짐을 확인할 수 있다. 이는 본원에 따른 추출물이 Wnt 신호가 과발현 되어 있는 대장암 치료에 유용하게 사용될 수 있음을 나타내는 것이다.As shown in FIG. 3, when telekteridium dongaense extract was added at 1, 2.5, and 5 μg / ml and evaluated for inhibitory activity against TCF / LEF luciferase activity in human colorectal cancer cell lines, it was statistically significant (* P < 0.05, respectively). In detail, the addition of 1.0 ㎍ / ㎖ of telecitabine Dongnaiens extract resulted in 37.7% of the addition of 2.5 ㎍ / ㎖, 49.7% of the addition of 5 ㎍ / ㎖ of TCF / LEF, Inhibiting transcriptional activity. From the above results, it can be confirmed that the telecitabine Dongnaeans extract has excellent TCF / LEF transcription inhibiting activity in colon cancer cell lines. This indicates that the extract according to the present invention can be useful for the treatment of colon cancer in which the Wnt signal is overexpressed.
[표 3][Table 3]
실시예Example 5. 5. 텔렉타디엄Telekta 동나이엔스Dong Naiens 지상부 추출물에 의한 사람 대장암 세포주에서의 β- In the human colon cancer cell line by topical extract, 카테닌Catechin 표적 유전자인 c- The target gene, c- MycMyc , , CyclinCyclin D1 및 D1 and SurvivinSurvivin 유전자 발현의 감소 확인 Confirm reduction of gene expression
c-Myc, Cyclin D1, Survivin 유전자는 β-카테닌의 하위 표적유전자로 알려져 있으며, 세포증식과 연관되어 있다 (Shih YL et al (2007) Inter J Cancer 121:1028-1035; Miller JR et al (1999) Oncogene 18:7860-7872; Staal FJ et al (2000) Hematol J 1:3-6; Logan CY et al (2004) Cell Dev Biol 20:781-810). 상기 실시예에서 얻은 시료의 대장암 세포주에서 β-카테닌 표적 유전자발현에 미치는 영향을 확인하기 위하여 문헌에 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Kang YJ et al (2012) Mol Pharm 82:168-177).C-Myc, Cyclin D1, and Survivin genes are known to be sub-target genes for β-catenin and are associated with cell proliferation (Shih YL et al (2007) Inter J Cancer 121: 1028-1035; Miller JR et al Oncogene 18: 7860-7872; Staal FJ et al (2000) Hematol J 1: 3-6; Logan CY et al (2004) Cell Dev Biol 20: 781-810). In order to confirm the effect of β-catenin on the expression of β-catenin target gene in the colon cancer cell line of the sample obtained in the above example, the following experiment was conducted by applying the method described in the literature (Kang YJ et al. (2012) Mol Pharm 82: 168-177).
HCT 116 (1 X 105 cells/ml)세포를 10% FBS가 포함된 RPMI 배지로 100mm dish 에서 37℃, 5% CO2 조건에서 24시간을 배양 후 배지에 희석된 시료를 넣고 다시 24시간 배양하였다. 부착된 세포를 PBS로 2회 세척한 후 TRI reagent (TRIZol (#15596-026, Invitrogen))를 이용하여 세포를 깨서 모은 후 CHCl3를 첨가하여 RNA를 추출하여 isopropyl alcohol을 이용하여 침전시켰다. RNA 침전물을 70% 에탄올로 세척한 후 공기 중에서 건조시킨 후 nuclease-free water (AM9937, Ambion)를 이용하여 녹였다. 55℃에서 10분간 가열하고, 70℃에서 5분간 가열하여 RNA가 single strand 상태로 존재하도록 하였다. Total RNA를 NanoDrop (ND-1000, Dae Myung Sceince Co., Ltd)을 이용하여 정량하여 1μg/μl으로 희석한 후 avian myeloblastosis virus (AMV) reverse transcriptase (M5108, Promega)과 oligo(dT)15 primer (C110B, Promega)를 이용하여 cDNA를 만들었다. iQ™ SYBR Green Supermix (#170-8880, Bio-Rad), target gene-specific primers [표 4]를 이용하여 target gene을 MiniOpticon™ Real-time PCR Detection system (CFB-3120, Bio-Rad)에서 증폭시켰다. Real-time PCR 조건은 95℃에서 20초간 변성(denaturation)시킨 뒤 95℃에서 20초 (denaturation), 56℃에서 20초 (annealing), 72℃에서 30초 (elongation)의 PCR cycle을 40회 반복하였고 이후 95℃에서 1분간 그리고 55℃에서 1분간 최종 단계를 거쳤다. MJ Opticon Monitor software (Opticon Monitor 3.1.32, Bio-rad)를 이용하여 리박 등 (Livak KJ et al (1996) Method 25:402-408)의 방법에 의하여 Ct 값을 결정하였고, 시료의 β-액틴의 Ct 값으로 보정하여 텔렉타디엄 동나이엔스 추출물에 의해 c-Myc, Cyclin D1 및 Survivin 유전자발현이 감소되는 것을 도 4에 나타냈다.HCT 116 cells (1 × 10 5 cells / ml) were cultured in RPMI medium containing 10% FBS in a 100 mm dish at 37 ° C and 5% CO 2 for 24 hours, then diluted in the medium and incubated for 24 hours Respectively. The cells were washed twice with PBS, and the cells were harvested using TRI reagent (TRIZol (# 15596-026, Invitrogen)), and then CHCl 3 was added to extract the RNA and precipitate with isopropyl alcohol. The RNA precipitate was washed with 70% ethanol, dried in air and dissolved in nuclease-free water (AM9937, Ambion). Heated at 55 占 폚 for 10 minutes, and heated at 70 占 폚 for 5 minutes so that RNA was present in a single stranded state. After the Total RNA quantified using a NanoDrop (ND-1000, Dae Myung Sceince Co., Ltd) diluted to 1μg / μl avian myeloblastosis virus (AMV ) reverse transcriptase (M5108, Promega) and the oligo (dT) 15 primer ( C110B, Promega). Target genes were amplified by MiniOpticon ™ Real-time PCR Detection System (CFB-3120, Bio-Rad) using iQ ™ SYBR Green Supermix (# 170-8880, Bio-Rad) and target gene- specific primers [Table 4] . Real-time PCR conditions were denaturation at 95 ° C for 20 seconds, followed by denaturation at 95 ° C for 20 seconds, annealing at 56 ° C for 20 seconds, and elongation at 72 ° C for 40 cycles Followed by a final step at 95 ° C for 1 min and at 55 ° C for 1 min. The Ct value was determined by the method of Leak et al. (Livak KJ et al (1996) Method 25: 402-408) using MJ Opticon Monitor software (Opticon Monitor 3.1.32, Bio-rad) Ct value of c-Myc, Cyclin D1 and Survivin gene expression was decreased by telecitabine Dong-Naiens extract, as shown in Fig.
[표 4] Real-time PCR primer[Table 4] Real-time PCR primer
도 4에 나타난 바와 같이, 텔렉타디엄 동나이엔스 추출물을 1, 2.5, 5 μg/ml 첨가하고 사람 대장암 세포주에서 β-카테닌 타겟 유전자인 C-Myc, Cyclin D1 및 Survivin 유전자발현을 평가한 결과, 농도의존적으로 발현 저해 활성을 나타냈으며, 자세하게는 c-Myc의 경우 텔렉타디엄 동나이엔스 추출물을 2.5μg/㎖ 첨가시 39.8%, 5μg/㎖ 첨가시 80.2%, 유전자 발현을 저해하였고; Cyclin D1의 경우 텔렉타디엄 동나이엔스 추출물을 1μg/㎖ 첨가시 22.4%, 2.5μg/㎖ 첨가시 40.2%, 5μg/㎖ 첨가시 54.0%, 유전자 발현을 저해하였으며; Survivin의 유전자 발현은 텔렉타디엄 동나이엔스 추출물을 1μg/㎖ 첨가시 26.3%, 2.5μg/㎖ 첨가시 49.7%, 5μg/㎖ 첨가시 88.7%, 저해하는 것으로 나타났다. 특히 c-Myc 및 survivin의 경우 2.5, 5 μg/㎖ 첨가시 모두 99% 신뢰구간에서 통계적으로 유의성을 나타냈다. 따라서 본 발명의 텔렉타디엄 동나이엔스 추출물의 대장암 세포주에 대한 세포독성은 암세포 증식과 관련된 Wnt/β-카테닌 신호전달경로의 하위조절인자인 c-Myc, Cyclin D1 및 Survivin 등과 관련이 있음을 확인할 수 있었다.As shown in Fig. 4, the expression of C-Myc, Cyclin D1 and Survivin genes in β-catenin target genes in human colorectal cancer cell lines was evaluated by adding telekteridium dongaense extract at 1, 2.5 and 5 μg / ml . In detail, in the case of c-Myc, the expression of telecitabine was inhibited by 39.8% when 2.5 μg / ml was added and 80.2% when 5 μg / ml was added. Cyclin D1 inhibited gene expression by 22.4% when 1 μg / ml of telecitabine Dongnaiens extract was added, 40.2% when 2.5 μg / ml was added, and 54.0% when 5 μg / ml was added; The expression of Survivin gene was inhibited by 26.3%, 49.7% and 88.7% when 1 ㎍ / ㎖ of telecitabine Dongnaiens extract was added and 2.5 ㎍ / ㎖ and 5 ㎍ / ㎖ respectively. In the case of c-Myc and survivin, the addition of 2.5 and 5 μg / ml showed statistical significance in the 99% confidence interval. Therefore, the cytotoxicity of telecitabine Dong-Naiens extract of the present invention to colon cancer cell line is related to c-Myc, Cyclin D1 and Survivin, which are subordinate regulators of Wnt / β-catenin signaling pathway related to cancer cell proliferation I could confirm.
실시예Example 6. 6. 텔렉타디엄Telekta 동나이엔스Dong Naiens 지상부 추출물에 의한 사람 대장암 세포주에서의 β- In the human colon cancer cell line by topical extract, 카테닌Catechin 표적 단백질인 c- The target protein c- MycMyc , , CyclinCyclin D1 및 D1 and SurvivinSurvivin 단백질 발현의 농도의존적 억제 확인 Confirmation of concentration-dependent inhibition of protein expression
Wnt/β-카테닌 신호전달경로에서 세포증식과 관련되는 하위조절인자의 단백질인자에 미치는 영향을 검토하기 위하여 기재된 방법을 응용하여 하기와 같이 실험을 수행하였다 (Hong JY et al (2011) J Nat Prod 74:2102-8).In order to investigate the effect of the sub-regulatory factors related to cell proliferation in the Wnt /? -Catenin signaling pathway on the protein factor, the following experiment was conducted by applying the method as described below (Hong JY et al (2011) J Nat Prod 74: 2102-8).
대장암세포주 (HCT116)를 10% FBS가 포함된 DMEM 배지로 100mm 배양접시에 1 ⅹ 105개의 농도로 깔고, 37℃, 5% CO2 조건에서 24시간을 배양한 후 인산 완충 생리식염수(PBS)로 2회 세척하였다. 미리 시료를 농도별로 희석해 둔 10% FBS가 포함된 DMEM 배지를 10ml 첨가한 후 일정 시간 배양하였다. 세포 배지 내에 부착되지 않은 세포와 부착된 세포를 모아 PBS로 2회 세척한 후 끓고 있는 2 ⅹ 시료 loading buffer (250 mM Tris-HCl (pH 6.8), 4% SDS, 10% glycerol, 0.006% bromophenol blue, 2% β-mercaptoethanol, 50 mM sodium fluoride와 5 mM sodium orthovanadate)를 넣어 세포를 파쇄시키고 이를 100℃ 중에 5분간 두었다. 식힌 후-20℃에서 보관하였고 사용 직전에 37℃에서 녹여 단백질 정량 및 전기영동에 이용하였다. 80μg의 단백질을 5 ~ 12% SDS-polyacrylamide gel (#456-1036, Bio-rad, Hercules, CA)을 이용하여 138 V에서 2시간 동안 전기영동 하였다. 분리된 단백질을 PVDF 멤브레인(membrane, ISEQ15150, Millipore, Bedford, MA)으로 100 V에서 1시간 동안 옮긴 후 TBST로 2회 세척하고 blocking buffer(5% Albumin from Bovine Serum in PBS containing 0.1% Tween-20 (TBST))에 넣어 상온에서 1시간 동안 진탕기에서 배양하였다. 그 다음 TBST로 5분간 3회씩 세척한 후 해당 단일항체를 TBST로 3% Albumin from Bovine Serum (BSA (A9647, Sigma))로 희석하여 멤브레인(membrane)과 함께 4℃에서 18시간 반응시켰다. 멤브레인(Membrane, ISEQ 1S150, Millipore, Bedford, MA)을 TBST로 5분간 3회 세척한 후 HRP(horseradish peroxidase)-결합 이차항체를 TBST로 3% BSA로 1:1,000 ~ 1:2,000의 비율로 희석하여 멤브레인(membrane)과 함께 상온에서 3 ~ 4시간 반응시켰다. 이후 TBST로 5분간 3회 세척한 후 웨스턴 블랏팅 기질 (WEST-ZOL PLUS(16021, Intron))을 처리하여 LAS-3000 (Fuji Film Corp., Japan)에서 단백질 발현 정도를 확인하였다.Colon cancer cells (HCT116) were cultured in DMEM medium containing 10% FBS at a concentration of 1 × 10 5 in a 100 mm culture dish, cultured at 37 ° C and 5% CO 2 for 24 hours, and then treated with phosphate buffered saline ) ≪ / RTI > twice. 10 ml of a DMEM medium containing 10% FBS diluted by concentration in advance was added and cultured for a predetermined time. Cells that were not attached to the cell culture medium and attached cells were collected and washed twice with PBS, and then boiled 2 × sample loading buffer (250 mM Tris-HCl (pH 6.8), 4% SDS, 10% glycerol, 0.006% bromophenol blue , 2% β-mercaptoethanol, 50 mM sodium fluoride and 5 mM sodium orthovanadate), and the cells were disrupted at 100 ° C. for 5 minutes. After cooling, the solution was stored at -20 ° C. The solution was dissolved at 37 ° C just before use and used for protein quantification and electrophoresis. 80 μg of the protein was electrophoresed at 138 V for 2 hours using 5-12% SDS-polyacrylamide gel (# 456-1036, Bio-Rad, Hercules, Calif.). The separated proteins were transferred to a PVDF membrane (ISEQ15150, Millipore, Bedford, Mass.) At 100 V for 1 hour, washed twice with TBST and blocked with blocking buffer (5% Albumin from Bovine Serum in PBS containing 0.1% Tween- TBST)) and cultured in a shaker at room temperature for 1 hour. After washing with TBST 3 times for 5 minutes, the monoclonal antibody was diluted with TBST in 3% Albumin from Bovine Serum (BSA (A9647, Sigma)) and reacted with membrane at 4 ° C for 18 hours. After washing the membranes (Membrane, ISEQ 1S150, Millipore, Bedford, MA) three times for 5 minutes with TBST, the HRP (horseradish peroxidase) -binding secondary antibody was diluted with TBST to a ratio of 1: 1,000-1: And reacted with the membrane at room temperature for 3 to 4 hours. After washing with TBST three times for 5 minutes, the western blotting substrate (WEST-ZOL PLUS (16021, Intron)) was treated to confirm protein expression level on LAS-3000 (Fuji Film Corp., Japan).
자세하게는 대장암 세포주 (HCT116)에 텔렉타디엄 동나이엔스 추출물 1, 2.5, 5 μg/ml을 처리하고 24시간 배양 후 단백질 발현 분석을 통해 텔렉타디엄 동나이엔스 추출물의 대장암세포주 (HCT116)에서의 신호전달체계 억제를 확인한 결과, 도 5에 나타난 바와 같이 c-Myc, Cyclin D1 및 Survivin 단백질 발현이 농도의존적으로 억제되었으며 특히 Survivin 유전자의 발현억제가 두드러짐을 확인하였다. 결과를 종합해 보면, 본원에 따른 텔렉타디엄 동나이엔스 추출물은 Wnt/β-카테닌 신호전달체계를 억제함으로써 대장암의 증식을 억제하는 것으로 판단된다.In detail, the cells were treated with telekteridium dongaense
하기에 본 발명의 화합물을 함유하는 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.Hereinafter, formulation examples of the composition containing the compound of the present invention will be described, but the present invention is not intended to be limited thereto but is specifically described.
제제예Formulation example 1. One. 산제의Sanje 제조 Produce
텔렉타디엄 동나이엔스 추출물 200 mgTelekteridium Dong Naiens extract 200 mg
유당 100 mg
탈크 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above components are mixed and filled in airtight bags to prepare powders.
제제예Formulation example 2. 정제의 제조 2. Preparation of tablets
텔렉타디엄 동나이엔스 추출물 200 mgTelekteridium Dong Naiens extract 200 mg
옥수수전분 100 mg
유당 100 mg
스테아린산 마그네슘 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
제제예Formulation example 3. 캅셀제의 제조 3. Preparation of capsules
텔렉타디엄 동나이엔스 추출물 200 mgTelekteridium Dong Naiens extract 200 mg
결정성 셀룰로오스 3 mgCrystalline cellulose 3 mg
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium stearate 0.2 mg
통상의 캅셀제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캅셀제를 제조한다.The above components are mixed in accordance with a conventional method for producing a capsule, and filled in a gelatin capsule to prepare a capsule.
제제예Formulation example 4. 주사제의 제조 4. Preparation of injections
텔렉타디엄 동나이엔스 추출물 200 mgTelekteridium Dong Naiens extract 200 mg
만니톨 180 mg180 mg mannitol
주사용 멸균 증류수 2974 mgSterile sterilized water for injection 2974 mg
Na2HPO4,12H2O 26 mgNa 2 HPO 4 , 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당 (2 ㎖) 상기의 성분 함량으로 제조한다.(2 ml) per ampoule in accordance with the usual injection method.
제제예Formulation example 5. 5. 액제의Liquid 제조 Produce
텔렉타디엄 동나이엔스 추출물 200 mgTelekteridium Dong Naiens extract 200 mg
이성화당 10 g10 g per isomer
만니톨 5 g5 g mannitol
정제수 적량Purified water quantity
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100ml로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.Each component was added to purified water in accordance with the usual liquid preparation method and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed, and then purified water was added thereto. The whole was adjusted to 100 ml by adding purified water, To prepare a liquid agent.
제제예Formulation example 6. 6. 건강 식품의Of health food 제조 Produce
텔렉타디엄 동나이엔스 추출물 1000 mgTelecardidium Dong Naiens extract 1000 mg
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 ㎍70 [mu] g of vitamin A acetate
비타민 E 1.0 ㎎Vitamin E 1.0 mg
비타민 B1 0.13 ㎎0.13 mg vitamin B1
비타민 B2 0.15 ㎎0.15 mg of vitamin B2
비타민 B6 0.5 ㎎0.5 mg vitamin B6
비타민 B12 0.2 ㎍0.2 [mu] g vitamin B12
비타민 C 10 ㎎10 mg vitamin C
비오틴 10 ㎍Biotin 10 μg
니코틴산아미드 1.7 ㎎Nicotinic acid amide 1.7 mg
엽산 50 ㎍50 ㎍ of folic acid
판토텐산 칼슘 0.5 ㎎Calcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75 ㎎1.75 mg of ferrous sulfate
산화아연 0.82 ㎎0.82 mg of zinc oxide
탄산마그네슘 25.3 ㎎Magnesium carbonate 25.3 mg
제1인산칼륨 15 ㎎15 mg of potassium phosphate monobasic
제2인산칼슘 55 ㎎Secondary calcium phosphate 55 mg
구연산칼륨 90 ㎎Potassium citrate 90 mg
탄산칼슘 100 ㎎100 mg of calcium carbonate
염화마그네슘 24.8 ㎎24.8 mg of magnesium chloride
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
제제예Formulation example 7. 건강 음료의 제조 7. Manufacture of health drinks
텔렉타디엄 동나이엔스 추출물 1000 mgTelecardidium Dong Naiens extract 1000 mg
구연산 1000 ㎎Citric acid 1000 mg
올리고당 100 g100 g of oligosaccharide
매실농축액 2 gPlum concentrate 2 g
타우린 1 gTaurine 1 g
정제수를 가하여 전체 900 ㎖Purified water was added to a total of 900 ml
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated for about 1 hour at 85 DEG C with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, ≪ / RTI >
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 수요계층, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is a mixture of the components suitable for the preferred beverage as a preferred embodiment, the blending ratio may be arbitrarily varied according to the regional and national preferences such as the demand level, the demanding country, and the intended use.
이상에서 본원의 예시적인 실시예에 대하여 상세하게 설명하였지만 본원의 권리범위는 이에 한정되는 것은 아니고 다음의 청구범위에서 정의하고 있는 본원의 기본 개념을 이용한 당업자의 여러 변형 및 개량 형태 또한 본원의 권리범위에 속하는 것이다.While the present invention has been described in connection with what is presently considered to be the preferred embodiments, it is to be understood that the invention is not limited to the disclosed embodiments, but, on the contrary, .
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 도입된다. All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. The contents of all publications referred to herein are incorporated herein by reference.
Claims (11)
Telectadium dongnaiense ) as an active ingredient.
The pharmaceutical composition for preventing and treating colon cancer according to claim 1, wherein the extract is an organic solvent extract.
The method according to claim 2, wherein the organic solvent is one or more mixed solvents selected from the group consisting of lower alcohols having 1 to 4 carbon atoms, chloroform, acetone, propylene glycol, ethyl acetate, butylene glycol, ≪ / RTI >
The method according to claim 3, wherein the organic solvent is a mixed solvent in which chloroform, acetone, and a lower alcohol having 1 to 4 carbon atoms are mixed at a ratio of 10: 1 to 10: 1 to 10 (v / v) ≪ / RTI >
The pharmaceutical composition for the prevention and treatment of colorectal cancer according to claim 1, wherein the colorectal cancer is a colon cancer whose Wnt /? -Catenin signaling system is hyperactivated.
A Wnt-targeted anticancer agent that inhibits the Wnt / β-catenin signaling system of cells containing telecitabine Dongnaeans extract as an active ingredient.
7. The Wnt target anticancer agent according to claim 6, wherein said cell is a colon cancer cell.
A Wnt target anticancer adjuvant that inhibits the Wnt / β-catenin signaling system of cells containing an organic solvent extract of Telektaadim Dong Naiens as an active ingredient.
9. The Wnt target anti-cancer adjuvant according to claim 8, wherein said cell is a colon cancer cell.
A health functional food for prevention and improvement of colorectal cancer, including telekteridium Dong Naiens extract.
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| PCT/KR2017/006376 WO2017222252A1 (en) | 2016-06-21 | 2017-06-19 | Pharmaceutical composition for preventing or treating colon cancer, containing extract of telectadium dongnaiense as active ingredient |
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