KR102511221B1 - Pharmaceutical composition for prevention or treatment of cancer comprising Leuconostoc sp. as active ingredient - Google Patents
Pharmaceutical composition for prevention or treatment of cancer comprising Leuconostoc sp. as active ingredient Download PDFInfo
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- KR102511221B1 KR102511221B1 KR1020200063684A KR20200063684A KR102511221B1 KR 102511221 B1 KR102511221 B1 KR 102511221B1 KR 1020200063684 A KR1020200063684 A KR 1020200063684A KR 20200063684 A KR20200063684 A KR 20200063684A KR 102511221 B1 KR102511221 B1 KR 102511221B1
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- South Korea
- Prior art keywords
- cancer
- leuconostoc mesenteroides
- composition
- strain
- preventing
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Abstract
본 발명은 김치로부터 분리된 류코노스톡(Leuconostoc) 속에 속하는 균주 또는 이의 배양물을 유효성분으로 포함하는 암의 예방 또는 치료용 조성물에 관한 것이다.
본 발명에 따른 류코노스톡 균주 또는 이의 배양물은 우수한 항암 활성을 나타내므로, 사람 또는 동물의 암의 치료, 예방 또는 개선 등의 용도를 위한 조성물로서 유용하게 이용될 수 있다.The present invention relates to a composition for preventing or treating cancer comprising a strain belonging to the genus Leuconostoc isolated from kimchi or a culture thereof as an active ingredient.
Since the Leuconostoc strain or culture thereof according to the present invention exhibits excellent anticancer activity, it can be usefully used as a composition for the treatment, prevention, or improvement of human or animal cancer.
Description
본 발명은 김치로부터 분리된 류코노스톡(Leuconostoc) 속 균주, 구체적으로는 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주 또는 이의 배양물을 유효성분으로 포함하는 암의 예방 또는 치료용 조성물에 관한 것이다.The present invention is a strain of the Leuconostoc genus isolated from kimchi, specifically Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain or a culture containing as an active ingredient Prevention or treatment of cancer It relates to therapeutic compositions.
암은 세계적으로 높은 사망률을 보이며, 서구 사회에서는 심혈관 질환 다음으로 가장 일반적인 사망 원인이다. 특히, 식생활이 서구화되어 고지방식의 섭취가 일반화되고, 환경 오염 물질의 급격한 증가, 음주량의 증가 등으로 대장암, 유방암, 전립선암 등이 지속적으로 증가하는 추세에 있으며, 인구의 고령화와 더불어 흡연 인구의 증가 및 대기 오염으로 인해 폐암이 증가하고 있는 실정이다. 이러한 실정에서 암의 조기 예방 및 치료를 가능하게 하여 인간 건강의 증진, 건강한 삶의 질 향상 및 인류 보건 증진에 기여할 수 있는 항암 물질의 창출이 절실히 요구되고 있다.Cancer has a high mortality rate worldwide and is the second most common cause of death in Western societies after cardiovascular disease. In particular, the consumption of high-fat diets has become common due to westernization of dietary life, and colorectal cancer, breast cancer, and prostate cancer are continuously increasing due to a rapid increase in environmental pollutants and an increase in alcohol consumption. Lung cancer is on the rise due to the increase in air pollution. In this situation, there is an urgent need to create an anti-cancer substance that can contribute to the improvement of human health, the improvement of healthy life quality, and the promotion of human health by enabling early prevention and treatment of cancer.
한편, 유산균은 인간과 동물의 구강, 장, 질, 분변, 그리고 김치와 같은 발효식품 등에 널리 분포하면서 사람과 동물의 건강과 밀접한 관련을 맺고 있다. 유산균은 정장작용, 유해균 억제, 면역조절, 혈중 콜레스테롤 저하, 항암 등 다양한 건강증진 효과를 나타내고 있다.On the other hand, lactic acid bacteria are widely distributed in the mouth, intestines, vagina, feces, and fermented foods such as kimchi of humans and animals, and are closely related to human and animal health. Lactic acid bacteria exhibit various health-promoting effects such as intestinal regulation, suppression of harmful bacteria, immune regulation, blood cholesterol lowering, and anti-cancer.
현재, 한국공개특허 제10-2010-0013184호에서는 류코노스톡 메센테로이데스 균주의 항암 활성을 개시하고 있으나, 대장암에 대한 예방 또는 치료 효과에 대해서만 구체적 실시예를 기재하고 있을 뿐, 이 외의 암종에 대해서는 구체적인 실험예나 실시예가 기재된 바 없다.Currently, Korean Patent Publication No. 10-2010-0013184 discloses the anti-cancer activity of the Leuconostoc mesenteroides strain, but only describes specific examples for the preventive or therapeutic effect on colorectal cancer, and other carcinomas No specific experimental examples or examples have been described for this.
본 발명의 목적은 류코노스톡 속 균주를 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물을 제공하기 위한 것이다.An object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising a strain of the genus Leuconostoc as an active ingredient.
또한 본 발명의 다른 목적은 류코노스톡 속 균주를 유효성분으로 포함하는 암의 예방 또는 개선용 식품 조성물 또는 식품 첨가제 조성물을 제공하기 위한 것이다.Another object of the present invention is to provide a food composition or food additive composition for preventing or improving cancer comprising a strain of the genus Leuconostoc as an active ingredient.
또한 본 발명의 또 다른 목적은 류코노스톡 속 균주를 유효성분으로 포함하는 암의 예방 또는 개선용 사료 조성물 또는 사료 첨가제 조성물을 제공하기 위한 것이다.Another object of the present invention is to provide a feed composition or feed additive composition for the prevention or improvement of cancer comprising a strain of the genus Leuconostoc as an active ingredient.
이에, 본 발명자들은 김치로부터 암의 예방 및 치료 효과를 나타내는 유산균 균주를 찾고자 노력한 결과, 여러 암종에 항암 활성을 갖는 신규한 류코노스톡(Leuconostoc) 속 균주를 분리, 동정하여 본 발명을 완성하게 되었다. Accordingly, the present inventors have tried to find lactic acid bacteria strains that exhibit cancer preventive and therapeutic effects from kimchi, and as a result, novel Leuconostoc genus strains having anticancer activity against various cancer types were isolated and identified, and the present invention was completed. .
상기 목적을 달성하기 위하여, 류코노스톡 속 균주 또는 이의 배양물을 유효성분으로 포함하는 암의 예방 또는 치료용 약학 조성물을 제공한다.In order to achieve the above object, it provides a pharmaceutical composition for the prevention or treatment of cancer comprising a Leuconostoc genus strain or a culture thereof as an active ingredient.
또한, 본 발명은 류코노스톡 속 균주 또는 이의 배양물을 유효성분으로 포함하는 암의 예방 또는 개선용 식품 조성물 또는 식품 첨가제 조성물을 제공한다.In addition, the present invention provides a food composition or food additive composition for preventing or improving cancer comprising a Leuconostoc genus strain or a culture thereof as an active ingredient.
또한, 본 발명은 류코노스톡 속 균주 또는 이의 배양물을 유효성분으로 포함하는 가축의 암 예방 또는 개선용 사료 조성물 또는 사료 첨가제 조성물을 제공한다.In addition, the present invention provides a feed composition or feed additive composition for preventing or improving livestock cancer comprising a Leuconostoc genus strain or a culture thereof as an active ingredient.
본 발명에 따른 류코노스톡 속 균주 또는 이의 배양물은 여러 암종에 대해 우수한 항암 활성을 나타내므로, 사람 또는 동물의 암의 치료, 예방 또는 개선 등의 용도를 위한 조성물로서 유용하게 이용될 수 있다.Since the Leuconostoc genus strain or culture thereof according to the present invention exhibits excellent anticancer activity against various cancer types, it can be usefully used as a composition for the treatment, prevention, or improvement of human or animal cancer.
도 1은 본 발명에 따른 조성물을 대장암 CT26 세포 이식 마우스에 1회 정맥 주사한 후 시간 경과에 따라 종양의 크기가 변화하는 것을 관찰한 종양의 사진을 나타낸 도이다.
도 2는 본 발명에 따른 조성물을 대장암 CT26 세포 이식 마우스에 1회 정맥 주사한 후 시간 경과에 따라 종양 성장률을 측정한 그래프를 나타낸 도이다.
도 3은 대장암 CT26, SW620 및 HCT116 세포주에 본 발명에 따른 조성물을 처리하고 세포 성장률(cell viability assay)을 측정한 그래프를 나타낸 도이다.
도 4는 췌장암 AsPC-1 세포주에 본 발명에 따른 조성물을 처리하고 세포 성장률(cell viability assay)을 측정한 그래프를 나타낸 도이다.
도 5는 방광암 T24 세포주에 본 발명에 따른 조성물을 처리하고 세포 성장률(cell viability assay)을 측정한 그래프를 나타낸 도이다.
도 6은 흑색종 B16-F10 세포주에 본 발명에 따른 조성물을 처리하고 세포 성장률(cell viability assay)을 측정한 그래프를 나타낸 도이다.
도 7은 정상 CCD986-sk 세포주에 본 발명에 따른 조성물을 처리하고 세포 성장률(cell viability assay)을 측정한 그래프를 나타낸 도이다.
도 8은 대장암 MC38 세포주에 본 발명에 따른 조성물을 처리하고 세포 전이(migration assay) 후 이미지를 촬영한 사진을 나타낸 도이다.
도 9는 대장암 MC38 세포주에 본 발명에 따른 조성물을 처리하고 세포 전이(migration assay) 억제능을 측정한 그래프를 나타낸 도이다. 1 is a diagram showing photographs of tumors observed to change in size of tumors over time after a single intravenous injection of a composition according to the present invention into a mouse transplanted with colon cancer CT26 cells.
FIG. 2 is a graph showing a tumor growth rate measured over time after intravenous injection of a composition according to the present invention once into a mouse transplanted with colon cancer CT26 cells.
3 is a graph showing colorectal cancer CT26, SW620 and HCT116 cell lines treated with the composition according to the present invention and cell growth rate (cell viability assay) measured.
4 is a graph showing a graph obtained by treating a pancreatic cancer AsPC-1 cell line with the composition according to the present invention and measuring cell viability assay.
5 is a graph showing a graph obtained by treating bladder cancer T24 cell line with the composition according to the present invention and measuring cell viability assay.
6 is a graph showing a graph obtained by treating a melanoma B16-F10 cell line with the composition according to the present invention and measuring cell viability assay.
7 is a diagram showing a graph obtained by treating a composition according to the present invention to a normal CCD986-sk cell line and measuring cell viability assay.
8 is a diagram showing a photograph taken after treatment of the composition according to the present invention to the colorectal cancer MC38 cell line and cell migration (migration assay).
FIG. 9 is a graph showing a cell migration assay inhibition ability after treatment with the composition according to the present invention in a colorectal cancer MC38 cell line.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for explaining the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
본 발명의 류코노스톡(Leuconostoc) 속 균주 또는 이의 배양물을 유효성분으로 포함하는 조성물은 암의 예방 또는 치료 효과를 가지며, 약제학적 조성물로 이용될 수 있다.A composition comprising the strain of the genus Leuconostoc or a culture thereof of the present invention as an active ingredient has an effect of preventing or treating cancer and can be used as a pharmaceutical composition.
본 발명의 류코노스톡(Leuconostoc) 속 균주는 유산균 균주이다. 상기 류코노스톡 속 균주는 프로바이오틱스로서, 유산균의 일반적인 정장 효과 및 면역 증강 효과를 갖는다. 류코노스톡 속의 유산균이 정장 효과 면역 증강 효과를 갖는 것은 잘 알려진 사실이다.Leuconostoc genus strain of the present invention is a lactic acid bacteria strain. The Leuconostoc genus strain is a probiotic, and has a general intestinal effect and immune enhancing effect of lactic acid bacteria. It is a well-known fact that lactic acid bacteria in Leuconostoc have an effect on intestinal regulation and an immune enhancing effect.
상기 류코노스톡 속 균주는 류코노스톡 메센테로이데스(Leuconostoc mesenteroides), 류코노스톡 카노섬(Leuconostoc carnosum), 류코노스톡 시트리움(Leuconostoc citreum), 류코노스톡 홀잡펠리(Leuconostoc holzapfelli) 또는 류코노스톡 락티스(Leuconostoc lactis) 중 하나일 수 있다.The Leuconostoc genus strain is Leuconostoc mesenteroides, Leuconostoc carnosum, Leuconostoc citreum, Leuconostoc holzapfelli or Leuconostoc It may be one of the stock lactis (Leuconostoc lactis).
본 발명의 실시예를 통해 김치로부터 분리된 류코노스톡 메센테로이데스 균주는 미생물의 동정 및 분류를 위한 16S rRNA 염기서열 분석 결과, 서열번호 1(SEQ ID NO: 1)의 핵산서열을 갖는 것으로 나타났다.As a result of 16S rRNA sequencing analysis for the identification and classification of microorganisms, the Leuconostoc mesenteroides strain isolated from kimchi through the examples of the present invention has a nucleic acid sequence of SEQ ID NO: 1 (SEQ ID NO: 1). .
따라서, 서열번호 1(SEQ ID NO: 1)의 16S rRNA 염기서열을 갖는 본 발명의 미생물을 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1)로 명명하였으며, 한국미생물보존센터에 2020년 04월 24일자로 기탁하였다(기탁번호 KCCM12701P).Therefore, the microorganism of the present invention having the 16S rRNA nucleotide sequence of SEQ ID NO: 1 was named Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1), and the Korea Microorganism Conservation Center in 2020 It was deposited on April 24, 2017 (Accession No. KCCM12701P).
상기 류코노스톡 균주는 MRS 액체배지에 0.1 내지 10% 접종하여 25 내지 37℃에서 4시간 내지 48시간 동안 배양하여 이용할 수 있다. The Leuconostok strain may be used by inoculating 0.1 to 10% of MRS liquid medium and incubating at 25 to 37 ° C. for 4 to 48 hours.
상기 배양의 방법은 정치배양 방법이 바람직하나, 이에 한정되지 않는다. The method of culturing is preferably a static culture method, but is not limited thereto.
본 발명에 있어서, '프로바이오틱스(probiotics)'는 사람을 포함한 동물의 위장관 내에서 숙주의 장내 미생물 환경을 개선하여 숙주의 건강에 유익한 영향을 주는 살아있는 미생물'이라는 의미로 이해된다. 프로바이오틱스는 프로바이오틱 활성을 갖는 살아있는 미생물로 단일 또는 복합균주 형태로 사람이나 동물에 건조된 세포 형태나 발효산물 형태로 급여될 경우, 숙주의 장내 균총에 유익한 영향을 미칠 수 있다.In the present invention, 'probiotics' is understood as a living microorganism that has a beneficial effect on the health of the host by improving the microbial environment of the host in the gastrointestinal tract of animals, including humans. Probiotics are live microorganisms with probiotic activity, which can have a beneficial effect on the host's intestinal flora when fed to humans or animals in the form of dried cells or fermentation products in the form of single or multiple strains.
상기 암은 방광암, 유방암, 흑색종양, 갑상선암, 부갑상선암, 인후암, 후두암, 식도암, 췌장암, 위암, 설암, 피부암, 뇌종양, 자궁암, 두담낭암, 구강암, 신장암, 간암, 폐암, 결장암, 직장암 및 대장암으로 이루어지는 군으로부터 선택되는 어느 하나의 암일 수 있으며, 이에 한정되지 않는다.The cancers include bladder cancer, breast cancer, melanoma, thyroid cancer, parathyroid cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, head gallbladder cancer, oral cancer, kidney cancer, liver cancer, lung cancer, colon cancer, rectal cancer, and large intestine. It may be any one cancer selected from the group consisting of cancer, but is not limited thereto.
본 발명에 따른 조성물에 포함되는 류코노스톡 속 균주는 생균체 또는 사균체로서 존재할 수 있으며, 또한 건조 또는 동결건조된 형태로 존재할 수도 있다. 또한, 류코노스톡 속 균주의 배양물이 유효성분일 수 있으며, 상기 배양물에는 생균 배양액 또는 사균 상등액이 포함될 수 있다. 다양한 조성물 내에 포함시키기 적합한 유산균의 형태 및 제제화 방법은 당업자에게 잘 알려져 있다.The strains of the genus Leuconostoc included in the composition according to the present invention may exist as live cells or dead cells, and may also exist in a dried or lyophilized form. In addition, a culture of a strain of the genus Leuconostoc may be an active ingredient, and the culture may include a live cell culture medium or a dead cell supernatant. Types of lactic acid bacteria suitable for inclusion in various compositions and formulation methods are well known to those skilled in the art.
상기 조성물은 경구 또는 비경구로 투여할 수 있다. 비경구 투여인 경우에는 정맥 내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비내 투여, 폐 내 투여 및 직장 내 투여 등으로 투여할 수 있으며, 바람직하게는 정맥 내 주입방법으로 투여할 수 있으나, 이에 한정되지 않는다.The composition may be administered orally or parenterally. In the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, local administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc., preferably intravenous injection. It may be administered, but is not limited thereto.
상기 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여시간, 투여경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다.A suitable dosage of the composition may be prescribed in various ways depending on factors such as formulation method, administration method, patient's age, weight, sex, medical condition, food, administration time, administration route, excretion rate and reaction sensitivity.
본 발명의 조성물이 약제학적 조성물로 활용될 경우, 본 발명의 약제학적 조성물은 상기 유효성분 이외에 약제학적으로 적합하고 생리학적으로 허용되는 보조제를 사용하여 제조될 수 있으며, 상기 보조제로는 부형제, 붕해제, 감미제, 결합제, 피복제, 팽창제, 윤활제, 활택제 또는 향미제 등을 사용할 수 있다.When the composition of the present invention is used as a pharmaceutical composition, the pharmaceutical composition of the present invention may be prepared using pharmaceutically suitable and physiologically acceptable adjuvants in addition to the above active ingredients, and the adjuvants include excipients, boron A releasing agent, a sweetening agent, a binding agent, a coating agent, an expanding agent, a lubricant, a lubricant, or a flavoring agent may be used.
상기 약제학적 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용가능한 담체를 1종 이상 포함하여 약제학적 조성물로 바람직하게 제제화할 수 있다.The pharmaceutical composition may be preferably formulated as a pharmaceutical composition by including one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration.
예를 들어, 정제 또는 캡슐제의 형태로의 제제화를 위해, 유효성분은 에탄올, 글리세롤, 물 등과 같은 경구, 무독성의 약제학적으로 허용가능한 불활성 담체와 결합될 수 있다. 또한, 원하거나 필요한 경우, 적합한 결합제, 윤활제, 붕해제 및 발색제 또한 혼합물로 포함될 수 있다. 적합한 결합제는 이에 제한되는 것은 아니나, 녹말, 젤라틴, 글루코스 또는 베타-락토오스와 같은 천연당, 옥수수감미제, 아카시아, 트래커캔스 또는 소듐올레이트와 같은 천연 및 합성검, 소듐 스테아레이트, 마그네슘 스테아레이트, 소듐 벤조에이트, 소듐아세테이트, 소듐클로라이드 등을 포함한다. 붕해제는 이에 제한되는 것은 아니나, 녹말, 메틸셀룰로스, 아가, 벤토니트, 잔탄검 등을 포함한다. 액상 용액으로 제제화되는 조성물에 있어서 허용가능한 약제학적 담체로는, 멸균 및 생체에 적합한 것으로서, 식염수, 멸균수, 링거액, 완충식염수, 알부민 주사 용액, 덱스트로즈 용액, 말토덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분이상을 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 있다.For example, for formulation in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. In addition, if desired or necessary, suitable binders, lubricants, disintegrants and coloring agents may also be included in the mixture. Suitable binders include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tracacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate. ate, sodium acetate, sodium chloride, and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. For compositions formulated as liquid solutions, acceptable pharmaceutical carriers are sterile and biocompatible, and include saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol and One or more of these components may be mixed and used, and other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added if necessary. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to prepare formulations for injections such as aqueous solutions, suspensions, and emulsions, pills, capsules, granules, or tablets.
나아가 해당 분야의 적절한 방법으로 Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.Furthermore, it can be preferably formulated according to each disease or component using a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA as an appropriate method in the field.
본 발명의 류코노스톡 속(Leuconostoc) 균주 또는 이의 배양물을 유효성분으로 포함하는 조성물은 암의 예방 또는 개선용 식품 조성물 또는 식품 첨가제 조성물로 이용될 수 있다.A composition comprising the Leuconostoc strain or its culture as an active ingredient of the present invention may be used as a food composition or food additive composition for preventing or improving cancer.
상기 식품 조성물은 건강기능식품의 형태일 수 있다.The food composition may be in the form of health functional food.
상기 "건강기능식품"은 건강기능식품에 관한 법률에 따라 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미(제3조 제1호)하며, "기능성"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것(동조 제2호)을 의미한다.The above "functional health food" refers to food manufactured and processed using raw materials or ingredients having functionality useful for the human body in accordance with the Health Functional Food Act (Article 3, Subparagraph 1), and "functional" means It refers to adjusting nutrients for the structure and function of the human body or obtaining useful effects for health purposes such as physiological actions (Article No. 2).
상기 식품 조성물은 식품 첨가물을 추가로 포함할 수 있으며, "식품첨가물"로서의 적합여부는 다른 규정이 없는 한 식품의약품안정청에 승인된 식품첨가물공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The food composition may additionally contain food additives, and the suitability as a "food additive" is determined by the general rules and general test methods of the Food Additive Code approved by the Korea Food and Drug Administration, unless otherwise specified. judged by criteria.
상기 "식품첨가물공전"에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀롤로오스, 구아검 등의 천연첨가물, L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합 제제류 들을 들 수 있다.Examples of items listed in the “Food Additives Codex” include chemical synthetic products such as ketones, glycine, potassium citrate, nicotinic acid, and cinnamic acid, natural additives such as dark pigment, licorice extract, crystalline cellulose, and guar gum, L- and mixed preparations such as sodium glutamate preparations, noodle-added alkali preparations, preservative preparations, and tar color preparations.
본 발명의 유효성분이 포함된 식품으로는 빵, 떡류, 건과류, 캔디류, 초콜릿류, 츄잉껌, 쨈류와 같은 과자류 아이스크림류, 빙과류, 아이스크림 분말류와 같은 아이스크림 제품류 우유류, 저지방 우유류, 유당분해 우유, 가공유류, 산양유, 발효유류, 버터유류, 농축유류, 유크림류, 버터유, 자연치즈, 가공치즈, 분유류, 유청류와 같은 유가공품류 식육가공품, 알가공품, 햄버거와 같은 식육제품류 어묵, 햄, 소세지, 베이컨 등의 어육가공품과 같은 어육제품류 라면류, 건면류, 생면류, 유탕면류, 호화건먼류, 개량숙면류, 냉동면류, 파스타류와 같은 면류 과실음료, 채소류음료, 탄산음료, 두유류, 요구르트 등의 유산균음료, 혼합음료와 같은 음료 간장, 된장, 고추장, 춘장, 청국장, 혼합장, 식초, 소스류, 토마토케첩, 카레, 드레싱과 같은 조미식품 마가린, 쇼트닝 및 피자를 들 수 있으나, 이에 한정되는 것은 아니다.Foods containing the active ingredient of the present invention include bread, rice cakes, dried confections, candies, chocolates, chewing gum, confectionery products such as jams, ice creams, ice creams, ice cream products such as ice cream powders, milks, low-fat milks, lactose-degraded milks, Processed milk, goat milk, fermented milk, buttermilk, concentrated milk, milk cream, buttermilk, natural cheese, processed cheese, powdered milk, dairy products such as whey Processed meat products, processed egg products, meat products such as hamburgers Fish cakes, ham, Fish meat products such as sausages and bacon, etc. Ramen, dried noodles, raw noodles, fried noodles, deluxe dried noodles, improved deep-fried noodles, frozen noodles, pasta, etc. Fruit drinks, vegetable drinks, carbonated drinks, soy milk, Lactobacillus beverages such as yogurt, beverages such as mixed drinks Soy sauce, soybean paste, gochujang, chunjang, chungkukjang, mixed soy sauce, vinegar, sauces, tomato ketchup, curry, seasoning foods such as dressings Margarine, shortening, and pizza, but limited to these it is not going to be
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 포함할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일주스, 과일주스 음료 및 야채 음료의 제조를 위한 과육을 포함할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. In addition to the above, the composition of the present invention contains various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, It may include a carbonation agent used in carbonated beverages and the like. In addition, the composition of the present invention may include fruit flesh for preparing natural fruit juice, fruit juice beverages, and vegetable beverages. These components may be used independently or in combination.
본 발명의 유효성분을 포함한 음료 조성물은 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가성분으로 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, (예를 들어, 포도당, 과당 등); 디사카라이드, (예를 들어 말토스, 슈크로스 등); 및 폴리사카라이드, (예를 들어 덱스트린, 시클로덱스트린 등)과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다.The beverage composition including the active ingredient of the present invention is not particularly limited in other ingredients, and may contain various flavoring agents or natural carbohydrates as additional ingredients like conventional beverages. Examples of the aforementioned natural carbohydrates include monosaccharides, (eg, glucose, fructose, etc.); disaccharides, (eg maltose, sucrose, etc.); and polysaccharides, common sugars such as (eg dextrin, cyclodextrin, etc.), and sugar alcohols such as xylitol, sorbitol, erythritol and the like. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can advantageously be used. .
또한, 본 발명의 류코노스톡 속(Leuconostoc) 균주 또는 이의 배양물을 유효성분으로 포함하는 조성물은 가축의 암 예방 또는 개선용 사료 조성물 또는 사료 첨가제 조성물로 이용될 수 있다.In addition, the composition comprising the Leuconostoc strain or its culture as an active ingredient of the present invention can be used as a feed composition or feed additive composition for preventing or improving livestock cancer.
상기 조성물이 사료 첨가제로서 제조될 경우, 상기 조성물은 20 내지 90% 고농축액이거나 분말 또는 과립 형태로 제조될 수 있다. 상기 사료 첨가제는 구연산, 후말산, 아디픽산, 젖산, 사과산등의 유기산이나 인산 나트륨, 인산 칼륨, 산성 피로인산염, 폴리인산염(중합인산염) 등의 인산염이나, 폴리페놀, 카테킨, 알파-토코페롤, 로즈마리 추출물, 비타민 C, 녹차 추출물, 감초 추출물, 키토산, 탄닌산, 피틴산 등의 천연 항산화제 중 어느 하나 또는 하나 이상을 추가로 포함할 수 있다. 사료로서 제조될 경우, 상기 조성물은 통상의 사료 형태로 제제화될 수 있으며, 통상의 사료 성분을 함께 포함할 수 있다.When the composition is prepared as a feed additive, the composition may be 20 to 90% high concentration or may be prepared in powder or granular form. The feed additives are organic acids such as citric acid, fumaric acid, adipic acid, lactic acid, and malic acid, sodium phosphate, potassium phosphate, acid pyrophosphate, polyphosphate (polyphosphate), polyphenol, catechin, alpha-tocopherol, and rosemary. extract, vitamin C, green tea extract, licorice extract, chitosan, tannic acid, phytic acid, and the like, or any one or more natural antioxidants may be further included. When prepared as a feed, the composition may be formulated in a conventional feed form, and may include common feed ingredients together.
상기 사료 및 사료 첨가제는 곡물, 예를 들면 분쇄 또는 파쇄된 밀, 귀리, 보리, 옥수수 및 쌀; 식물성 단백질 사료, 예를 들면 평지, 콩, 및 해바라기를 주성분으로 하는 사료; 동물성 단백질 사료, 예를 들면 혈분, 육분, 골분 및 생선분; 당분 및 유제품, 예를 들면 각종 분유 및 유장 분말로 이루어지는 건조성분 등을 더 포함할 수 있으며, 이외에도 영양보충제, 소화 및 흡수향상제, 성장촉진제 등을 더 포함할 수 있다.The feed and feed additives include grains such as milled or ground wheat, oats, barley, corn and rice; vegetable protein feeds such as those based on rape, soybean, and sunflower; animal protein feed such as blood meal, meat meal, bone meal and fish meal; It may further include sugar and dairy products, for example, dry ingredients composed of various powdered milk and whey powder, etc., and may further include nutritional supplements, digestion and absorption enhancers, growth promoters, and the like.
상기 사료 첨가제는 동물에게 단독으로 투여하거나 식용 담체 중에서 다른 사료 첨가제와 조합하여 투여할 수도 있다. 또한, 상기 사료 첨가제는 탑드레싱으로서 또는 이들을 동물사료에 직접 혼합하거나 또는 사료와 별도의 경구제형으로 용이하게 동물에게 투여할 수 있다. 상기 사료 첨가제를 동물사료와 별도로 투여할 경우, 당해 기술분야에 잘 알려진 바와 같이 약제학적으로 허용 가능한 식용 담체와 조합하여, 즉시 방출 또는 서방성 제형으로 제조할 수 있다. 이러한 식용 담체는 고체 또는 액체, 예를 들어 옥수수전분, 락토오스, 수크로오스, 콩플레이크, 땅콩유, 올리브유, 참깨유 및 프로필렌글리콜일 수 있다. 고체 담체가 사용될 경우, 사료 첨가제는 정제, 캡슐제, 산제, 트로키제 또는 함당정제 또는 미분산성 형태의 탑 드레싱일 수 있다. 액체 담체가 사용될 경우, 사료 첨가제는 젤라틴 연질 캡슐제, 또는 시럽제나 현탁액, 에멀젼제, 또는 용액제의 제형일 수 있다.The feed additive may be administered to animals alone or in combination with other feed additives in an edible carrier. In addition, the feed additives can be easily administered to animals as a top dressing, directly mixed with animal feed, or in an oral formulation separate from feed. When the feed additive is administered separately from animal feed, it can be prepared as an immediate release or sustained release formulation by combining it with a pharmaceutically acceptable edible carrier, as is well known in the art. Such edible carriers can be solid or liquid, for example corn starch, lactose, sucrose, soybean flakes, peanut oil, olive oil, sesame oil and propylene glycol. When a solid carrier is used, the feed additive may be a tablet, capsule, powder, troche or sugar-containing tablet or top dressing in a microdispersible form. When a liquid carrier is used, the feed additive may be in the form of a gelatin soft capsule, or a syrup, suspension, emulsion, or solution formulation.
또한, 상기 사료 및 사료 첨가제는 보조제, 예를 들어 보존제, 안정화제, 습윤제 또는 유화제, 용액 촉진제 등을 함유할 수 있다. 상기 사료 첨가제는 침주, 분무 또는 혼합하여 동물의 사료에 첨가하여 이용될 수 있다.In addition, the feed and feed additives may contain auxiliary agents, such as preservatives, stabilizers, wetting agents or emulsifying agents, solution accelerators, and the like. The feed additive may be used by adding it to an animal's feed by steeping, spraying or mixing.
본 발명의 사료 또는 사료 첨가제는 포유류, 가금 및 어류를 포함하는 다수의 동물 식이에 적용할 수 있다.The feed or feed additive of the present invention can be applied to a number of animal diets including mammals, poultry and fish.
상기 포유류로서 돼지, 소, 말, 양, 토끼, 염소, 설치동물 및 실험용 설치동물인 쥐, 햄스터, 기니피그 뿐만 아니라, 애완동물(예: 개, 고양이) 등에게 사용할 수 있으며, 상기 가금류로서 닭, 칠면조, 오리, 거위, 꿩, 및 메추라기 등에도 사용할 수 있고, 상기 어류로서 잉어, 붕어 및 송어 등에 이용될 수 있으나, 이에 한정되는 것은 아니다.As the mammal, it can be used for pigs, cows, horses, sheep, rabbits, goats, rats, hamsters, and guinea pigs, which are rodents and laboratory rodents, as well as pets (eg, dogs and cats), and as the poultry, chickens, It can also be used for turkeys, ducks, geese, pheasants, and quails, and can be used for carp, crucian carp, and trout as the fish, but is not limited thereto.
실시예 1. 균주의 분리 및 동정Example 1. Isolation and identification of strains
여러 종류의 김치 시료를 파쇄한 후, 김치액을 PBS(phosphate buffered saline)로 연속희석(serial dilution, 103~108)하여 1차 젖산균 선택 배지인 MRS에 도말한 후 30℃ 또는 37℃에서 각각 24시간 배양한다. 형성된 콜로니를 단일 콜로니로 분리한 뒤, 류코노스톡 선택 배지인 Phenylethyl alcohol sucrose agar 배지에 선상 도말하여 20℃에서 24시간 배양하였다. 배양 후, 형성된 단일 콜로니를 수거하여 MRS 액체배지에 넣고 배양하였다. 24시간 배양한 배양액으로부터 genomic DNA를 추출하였다. 16S rDNA 염기서열을 확인하기 위해, 얻어진 genomic DNA 산물은 마크로젠에 분석 의뢰하였다. 확인한 염기서열을 National Center for Biotechnology information (NCBI, www.ncbi.nlm.nih.gov)의 Basic Local Alignment Search Tool (BLAST)을 이용하여 유사도 분석하였고, 이 결과를 통해 최종적으로 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주로 명명하고, 한국미생물 보존센터에 2020년 4월 24일자로 기탁하였다.After crushing various kinds of kimchi samples, serial dilution (10 3 ~ 10 8 ) of kimchi liquid with PBS (phosphate buffered saline) is applied to the primary lactic acid bacteria selection medium, MRS, and then at 30 ° C or 37 ° C. Incubate for 24 hours each. After separating the formed colonies into single colonies, they were streak-stained on Phenylethyl alcohol sucrose agar medium, which is a Leuconostok selection medium, and incubated at 20 ° C for 24 hours. After culturing, the formed single colonies were collected and cultured in MRS liquid medium. Genomic DNA was extracted from the culture medium cultured for 24 hours. To confirm the 16S rDNA base sequence, the obtained genomic DNA product was requested for analysis by Macrogen. The confirmed nucleotide sequence was analyzed for similarity using the Basic Local Alignment Search Tool (BLAST) of the National Center for Biotechnology information (NCBI, www.ncbi.nlm.nih.gov), and based on this result, Leuconostoc mecenteroides was finally It was named LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain and deposited with the Korea Microorganism Conservation Center on April 24, 2020.
실시예 2. 균주의 배양Example 2. Cultivation of strains
분리한 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 MRS 액체배지 30ml에 1% 접종하여 37℃에서 6시간 동안 정치배양 하였다. 배양 후, 3500 rpm에서 10분 동안 원심분리하여 배양액은 제거하고 균체는 PBS(phosphate buffered saline) 용액으로 3회 세척하여 남아 있는 배지 성분을 제거하였다. The isolated Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain was inoculated with 1% in 30 ml of MRS liquid medium and cultured at 37 ° C. for 6 hours. After culturing, the culture medium was removed by centrifugation at 3500 rpm for 10 minutes, and the cells were washed three times with a PBS (phosphate buffered saline) solution to remove remaining media components.
실시예Example 3. 실험동물(마우스)의 조건 3. Experimental animal (mouse) conditions
실험에 사용된 실험동물은 수컷 5주령의 BALB/c 마우스(오리엔트바이오, 한국)를 공급받았고, 실내 온도 20±2℃ 습도 55±15%가 유지되는 SPF 환경의 동물 사육실에서 1주일의 안정화 기간을 거쳐 실험기간 동안 사육하였다. 사료는 항생제가 첨가되지 않은 일반적인 팰렛 사료를 공급하였고, 물은 수시로 섭취할 수 있게 하였다. 종양 크기 변화의 관찰은 3.14 x (길이 x 높이 x 넓이)/6의 식을 사용하여 종양의 부피(mm3)를 측정하여 진행하였다. Experimental animals used in the experiment were supplied with male 5-week-old BALB/c mice (Orient Bio, Korea), and a stabilization period of 1 week in an animal breeding room in an SPF environment maintained at a room temperature of 20±2°C and a humidity of 55±15%. and reared during the experimental period. Feed was supplied with common pellet feed without antibiotics, and water was allowed to be consumed at any time. Observation of changes in tumor size was performed by measuring the volume (mm 3 ) of the tumor using the formula of 3.14 x (length x height x width)/6.
실시예Example 4. 대장암 CT26 세포 이식 마우스 모델에서의 항종양 효과 분석 4. Analysis of anti-tumor effect in CT26 cell-transplanted mouse model of colorectal cancer
4-1. 세포 배양4-1. cell culture
CT26 대장암 세포는 한국세포주은행에서 구입하였고, DMEM 배지에 10% FBS(fetal bovine serum)와 1% 항생제(penicillin/streptomycin)를 첨가하여 5% CO2, 37℃ 조건에서 배양하였다. CT26 colorectal cancer cells were purchased from Korea Cell Line Bank, and cultured in DMEM medium with 10% fetal bovine serum (FBS) and 1% antibiotics (penicillin/streptomycin) in 5% CO 2 at 37°C.
4-2. CT26 세포 이식 암 동물모델 제작4-2. Production of CT26 cell transplant cancer animal model
CT26 세포 이식 동물모델 제작을 위해서 6주령 BALB/c 마우스(18-21g)를 실험에 이용하였다. 배양한 대장암 세포 CT26은 1x105 cell을 수확(harvest)한 후, 50㎕의 PBS에서 재부유하여 마우스의 오른쪽 대퇴부 피하에 주입하였다. 6-week-old BALB/c mice (18-21 g) were used for the experiment to construct a CT26 cell transplantation animal model. The cultured colon cancer cells CT26 were harvested at 1x10 5 cells, resuspended in 50 μl of PBS, and injected subcutaneously into the right thigh of a mouse.
4-3. 항종양 효과 분석4-3. Antitumor effect analysis
종양이 약 80~100mm3의 부피로 형성된 CT26 세포 이식 마우스의 꼬리에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1)을 정맥 내 주사하였다. PBS에 준비한 류코노스톡 메센테로이데스 LB-LM1 0.1ml(1x109 CFU)을 정맥 주사하였고, 대조군에는 PBS를 투여하였다. 시간 경과에 따라 CT26 세포 이식 마우스의 종양 크기의 변화를 육안으로 확인한 결과를 도 1에 나타내었다. Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) was intravenously injected into the tail of CT26 cell-transplanted mice in which tumors were formed with a volume of about 80 to 100 mm 3 . 0.1ml (1x10 9 CFU) of Leuconostoc Mesenteroides LB-LM1 prepared in PBS was intravenously injected, and PBS was administered to the control group. Figure 1 shows the results of visually confirming the change in tumor size of CT26 cell-transplanted mice over time.
도 1에 나타난 바와 같이, 대조군(PBS)에 비해 류코노스톡 메센테로이데스 LB-LM1을 투여한 그룹이 14일이 지난 후에 종양의 크기가 현저하게 줄어든 것을 관찰하였다. As shown in Figure 1, compared to the control group (PBS), it was observed that the size of the tumor was significantly reduced after 14 days in the group administered with Leuconostoc mecenteroides LB-LM1.
또한, 시간 경과에 따른 CT26 세포 이식 마우스에서 종양의 부피 변화를 측정한 결과를 도 2에 나타내었다. In addition, the results of measuring the change in tumor volume in CT26 cell-transplanted mice over time are shown in FIG. 2 .
도 2에 나타난 바와 같이, CT26세포 이식 마우스의 종양 크기가 대조군과 비교하였을 때 류코노스톡 메센테로이데스 LB-LM1을 투여한 그룹에서 약 80% 정도 감소한 것을 확인하였다. As shown in FIG. 2, it was confirmed that the tumor size of CT26 cell-transplanted mice was reduced by about 80% in the group administered with Leuconostoc mecenteroides LB-LM1 when compared to the control group.
실시예Example 5. In vitro 항암 활성 효능 분석 5. In vitro anticancer activity efficacy analysis
5-1. 세포주의 준비5-1. Preparation of cell lines
분리한 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주의 항암 활성 효과를 관찰하기 위해 Cell counting Kit-8을 이용하여 세포 성장률(cell viability assay)을 측정하였다. 항암 활성 효능실험에 사용된 세포는 대장암 CT26, SW620, HCT116 세포주, 췌장암 AsPC-1 세포주, 방광암 T24 세포주, 흑색종 B16-F10 세포주, 그리고 정상 피부 세포주인 CCD-986sk이다.In order to observe the anticancer activity effect of the isolated Leuconostoc mesenteroides LB-LM1 strain, cell viability assay was measured using Cell counting Kit-8. The cells used in the anticancer activity efficacy test were colorectal cancer CT26, SW620, HCT116 cell lines, pancreatic cancer AsPC-1 cell line, bladder cancer T24 cell line, melanoma B16-F10 cell line, and normal skin cell line CCD-986sk.
SW620, H1650, AsPC-1, T24 세포주는 RPMI 배지에, CT26, HCT116, B16-F10 세포주는 DMEM 배지에, CCD-986sk 세포주는 IMDM 배지에 10% FBS(fetal bovine serum)와 1% 항생제(penicillin/streptomycin)를 첨가하여 5% CO2, 37℃ 조건에서 계대배양하여 성장기의 세포를 사용하여 실험하였다. 배양된 세포는 0.25% trypsin-EDTA를 37℃ 배양기에서 3분간 처리하여 세포를 탈착한 다음 DPBS로 2회 세척하였고, 각 세포가 96-well plate의 한 well당 80% 합류(confluency)가 되도록 준비하였다. SW620, H1650, AsPC-1, T24 cell lines were cultured in RPMI medium, CT26, HCT116, B16-F10 cell lines were in DMEM medium, and CCD-986sk cell line was in IMDM medium with 10% FBS (fetal bovine serum) and 1% antibiotic (penicillin). /streptomycin) was added and subcultured under 5% CO 2 , 37°C conditions, and experiments were performed using cells in the growth phase. The cultured cells were treated with 0.25% trypsin-EDTA for 3 minutes in a 37°C incubator to detach the cells, and then washed twice with DPBS, preparing each cell to reach 80% confluency per well of a 96-well plate. did
5-2. 세포 성장률(cell viability assay) 측정 결과5-2. Cell viability assay measurement results
본 발명은 대장암(3종), 췌장암(1종), 방광암(1종), 흑색종(1종) 세포 및 정상 피부 세포(1종)를 배양한 후 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장(cell viability)을 측정하였다. In the present invention, after culturing colon cancer (type 3), pancreatic cancer (type 1), bladder cancer (type 1), melanoma (type 1) and normal skin cells (type 1), Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain was treated and cell viability was measured.
세포 성장률(cell viability assay)은 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 각 세포에 MOI 1로 처리한 다음 72시간 동안 배양하였고, 배양 후 Cell counting Kit-8 시약을 처리하여 흡광도(OD 450nm)를 측정하였다. 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하지 않은 세포들의 흡광도를 100% 기준으로, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 세포의 성장률을 계산하였으며, 실험 결과를 하기에 기재하였다.For cell viability assay, Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain was treated with
대장암 CT26, SW620 및 HCT116 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장률을 측정한 결과를 도 3에 나타내었다.Colon cancer CT26, SW620, and HCT116 cell lines were treated with Leuconostoc mesenteroides LB-LM1 strain, and cell growth rates were measured. The results are shown in FIG. 3 .
도 3에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 CT26, SW620, HCT116 대장암 세포주의 세포 성장률이 각각 31.2%, 30.9%, 22.7% 감소하는 것을 확인함에 따라 류코노스톡 메센테로이데스 LB-LM1 균주가 대장암에 대해 우수한 항암 활성 효능을 가짐을 확인할 수 있다.As shown in Figure 3, the cell growth rates of CT26, SW620, and HCT116 colorectal cancer cell lines treated with Leuconostoc mesenteroides LB-LM1 strain were reduced by 31.2%, 30.9%, and 22.7%, respectively. As confirmed, it can be confirmed that the Leuconostoc mecenteroides LB-LM1 strain has excellent anticancer activity against colorectal cancer.
또한, 췌장암 AsPC-1 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장률을 측정한 결과를 도 4에 나타내었다.In addition, the pancreatic cancer AsPC-1 cell line was treated with Leuconostoc mesenteroides LB-LM1 strain, and the cell growth rate was measured. The results are shown in FIG. 4 .
도 4에 나타낸 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 AsPC-1 췌장암 세포주의 세포 성장률이 58.1% 감소하는 것을 확인함에 따라 류코노스톡 메센테로이데스 LB-LM1 균주가 췌장암에 대해 우수한 항암 활성 효능을 가짐을 확인할 수 있다.As shown in Figure 4, Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) according to the confirmation that the cell growth rate of AsPC-1 pancreatic cancer cell line treated with the strain was reduced by 58.1%, as shown in Figure 4, Leuconostoc mesenteroides It can be confirmed that the LB-LM1 strain has excellent anticancer activity against pancreatic cancer.
또한, 방광암 T24 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장률을 측정한 결과를 도 5에 나타내었다.In addition, the bladder cancer T24 cell line was treated with Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain and the results of measuring the cell growth rate are shown in FIG. 5 .
도 5에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 T24 방광암 세포주의 세포 성장률이 29.8% 감소하는 것을 확인함에 따라 류코노스톡 메센테로이데스 LB-LM1 균주가 방광암에 대해 우수한 항암 활성 효능을 가짐을 확인할 수 있다.As shown in Figure 5, as confirmed that the cell growth rate of the T24 bladder cancer cell line treated with the Leuconostoc mesenteroides LB-LM1 strain was reduced by 29.8%, Leuconostoc mesenteroides LB-LM1 It can be confirmed that the LM1 strain has excellent anticancer activity against bladder cancer.
또한, 흑색종 B16-F10 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장률을 측정한 결과를 도 6에 나타내었다.In addition, the melanoma B16-F10 cell line was treated with the Leuconostoc mesenteroides LB-LM1 strain and the cell growth rate was measured. The results are shown in FIG. 6 .
도 6에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 B16-F10 흑색종 세포주의 세포 성장률이 23.9% 감소하는 것을 확인함에 따라 류코노스톡 메센테로이데스 LB-LM1 균주가 흑색종에 대해 우수한 항암 활성 효능을 가짐을 확인할 수 있다.As shown in Figure 6, as confirmed that the cell growth rate of the B16-F10 melanoma cell line treated with the Leuconostoc mesenteroides LB-LM1 strain was reduced by 23.9%, Leuconostoc mesenteroides It can be confirmed that the des LB-LM1 strain has excellent anticancer activity against melanoma.
상기 실험과 대비하여 정상 피부 CCD-986sk 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 세포 성장률을 측정한 결과를 도 7에 나타내었다.In contrast to the above experiment, the normal skin CCD-986sk cell line was treated with Leuconostoc mesenteroides LB-LM1 strain and the cell growth rate was measured. The results are shown in FIG. 7 .
도 7에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주는 CCD-986sk 정상 피부 세포주에 대해서는 독성을 보이지 않음을 확인할 수 있다.As shown in FIG. 7, it can be confirmed that the Leuconostoc mesenteroides LB-LM1 strain is not toxic to the CCD-986sk normal skin cell line.
실시예Example 6. In vitro 전이 (migration assay) 억제 능력 확인 6. Confirmation of in vitro metastasis (migration assay) inhibitory ability
6-1. 세포주의 준비6-1. Preparation of cell lines
분리한 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주의 전이 억제 능력을 확인하기 위해 대장암 세포주인 MC38을 이용하였다. 100mm 배양 접시에 MC38 세포가 2x106 cell이 되도록 준비한 후, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 MOI 1로 처리하여, 5% CO2, 37℃ 조건에서 24시간 배양하였다. 배양 후, PBS로 2번 세척하고 0.25% trypsin-EDTA를 처리하여 세포를 탈착하였다. Trans-well chamber membrane 바깥쪽을 10ug/ml fibronectin으로 미리 코팅하고, 탈착한 세포는 챔버(chamber) 안쪽에 넣어서 5% CO2, 37℃ 조건에서 24시간 배양하였다. 배양 후, PBS로 2회 세척하고 Diff Quik 용액으로 염색하였다. 충분히 건조를 한 후에 현미경으로 이미지를 촬영하여 세포수를 측정하여 전이율 결과를 산출하였다.In order to confirm the ability of the isolated Leuconostoc mesenteroides LB-LM1 strain to inhibit metastasis, MC38, a colorectal cancer cell line, was used. After preparing MC38 cells to be 2x10 6 cells in a 100mm culture dish, Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1) strain was treated with
류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 후 대장암 MC38 세포가 전이된 후의 이미지를 촬영한 사진을 도 8에 나타내었다.8 shows a photograph taken after metastasis of colon cancer MC38 cells after treatment with Leuconostoc mesenteroides LB-LM1 strain.
도 8에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB- LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 MC38 대장암 세포주가 대조군에 비해 챔버(chamber)를 통과하여 이동한 세포의 수가 감소되어있는 것을 확인하였다. As shown in FIG. 8, the MC38 colorectal cancer cell line treated with the Leuconostoc mesenteroides LB-LM1 strain has a reduced number of cells that have migrated through the chamber compared to the control group. confirmed that
또한, 대장암 MC38 세포주에 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리하여 계산한 전이율을 도 9에 나타내었다. In addition, the metastasis rate calculated by treating the colon cancer MC38 cell line with the Leuconostoc mesenteroides LB-LM1 strain is shown in FIG. 9 .
도 9에 나타난 바와 같이, 류코노스톡 메센테로이데스 LB-LM1(Leuconostoc mesenteroides LB-LM1) 균주를 처리한 MC38 대장암 세포주의 전이율이 27.5% 감소하는 것을 확인함에 따라 류코노스톡 메센테로이데스 LB-LM1 균주가 대장암의 전이를 억제하는 효능이 우수함을 확인하였다.As shown in FIG. 9, it was confirmed that the metastasis rate of the MC38 colorectal cancer cell line treated with the Leuconostoc mesenteroides LB-LM1 strain was reduced by 27.5%, so that Leuconostoc mesenteroides LB - It was confirmed that the LM1 strain was excellent in inhibiting metastasis of colorectal cancer.
<110> LISCure Biosciences Inc. <120> Pharmaceutical composition for prevention or treatment of cancer comprising Leuconostoc sp. as active ingredient <130> KP20-0013-1 <150> KR 1020200027655 <151> 2020-03-05 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1487 <212> DNA <213> Leuconostoc mesenteroides <400> 1 tctgtcagga tgaacgctgg cggcgtgcct aatacatgca agtcgaacgc acagcgaaag 60 gtgcttgcac ctttcaagtg agtggcgaac gggtgagtaa cacgtggaca acctgcctca 120 aggctgggga taacatttgg aaacagatgc taataccgaa taaaacttag tgtcgcatga 180 cacaaagtta aaaggcgctt cggcgtcacc tagagatgga tccgcggtgc attagttagt 240 tggtggggta aaggcctacc aagacaatga tgcatagccg agttgagaga ctgatcggcc 300 acattgggac tgagacacgg cccaaactcc tacgggaggc tgcagtaggg aatcttccac 360 aatgggcgaa agcctgatgg agcaacgccg cgtgtgtgat gaaggctttc gggtcgtaaa 420 gcactgttgt atgggaagaa cagctagaat aggaaatgat tttagtttga cggtaccata 480 ccagaaaggg acggctaaat acgtgccagc agccgcggta atacgtatgt cccgagcgtt 540 atccggattt attgggcgta aagcgagcgc agacggttta ttaagtctga tgtgaaagcc 600 cggagctcaa ctccggaatg gcattggaaa ctggttaact tgagtgcagt agaggtaagt 660 ggaactccat gtgtagcggt ggaatgcgta gatatatgga agaacaccag tggcgaaggc 720 ggcttactgg actgcaactg acgttgaggc tcgaaagtgt gggtagcaaa caggattaga 780 taccctggta gtccacaccg taaacgatga acactaggtg ttaggaggtt tccgcctctt 840 agtgccgaag ctaacgcatt aagtgttccg cctggggagt acgaccgcaa ggttgaaact 900 caaaggaatt gacggggacc cgcacaagcg gtggagcatg tggtttaatt cgaagcaacg 960 cgaagaacct taccaggtct tgacatcctt tgaagctttt agagatagaa gtgttctctt 1020 cggagacaaa gtgacaggtg gtgcatggtc gtcgtcagct cgtgtcgtga gatgttgggt 1080 taagtcccgc aacgagcgca acccttattg ttagttgcca gcattcagat gggcactcta 1140 gcgagactgc cggtgacaaa ccggaggaag gcggggacga cgtcagatca tcatgcccct 1200 tatgacctgg gctacacacg tgctacaatg gcgtatacaa cgagttgcca gcccgcgagg 1260 gtgagctaat ctcttaaagt acgtctcagt tcggattgta gtctgcaact cgactacatg 1320 aagtcggaat cgctagtaat cgcggatcag cacgccgcgg tgaatacgtt cccgggtctt 1380 gtacacaccg cccgtcacac catgggagtt tgtaatgccc aaagccggtg gcctaacctt 1440 ttaggaagga gccgtctaag gcaggacaga tgactggggt gaagtct 1487 <110> LISCure Biosciences Inc. <120> Pharmaceutical composition for prevention or treatment of cancer comprising Leuconostoc sp. as active ingredient <130> KP20-0013-1 <150> KR 1020200027655 <151> 2020-03-05 <160> 1 <170> KoPatentIn 3.0 <210> 1 <211> 1487 <212> DNA <213> Leuconostoc mesenteroides <400> 1 tctgtcagga tgaacgctgg cggcgtgcct aatacatgca agtcgaacgc acagcgaaag 60 gtgcttgcac ctttcaagtg agtggcgaac gggtgagtaa cacgtggaca acctgcctca 120 aggctgggga taacatttgg aaacagatgc taataccgaa taaaacttag tgtcgcatga 180 cacaaagtta aaaggcgctt cggcgtcacc tagagatgga tccgcggtgc attagttagt 240 tggtggggta aaggcctacc aagacaatga tgcatagccg agttgagaga ctgatcggcc 300 acattgggac tgagacacgg cccaaactcc tacgggaggc tgcagtaggg aatcttccac 360 aatgggcgaa agcctgatgg agcaacgccg cgtgtgtgat gaaggctttc gggtcgtaaa 420 gcactgttgt atgggaagaa cagctagaat aggaaatgat tttagtttga cggtaccata 480 ccagaaaggg acggctaaat acgtgccagc agccgcggta atacgtatgt cccgagcgtt 540 atccggattt attgggcgta aagcgagcgc agacggttta ttaagtctga tgtgaaagcc 600 cggagctcaa ctccggaatg gcattggaaa ctggttaact tgagtgcagt agaggtaagt 660 ggaactccat gtgtagcggt ggaatgcgta gatatatgga agaacaccag tggcgaaggc 720 ggcttactgg actgcaactg acgttgaggc tcgaaagtgt gggtagcaaa caggattaga 780 taccctggta gtccacaccg taaacgatga acactaggtg ttaggaggtt tccgcctctt 840 agtgccgaag ctaacgcatt aagtgttccg cctggggagt acgaccgcaa ggttgaaact 900 caaaggaatt gacggggacc cgcacaagcg gtggagcatg tggtttaatt cgaagcaacg 960 cgaagaacct taccaggtct tgacatcctt tgaagctttt agagatagaa gtgttctctt 1020 cggagacaaa gtgacaggtg gtgcatggtc gtcgtcagct cgtgtcgtga gatgttgggt 1080 taagtcccgc aacgagcgca acccttattg ttagttgcca gcattcagat gggcactcta 1140 gcgagactgc cggtgacaaa ccggaggaag gcggggacga cgtcagatca tcatgcccct 1200 tatgacctgg gctacacacg tgctacaatg gcgtatacaa cgagttgcca gcccgcgagg 1260 gtgagctaat ctcttaaagt acgtctcagt tcggattgta gtctgcaact cgactacatg 1320 aagtcggaat cgctagtaat cgcggatcag cacgccgcgg tgaatacgtt cccgggtctt 1380 gtacacaccg cccgtcacac catgggagtt tgtaatgccc aaagccggtg gcctaacctt 1440 ttaggaagga gccgtctaag gcaggacaga tgactggggt gaagtct 1487
Claims (13)
상기 암은 대장암, 췌장암, 방광암, 피부암 또는 흑색종양의 예방 또는 치료용 약학 조성물.According to claim 1,
The pharmaceutical composition for the prevention or treatment of colorectal cancer, pancreatic cancer, bladder cancer, skin cancer or melanoma.
상기 조성물은 경구 투여 또는 비경구 투여의 방법으로 투여 가능한 것을 특징으로 하는 암의 예방 또는 치료용 약학 조성물.According to claim 1,
The composition is a pharmaceutical composition for preventing or treating cancer, characterized in that it can be administered by oral administration or parenteral administration.
상기 비경구 투여의 방법은 정맥 내 주입, 피하 주입, 근육 주입, 복강 주입, 내피 투여, 국소 투여, 비내 투여, 폐 내 투여 또는 직장 내 투여인 것인, 암의 예방 또는 치료용 약학 조성물.According to claim 5,
The method of parenteral administration is intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, endothelial administration, topical administration, intranasal administration, intrapulmonary administration or intrarectal administration, which is a pharmaceutical composition for preventing or treating cancer.
상기 식품은 건강기능식품인, 암의 예방 또는 개선용 식품 조성물.According to claim 7,
The food is a health functional food, a food composition for preventing or improving cancer.
상기 식품은 빵, 떡, 캔디, 초콜릿, 껌, 아이스크림, 우유, 치즈, 식육가공품, 어육가공품, 김치, 간장, 된장, 고추장, 춘장, 청국장, 식초, 케첩, 카레, 드레싱, 음료 및 발효유로 이루어지는 군으로부터 선택되는 어느 하나의 식품인 것을 특징으로 하는 암의 예방 또는 개선용 식품 조성물.According to claim 7,
The food consists of bread, rice cake, candy, chocolate, gum, ice cream, milk, cheese, processed meat products, processed fish products, kimchi, soy sauce, soybean paste, gochujang, chunjang, cheonggukjang, vinegar, ketchup, curry, dressing, beverages and fermented milk A food composition for the prevention or improvement of cancer, characterized in that any one food selected from the group.
상기 가축은 돼지, 소, 말, 양, 토끼, 염소, 쥐, 햄스터, 기니피그, 개, 고양이, 닭, 칠면조, 오리, 거위, 꿩, 메추라기, 잉어, 붕어 및 송어로 이루어지는 군으로부터 선택되는 어느 하나인 것인, 가축의 암 예방 또는 개선용 사료 조성물.According to claim 11,
The livestock is any one selected from the group consisting of pigs, cows, horses, sheep, rabbits, goats, mice, hamsters, guinea pigs, dogs, cats, chickens, turkeys, ducks, geese, pheasants, quails, carp, carp and trout Which is, a feed composition for preventing or improving livestock cancer.
Leuconostoc mesenteroides LB-LM1 (Leuconostoc mesenteroides LB-LM1, accession number KCCM12701P) or a feed additive composition for preventing or improving livestock cancer comprising a culture thereof as an active ingredient.
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BR112022017706A BR112022017706A2 (en) | 2020-03-05 | 2021-01-27 | PHARMACEUTICAL COMPOSITION FOR PREVENTION OR TREATMENT OF CANCER COMPRISING LEUCONOSTOC SP. AS ACTIVE INGREDIENT |
PCT/KR2021/001060 WO2021177600A1 (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition comprising genus leuconostoc strain as active ingredient for prevention or treatment of cancer |
CA3169371A CA3169371A1 (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition for prevention or treatment of cancer comprising leuconostoc sp. as active ingredient |
AU2021231055A AU2021231055A1 (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition comprising genus leuconostoc strain as active ingredient for prevention or treatment of cancer |
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JP2022552893A JP2023517869A (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition for prevention or treatment of cancer containing Leuconostoc as an active ingredient |
EP21765170.2A EP4134089A1 (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition comprising genus leuconostoc strain as active ingredient for prevention or treatment of cancer |
US17/909,167 US20230120406A1 (en) | 2020-03-05 | 2021-01-27 | Pharmaceutical composition for prevention or treatment of cancer comprising leuconostoc sp. as active ingredient |
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