KR102555685B1 - Composition for preventing or treating gastric cancer containing a mixed strain of probiotics as an active ingredient - Google Patents
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- KR102555685B1 KR102555685B1 KR1020230003509A KR20230003509A KR102555685B1 KR 102555685 B1 KR102555685 B1 KR 102555685B1 KR 1020230003509 A KR1020230003509 A KR 1020230003509A KR 20230003509 A KR20230003509 A KR 20230003509A KR 102555685 B1 KR102555685 B1 KR 102555685B1
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Abstract
Description
본 발명은 프로바이오틱스 혼합균주를 유효성분으로 포함하는 위암의 예방 또는 치료용 조성물에 관한 것으로, 구체적으로는 비피도박테리움 비피덤, 락토바실루스 루테리 및 락토바실루스 람노수스의 혼합 사균체를 포함하는 위암의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing or treating gastric cancer comprising a mixed strain of probiotics as an active ingredient, and specifically, for treating gastric cancer comprising a mixed dead cell of Bifidobacterium bifidum, Lactobacillus reuteri and Lactobacillus rhamnosus. It relates to a composition for prevention, improvement or treatment.
파라바이오틱스(Para-biotics)란 생존 활동을 하지 않는 죽은 상태의 유산균으로 유산균 사균체, 틴달화 유산균, 열처리 유산균 등의 이름으로도 불린다. 체내에서 생존 활동을 하지 않지만 효소, 당단백, 단쇄지방산, DNA 성분 등 건강에 도움을 줄 수 있는 미생물 균체성분을 그대로 담고 있어 이러한 생리활성 화합물을 통해 인간에게 다양한 생리학적 이점을 제공하는 것으로 최근 주목받고 있다. Para-biotics are dead lactic acid bacteria that do not have survival activities, and are also called names such as dead lactic acid bacteria, tindalized lactic acid bacteria, and heat-treated lactic acid bacteria. Although it does not survive in the body, it contains enzymes, glycoproteins, short-chain fatty acids, DNA components, and other microbial cell components that can help health. there is.
우선 유산균 섭취 후 나타날 수 있는 혈중 젖산 농도 상승이나 가스 유발 등의 이상 반응은 생균의 생존 활동에서 기인하는 경우가 대부분이라는 점에서 파라바이오틱스는 죽은 상태의 유산균을 섭취하는 것이기 때문에 이러한 이상 반응으로부터 자유롭다. 따라서, 파라바이오틱스는 생균 제품으로 대표되는 프로바이오틱스와 비교하여 높은 안정성을 가지고 있어 수천억에서 조 단위의 고농도 섭취가 가능하다는 최대의 장점을 지닌다. 또한 내열성이 우수하며, 외부 환경에 대한 안정성이 높아 기존 생균 제품보다 보관이 용이하고 유통기간을 늘일 수 있다는 점 또한 손에 꼽히는 장점이다. First of all, in that most of the abnormal reactions that may occur after ingestion of lactic acid bacteria, such as an increase in the concentration of lactic acid in the blood or induction of gas, are caused by the survival activity of viable bacteria, parabiotics is free from these adverse reactions because it is the intake of dead lactic acid bacteria. it's bad Therefore, parabiotics have a high stability compared to probiotics represented by probiotic products, and thus have the greatest advantage of being able to consume hundreds of billions to trillions of high concentrations. In addition, it has excellent heat resistance and high stability to the external environment, so it is easier to store than existing probiotic products and the shelf life can be extended.
이러한 장점을 바탕으로, 기존의 유산균 생균이 적용되어 온 건강기능식품, 식품첨가제, 의약품 등과 같은 분야에서 빠른 성장세를 보이고 있다. 또한, 의약 분야에서의 항생제 사용에 대한 규제가 강화되고 있기 때문에 대체제로서의 유용성을 갖추고 있고 아직 파라바이오틱스 제품 생산에 본격적으로 뛰어든 업체가 손에 꼽을 정도이기 때문에 시장성과 성장 가능성은 크다고 할 수 있다. Based on these advantages, it is showing rapid growth in fields such as health functional foods, food additives, and pharmaceuticals to which existing lactic acid bacteria have been applied. In addition, since regulations on the use of antibiotics in the pharmaceutical field are being strengthened, they have usefulness as an alternative and there are only a handful of companies that have entered the production of parabiotics products in earnest, so the marketability and growth potential are great.
이러한 유산균의 사균체가 산업적 이용성이 더 유리함에도 불구하고, 이들 생리효능에 대한 세포 및 인체 내에서의 작용기전이나 보다 다양한 생리 기능성에 대한 연구는 현재 우리나라뿐만 아니라 전 세계적으로도 많이 이루어지지 않고 있는 실정이다.Although these dead cells of lactic acid bacteria are more advantageous for industrial use, studies on the mechanism of action in cells and the human body for these physiological effects or more diverse physiological functions are not currently being conducted not only in Korea but also around the world. The situation is.
상기 기술적 배경하에, 본 발명의 목적은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(nosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는, 위암의 예방, 개선 또는 치료용 조성물 및 이의 제조방법을 제공하는 것이다.Under the above technical background, the object of the present invention is to treat Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( nosus MG5200, accession number: KCTC14424BP) to provide a composition for preventing, improving or treating gastric cancer, including a mixed strain or a culture thereof, and a method for preparing the same.
본 발명이 해결하고자 하는 과제는 이상에서 언급한 과제(들)로 제한되지 않으며, 언급되지 않은 또 다른 과제(들)는 이하의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.The problem to be solved by the present invention is not limited to the above-mentioned problem (s), and another problem (s) not mentioned will be clearly understood by those skilled in the art from the following description.
상기 과제를 해결하기 위해 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는, 위암의 예방 또는 치료용 약학 조성물을 제공한다.In order to solve the above problems, the present invention provides Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP) provides a pharmaceutical composition for preventing or treating gastric cancer, including a mixed strain or culture thereof.
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일 수 있다.The strain may be heat-killed parabiotics.
상기 가열 사멸은 70℃ 내지 130℃ 온도에서 10분 내지 60분간 열처리되는 것일 수 있다.The heat killing may be heat treatment at a temperature of 70 ° C to 130 ° C for 10 minutes to 60 minutes.
상기 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200은 1 : 1 내지 2 : 1 내지 2 의 세포수 비로 포함될 수 있다.The Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346, and Lactobacillus rhamnosus MG5200 may be included in a cell count ratio of 1:1 to 2:1 to 2.
또한 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는, 위암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention relates to Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, Accession number: It provides a health functional food composition for preventing or improving gastric cancer, including a mixed strain or a culture thereof including KCTC14424BP).
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일수 있다.The strain may be heat-killed parabiotics.
또한 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는, 위암의 예방 또는 개선용 사료 첨가제 조성물을 제공한다. In addition, the present invention relates to Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, Accession number: It provides a feed additive composition for preventing or improving gastric cancer, including a mixed strain or culture thereof, including KCTC14424BP).
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일 수 있다.The strain may be heat-killed parabiotics.
또한 본 발명은 가열 사멸(Heat-killed)한 균체를 혼합하는 단계; 를 포함하며, 상기 균체는 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)인 것인, 위암의 예방, 개선 또는 치료용 조성물의 제조방법을 제공한다.In addition, the present invention comprises the steps of mixing heat-killed cells; Including, the cell body is Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP), which provides a method for preparing a composition for preventing, improving or treating gastric cancer.
상기 제조방법은 상기 가열 사멸한 균체 혼합물을 동결건조하여 분말화하는 단계; 를 더 포함할 수 있다.The manufacturing method comprises the steps of lyophilizing and powdering the heat-killed cell mixture; may further include.
상기 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200은 1 : 1 내지 2 : 1 내지 2 의 세포수 비로 포함될 수 있다.The Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346, and Lactobacillus rhamnosus MG5200 may be included in a cell count ratio of 1:1 to 2:1 to 2.
본 발명에 따른 조성물은 위암 세포에서 세포자멸 관련 신호분자를 활성화하고, 위암 세포 유래 종양의 성장을 억제하는 효과가 우수한 것으로 확인되어 위암의 예방, 개선 또는 치료용 등의 용도로 의약, 식품 등의 다양한 산업분야에서 유용하게 활용될 수 있다.The composition according to the present invention has been found to be effective in activating apoptosis-related signaling molecules in gastric cancer cells and inhibiting the growth of gastric cancer cell-derived tumors. It can be usefully used in various industrial fields.
본 발명의 효과는 상기한 효과로 한정되는 것은 아니며, 본 발명의 상세한 설명 또는 청구범위에 기재된 발명의 구성으로부터 추론 가능한 모든 효과를 포함하는 것으로 이해되어야 한다.The effects of the present invention are not limited to the above effects, and should be understood to include all effects that can be inferred from the detailed description of the present invention or the configuration of the invention described in the claims.
도 1은 11종의 파라바이오틱스를 각각 처리한 MKN1 세포의 세포 생존율을 나타낸 도이다(평균 ± SD, *: p<0.05).
도 2는 11종의 파라바이오틱스를 각각 처리한 MKN1 세포의 세포자멸사(Apoptosis)를 나타낸 도이다(평균 ± SD, *: p<0.05). a: Annexin V-FITC 및 PI 염색 반응에 의한 백분율 분포, b: 총 세포자멸(Total apoptosis)% 비교.
도 3은 인간 위암 이종이식 동물모델에서 대조군 및 3MIX 파라바이오틱스 실험군의 종양 크기를 비교한 도이다.
도 4는 인간 위암 이종이식 동물모델에서 대조군 및 3MIX 파라바이오틱스 실험군의 종양 억제 효과를 비교한 도이다(평균 ± SD, n=3, *: p<0.05). a: 3주간의 종양 성장 곡선, b: 종양의 무게 비교, c: 3주간의 체중변화.
도 5는 인간 위암 이종이식 동물모델에서 대조군 및 3MIX 파라바이오틱스 실험군의 세포자멸 신호분자 활성 비교를 나타낸 도이다(평균 ± SD, *: p<0.05). a: p-AKT/AKT 발현량, b: p53/GAPDH 발현량, c: Bax/GAPDH 발현량, d: Bak/GAPDH 발현량.
도 6은 인간 위암 이종이식 동물모델에서 대조군 및 3MIX 파라바이오틱스 실험군의 caspase 활성 비교를 나타낸 도이다(평균 ± SD, *: p<0.05). a: 웨스턴 블롯 데이터, b: 절단된 caspse-9/caspase-9 발현 비교, c: 절단된 caspse-3/caspase-3 발현 비교, d: 절단된 PARP/PARP 발현 비교.
도 7은 인간 위암 이종이식 동물모델에서 3MIX 파라바이오틱스 실험군의 세포자멸 신호분자 활성을 면역조직화학(IHC) 염색 이미지로 나타낸 도이다.Figure 1 is a diagram showing the cell viability of MKN1 cells treated with 11 kinds of parabiotics, respectively (mean ± SD, *: p <0.05).
Figure 2 is a diagram showing apoptosis (Apoptosis) of MKN1 cells treated with each of 11 kinds of parabiotics (mean ± SD, *: p <0.05). a: Percentage distribution by Annexin V-FITC and PI staining reactions, b: Total apoptosis % comparison.
Figure 3 is a diagram comparing the tumor size of the control group and the 3MIX parabiotics experimental group in human gastric cancer xenograft animal models.
Figure 4 is a diagram comparing the tumor suppression effect of the control group and the 3MIX parabiotics experimental group in human gastric cancer xenograft animal models (mean ± SD, n = 3, *: p <0.05). a: Tumor growth curve at 3 weeks, b: Comparison of tumor weight, c: Weight change at 3 weeks.
5 is a diagram showing a comparison of apoptosis signaling molecule activity between a control group and a 3MIX parabiotics experimental group in a human gastric cancer xenograft animal model (mean ± SD, *: p<0.05). a: p-AKT/AKT expression level, b: p53/GAPDH expression level, c: Bax/GAPDH expression level, d: Bak/GAPDH expression level.
6 is a diagram showing a comparison of caspase activity between a control group and a 3MIX parabiotics experimental group in a human gastric cancer xenograft animal model (mean ± SD, *: p<0.05). a: Western blot data, b: Comparison of cleaved caspse-9/caspase-9 expression, c: Comparison of cleaved caspse-3/caspase-3 expression, d: Comparison of cleaved PARP/PARP expression.
7 is a diagram showing the apoptosis signal molecule activity of the 3MIX parabiotics experimental group in a human gastric cancer xenograft animal model as an immunohistochemical (IHC) staining image.
달리 정의되지 않는 한, 기술적이거나 과학적인 용어를 포함해서 여기서 사용되는 모든 용어들은 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자에 의해 일반적으로 이해되는 것과 동일한 의미를 갖고 있다. Unless defined otherwise, all terms used herein, including technical or scientific terms, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
일반적으로 사용되는 사전에 정의되어 있는 것과 같은 용어들은 관련 기술의 문맥상 갖는 의미와 일치하는 의미를 갖는 것으로 해석되어야 하며, 본 출원에서 명백하게 정의하지 않는 한, 이상적이거나 과도하게 형식적인 의미로 해석되지 않는다. 또한, 본 발명을 설명함에 있어서 관련된 공지 기술에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우 그 상세한 설명을 생략한다. Terms such as those defined in commonly used dictionaries should be interpreted as having a meaning consistent with the meaning in the context of the related art, and unless explicitly defined in this application, it should not be interpreted in an ideal or excessively formal meaning. don't In addition, in describing the present invention, if it is determined that a detailed description of a related known technology may unnecessarily obscure the subject matter of the present invention, the detailed description will be omitted.
본 발명자들은 가열 사멸된 비피도박테리움 비피덤, 락토바실루스 루테리 및 락토바실루스 람노수스로 구성된 혼합균체의 위암에 대한 항종양 활성의 분자적 기전을 규명하고, 위암의 예방 또는 치료 효능을 나타내는 혼합 파라바이오틱스를 발명하였다.The present inventors identified the molecular mechanism of antitumor activity against gastric cancer of a mixed strain composed of heat-killed Bifidobacterium bifidum, Lactobacillus reuteri and Lactobacillus rhamnosus, and found a mixed parasite showing efficacy in preventing or treating gastric cancer. Invented biotics.
구체적으로, 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는, 위암의 예방 또는 치료용 약학 조성물에 관한 것이다.Specifically, the present invention relates to Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP) relates to a pharmaceutical composition for preventing or treating gastric cancer, including a mixed strain or culture thereof.
본 발명에서 “위암”이란 위에 발생하는 모든 악성종양을 포함하며 구체적으로 위 선암, 림프종, 위 점막하 종양, 평활 근육종 등이 있고, 이 중 위 선암이 98%를 차지하므로 일반적으로 위 선암을 의미할 수 있다.In the present invention, “gastric cancer” includes all malignant tumors occurring in the stomach, specifically gastric adenocarcinoma, lymphoma, gastric submucosal tumor, leiomyoma, etc. can
본 발명에 따른 조성물은 종양의 성장 억제 활성 또는 암세포의 세포자멸(Apoptosis) 유도 활성을 갖는 것으로, 본 발명의 일실시예에 따르면, 위암 세포주 피하 주사를 통해 위암이 발생된 동물 모델에서 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200로 구성된 혼합 파라바이오틱스의 세포자멸(Apoptosis) 유도 활성 및 종양의 성장 억제 활성을 확인하고 상기 혼합 균주를 위암에 대한 예방 또는 치료제로 활용할 수 있음을 제시하였다.The composition according to the present invention has tumor growth inhibitory activity or cancer cell apoptosis inducing activity. Apoptosis-inducing activity and tumor growth inhibitory activity of mixed parabiotics composed of Leeum bifiderm MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 were confirmed, and the mixed strain was utilized as a preventive or therapeutic agent for gastric cancer. It was suggested that it can.
상기 비피도박테리움 비피덤 MG731은 2018년 01월 4일 생물자원센터에 특허기탁하여 수탁번호 KCTC13452BP를 부여받았다.The Bifidobacterium bifidum MG731 was patented at the Center for Biological Resources on January 4, 2018 and received accession number KCTC13452BP.
상기 락토바실루스 루테리 MG5346는 2021년 3월 22일 생물자원센터에 특허기탁하여 수탁번호 KCTC14507BP를 부여받았다.The Lactobacillus reuteri MG5346 was patented at the Center for Biological Resources on March 22, 2021 and was given accession number KCTC14507BP.
상기 락토바실루스 람노수스 MG5200는 2021년 01월 05일 생물자원센터에 특허기탁하여 수탁번호 KCTC14424BP를 부여받았다.The Lactobacillus rhamnosus MG5200 was patented at the Center for Biological Resources on January 05, 2021 and received accession number KCTC14424BP.
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일 수 있다.The strain may be heat-killed parabiotics.
본 발명에서 “파라바이오틱스(Para-biotics)”란 일정한 조건에서 생균 등을 배양 후에 열처리, 화학처리, 방사선처리 등의 방법으로 균의 생장이 일어나지 못하도록 한 형태이며 균의 사체인 동시에 유산균체의 분해물이다. 즉, 사멸된 상태로 대사산물을 비롯한 세포질(Cytoplasm), 세포벽(Cell wall), 박테리오신(Bacteriocin), 다당류 (Polysaccharide), 유기산 등을 포함하는 것을 특징으로 한다. 유산균의 생리활성성분은 대부분 유산균의 세포벽에 집중되어 있고 이러한 세포벽은 유산균이 사멸한 후에 장내 M세포에 의해 흡수되기 때문에 사균체는 생균체에 준하는 역할을 한다는 의미에서 파라바이오틱스(Parabiotics)라 불린다. 본 발명에서 파라바이오틱스는 유산균의 사균체, 사균체 배양물, 사균체 추출물, 사균체 균체성분을 모두 포함하는 의미이다.In the present invention, "Para-biotics" is a form of preventing the growth of bacteria by methods such as heat treatment, chemical treatment, radiation treatment, etc. after culturing viable bacteria under certain conditions. is a decomposition product That is, it is characterized in that it contains metabolites, cytoplasm, cell wall, bacteriocin, polysaccharide, organic acid, etc., in a dead state. Most of the physiologically active components of lactic acid bacteria are concentrated in the cell walls of lactic acid bacteria, and these cell walls are absorbed by intestinal M cells after the lactic acid bacteria die, so dead cells are called parabiotics in the sense that they play a role similar to live cells. . In the present invention, parabiotics is meant to include all of the dead cells of lactic acid bacteria, dead cell cultures, dead cell extracts, and dead cells cell components.
본 발명에서 “혼합 파라바이오틱스”란 파라바이오틱스의 혼합물을 의미하며, 각 유산균을 사균 처리 후 혼합한 혼합물 또는 각 유산균을 혼합 후 사균 처리한 혼합물일 수 있으며 특별히 제한되지는 않는다. In the present invention, "mixed parabiotics" means a mixture of parabiotics, and may be a mixture in which each lactic acid bacteria is killed after treatment or a mixture in which each lactic acid bacteria is killed and treated after mixing, and is not particularly limited.
본 발명에 따른 혼합 파라바이오틱스는 바람직하게는 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200로 구성된 혼합 균주의 파라바이오틱스 또는 비피도박테리움 비피덤 MG731 파라바이오틱스, 락토바실루스 루테리 MG5346 파라바이오틱스 및 락토바실루스 람노수스 MG5200 파라바이오틱스의 혼합물일 수 있다. The mixed parabiotics according to the present invention is preferably a mixed strain of parabiotics consisting of Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 or Bifidobacterium bifidum MG731 parabiotics, It may be a mixture of Lactobacillus reuteri MG5346 parabiotics and Lactobacillus rhamnosus MG5200 parabiotics.
본 발명에 따른 파라바이오틱스는 유산균 균체를 열처리, 방사선처리, 화학약품처리 등의 방법으로 사균 처리한 것일 수 있으며 바람직하게는 열처리 방법으로 사균 처리할 수 있고, 더욱 구체적으로는 70℃ 내지 130℃ 온도에서 10분 내지 60분간 가열 사멸(Heat-killed)한 것일 수 있다.Parabiotics according to the present invention may be obtained by killing lactic acid bacteria cells by heat treatment, radiation treatment, chemical treatment, etc., and preferably by heat treatment. It may be heat-killed for 10 minutes to 60 minutes at a temperature.
본 발명에서 혼합 파라바이오틱스는 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200를 1:1 내지 2:1 내지 2 세포수 비로 포함한 후 사균 처리할 수 있고 또는 사균 처리한 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200를 1:1 내지 2: 1 내지 2 세포수 비로 포함할 수 있다.In the present invention, the mixed parabiotics may include Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346, and Lactobacillus rhamnosus MG5200 at a cell number ratio of 1: 1 to 2: 1 to 2 and then be killed or treated. Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 may be included in a cell count ratio of 1:1 to 2:1 to 2.
본 발명의 일실시예에 따르면, 위암 세포에 대한 세포 독성 및 세포자멸(Apoptosis) 유도 활성이 우수한 파라바이오틱스 3종 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200를 확인하고, 상기 파라바이오틱스를 혼합한 구성으로 위암 발생 동물모델에 1×109 CFU/mouse 또는 3×109 CFU/mouse 농도로 투여한 경우 농도의존적으로 종양 성장 억제 활성 및 세포자멸 유도 활성에 향상된 효과를 나타냄을 확인하였다. 또한 상기 혼합 파라바이오틱스는 세포자멸 관련 신호 경로에 관여하여 동물모델의 종양이 성장 억제가 된 것은 종양의 괴사가 아닌 혼합 파라바이오틱스의 세포자멸 신호 유도에 의한 항종양 활성임을 확인하였다. 따라서 본 발명에 따른 혼합 파라바이오틱스를 포함하는 조성물을 위암의 예방 또는 치료용 약학 조성물로 제공할 수 있다.According to an embodiment of the present invention, three types of parabiotics, Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346, and Lactobacillus rhamnosus MG5200, having excellent cytotoxicity and apoptosis inducing activity against gastric cancer cells, were identified And, when administered at a concentration of 1×10 9 CFU/mouse or 3×10 9 CFU/mouse to gastric cancer-causing animal models with a mixture of the parabiotics, the tumor growth inhibitory activity and apoptosis inducing activity were improved in a concentration-dependent manner. It was confirmed that the effect was shown. In addition, it was confirmed that the mixed parabiotics were involved in an apoptosis-related signal pathway, and thus the inhibition of tumor growth in the animal model was not tumor necrosis, but the antitumor activity by induction of apoptotic signals of the mixed parabiotics. Therefore, the composition containing the mixed parabiotics according to the present invention can be provided as a pharmaceutical composition for preventing or treating gastric cancer.
본 발명의 약학 조성물은 위암으로 진단되거나, 위암 발병 위험이 있는 것으로 확인된 환자에게 투여될 수 있다. 상기 조성물을 사용한 위암의 예방 또는 치료는 암세포의 종양 형성 또는 종양의 성장 지연 및/또는 억제 활성 외에 암세포의 전이를 감소시키는 활성을 추가로 가질 수 있다.The pharmaceutical composition of the present invention may be administered to a patient diagnosed with gastric cancer or confirmed to be at risk of developing gastric cancer. Prevention or treatment of gastric cancer using the composition may further have an activity of reducing metastasis of cancer cells in addition to an activity of delaying and/or suppressing tumor formation or tumor growth of cancer cells.
상기 조성물은 단독으로 또는 다른 요법, 예컨대 수술, 방사선 치료, 유전자 치료, 면역치료 (예, 표적 항체 면역요법, CAR-T 세포 요법), 온콜리틱 바이러스, 골수 이식, 줄기세포 이식, 호르몬 요법, 표적 치료, 냉동요법, 초음파 치료, 광역동 치료, 화학요법 등과 함께 수행될 수 있다. 추가로, 증식성 질환이 발병할 위험이 높은 사람은 질환의 발병을 억제 및/또는 지연하기 위한 치료를 받을 수 있다. 본 발명에 따른 조성물의 항암 활성은 보다 직접적인 항암제와 조합될 때 효과적일 수 있다. 따라서, 특정의 구현예에서, 본 발명은 혼합 사균체 및 항암제를 포함하는 조성물을 제공할 수 있다.The composition may be used alone or in other therapies, such as surgery, radiation therapy, gene therapy, immunotherapy (eg, targeted antibody immunotherapy, CAR-T cell therapy), oncolytic viruses, bone marrow transplantation, stem cell transplantation, hormone therapy, It can be performed in combination with targeted therapy, cryotherapy, ultrasound therapy, photodynamic therapy, chemotherapy, and the like. Additionally, persons at high risk of developing a proliferative disease may receive treatment to inhibit and/or delay the onset of the disease. The anti-cancer activity of the composition according to the present invention may be effective when combined with more direct anti-cancer agents. Thus, in certain embodiments, the present invention may provide a composition comprising dead mixed cells and an anti-cancer agent.
본 발명에 따른 조성물의 유효성분인 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200로 구성된 혼합 균주 또는 혼합 파라바이오틱스는 전체 항암 조성물 중에서 0.00001 중량% 내지 100 중량%, 0.001 중량% 내지 99.9 중량 %, 0.1 중량% 내지 99 중량 %, 더욱 바람직하게는 1 중량% 내지 50 중량%로 포함할 수 있다.Mixed strains or mixed parabiotics composed of Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200, which are active ingredients of the composition according to the present invention, are 0.00001 to 100% by weight, 0.001% by weight, of the total anticancer composition. It may be included in weight % to 99.9 weight %, 0.1 weight % to 99 weight %, and more preferably 1 weight % to 50 weight %.
본 발명에서 약학 조성물은 인간을 포함하는 포유동물에 다양한 경로로 투여될 수 있다. 투여 방식은 통상적으로 사용되는 모든 방식일 수 있으며, 예컨대, 경구, 피부, 정맥, 근육 또는 피하 등의 경로로 투여될 수 있으며, 바람직하게는 경구로 투여될 수 있다.In the present invention, the pharmaceutical composition may be administered to mammals including humans through various routes. The administration method may be any method commonly used, and may be administered by, for example, oral, dermal, intravenous, intramuscular or subcutaneous routes, preferably orally.
상기 조성물은 약학적으로 허용 가능한 부형제 또는 담체를 포함할 수 있다. 치료적 사용을 위한 허용 가능한 담체 또는 희석제는 약학 분야에 잘 알려져 있다. 적합한 담체의 예로는 락토오스, 전분, 글루코오스, 메틸 셀룰로오스, 마그네슘 스테아레이트, 만니톨, 솔비톨 등이 포함된다. 적합한 희석제의 예는 에탄올, 글리세롤 및 물을 포함한다. 약학적 담체, 부형제 또는 희석제의 선택은 의도된 투여 경로 및 표준 약제 실습과 관련하여 선택될 수 있다. 약학적 조성물은 담체, 부형제 또는 희석제로서 또는 이들 외에 임의의 적합한 결합제, 윤활제, 현탁화제, 코팅제, 가용화제를 포함할 수 있다. 상기 담체, 부형제, 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톤, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시 벤조에이트, 프로필히드록시 벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유 등이 있다. The composition may include a pharmaceutically acceptable excipient or carrier. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical arts. Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like. Examples of suitable diluents include ethanol, glycerol and water. The choice of pharmaceutical carrier, excipient or diluent may be selected with reference to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition may include any suitable binder, lubricant, suspending agent, coating agent, solubilizing agent, as or in addition to a carrier, excipient or diluent. The carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitone, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, mineral oil, and the like.
상기 약학적 조성물을 제제화나 제형화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 조성물에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카보네이트(calcium carbonate), 수크로오스, 락토오스, 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다.When formulating or formulating the pharmaceutical composition, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose, lactose, It is prepared by mixing gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.
경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다. 상기 성분들은 유효성분 즉, 혼합 균주, 이의 배양물, 이의 추출물, 이의 균체성분 또는 혼합 파라바이오틱스에 조합하여 추가될 수 있다.Liquid preparations for oral use include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. . Preparations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol,
또한 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. In addition, it may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.
본 발명에 따른 약학 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성별, 병적상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있으며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. 예컨대, 유효성분 함량을 기준으로 1일 투여량이 0.1 내지 10,000 ㎎/kg, 바람직하게는 1 내지 2,000 ㎎/kg일 수 있다. 상기한 투여량은 평균적인 경우를 예시한 것으로서 투여될 최적의 투여량은 당업자에 의해 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 당업계의 전문가에 의해 조절될 수 있다. A suitable dosage of the pharmaceutical composition according to the present invention is variously prescribed by factors such as formulation method, administration method, patient's age, weight, sex, morbid condition, food, administration time, administration route, excretion rate and response sensitivity. It may be administered once or several times a day at regular time intervals according to the judgment of the doctor or pharmacist. For example, the daily dosage may be 0.1 to 10,000 mg/kg, preferably 1 to 2,000 mg/kg, based on the active ingredient content. The above dosage is an example of an average case, and the optimal dosage to be administered can be determined by those skilled in the art, and the type of disease, the severity of the disease, the content of active ingredients and other ingredients contained in the composition, the type of formulation, And it can be adjusted by an expert in the art according to various factors including the patient's age, weight, general health condition, sex and diet, administration time, administration route and secretion rate of the composition, treatment period, and concurrently used drugs.
또한 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는 혼합 균주 또는 이의 배양물을 포함하는 위암의 예방 또는 개선용 건강기능식품 조성물을 제공할 수 있다.In addition, the present invention relates to Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, Accession number: KCTC14424BP) can provide a health functional food composition for preventing or improving gastric cancer comprising a mixed strain or a culture thereof.
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일 수 있다. 따라서 상기 조성물은 바람직하게는 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200로 이루어진 혼합 파라바이오틱스를 포함할 수 있다.The strain may be heat-killed parabiotics. Therefore, the composition may preferably include mixed parabiotics consisting of Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200.
상기 건강기능식품 조성물은 기능성 식품(functional food), 영양보조제(nutritional supplement), 건강기능(성)식품(health functional food) 및 식품 첨가제(food additives) 등의 모든 형태를 포함한다. 상기 유형의 식품 조성물은 당업계에 공지된 통상적인 방법에 따라 다양한 형태로 제조할 수 있다. The health functional food composition includes all forms such as functional food, nutritional supplement, health functional food and food additives. Food compositions of this type can be prepared in various forms according to conventional methods known in the art.
상기 기능성 식품으로는 음료, 과실 및 그의 가공식품, 어류, 육류 및 그 가공식품, 빵류 및 면류, 과즙, 각종 드링크, 쿠키, 엿, 유제품, 식용 식물유지, 마아가린, 식물성 단백질, 레토르트 식품, 냉동식품, 각종 조미료 등의 형태로 제조할 수 있다.The functional foods include beverages, fruits and their processed foods, fish, meat and their processed foods, breads and noodles, fruit juices, various drinks, cookies, taffy, dairy products, edible vegetable oils, margarine, vegetable proteins, retort foods, frozen foods , It can be prepared in the form of various seasonings, etc.
상기 건강기능(성)식품(health functional food)은 특정보건용 식품(food for special health use, FoSHU)과 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 '기능(성)'은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 건강식품(health food)은 일반식품에 비해 적극적인 건강 유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강기능식품, 건강식품, 건강보조식품의 용어는 혼용될 수 있다. The health functional food (health functional food) is the same term as food for special health use (FoSHU), and in addition to supplying nutrients, it is processed to efficiently display bioregulatory functions, and has high medical effects. means food. Here, 'function (sex)' means obtaining useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions. Health food refers to food that has a more active health maintenance or promotion effect than general food, and health supplement food refers to food for the purpose of supplementing health. In some cases, the terms health functional food, health food, and health supplement food may be used interchangeably.
구체적으로, 상기 건강기능(성)식품은 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다. Specifically, the health functional (sex) food is a food manufactured by encapsulation, powdering, suspension, etc., and means that when ingested, it brings a specific effect on health, but unlike general medicines, it is a medicine using food as a raw material. It has the advantage of not having side effects that may occur when taking it for a long time.
본 발명의 식품 조성물의 바람직한 함유량으로는 이에 한정되지 않지만 예를 들어 최종적으로 제조된 식품 중 0.01 내지 80 중량%일 수 있으며, 바람직하게는 최종적으로 제조된 식품 중 0.01 내지 50 중량%일 수 있다.Preferred content of the food composition of the present invention is not limited thereto, but may be, for example, 0.01 to 80% by weight of the finally prepared food, preferably 0.01 to 50% by weight of the finally prepared food.
본 발명의 식품 조성물은 당업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 당업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 상기 식품 조성물은 식품으로 인정되는 제형이면 다양한 형태의 제형으로 제한 없이 제조될 수 있다. 또한, 상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다. 또한, 상기 식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄; 및 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. 또한, 상기 식품 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별하고 적절한 양으로 사용할 수 있다.The food composition of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components commonly added in the art. In addition, the food composition can be prepared without limitation in various types of formulations as long as they are recognized as food. In addition, the food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited, any carrier commonly used in the art may be used. In addition, the food composition may include additional ingredients that are commonly used in food compositions and can improve smell, taste, and vision. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chrome (Cr); and amino acids such as lysine, tryptophan, cysteine, and valine. In addition, the food composition may include preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), bactericides (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butyl hydroxy Loxytoluene (BHT), etc.), coloring agents (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite, etc.), seasonings (MSG sodium glutamate, etc.), sweeteners (dulcin, cyclemate, saccharin) , sodium, etc.), flavoring (vanillin, lactones, etc.), expanding agent (alum, D-potassium hydrogen stannate, etc.), strengthening agent, emulsifier, thickener (thickener), coating agent, gum base agent, foam inhibitor, solvent, improver, etc. food May contain food additives. The additives may be selected according to the type of food and used in an appropriate amount.
또한 본 발명은 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)을 포함하는혼합 균주 또는 이의 배양물을 포함하는 위암의 예방 또는 개선용 사료 첨가제 조성물을 제공할 수 있다.In addition, the present invention relates to Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, Accession number: KCTC14424BP) may provide a feed additive composition for preventing or improving gastric cancer comprising a mixed strain or a culture thereof.
상기 균주는 가열 사멸(Heat-killed)된 파라바이오틱스일 수 있다. 따라서 상기 조성물은 바람직하게는 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200로 이루어진 혼합 파라바이오틱스를 포함할 수 있다.The strain may be heat-killed parabiotics. Therefore, the composition may preferably include mixed parabiotics consisting of Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200.
상기 조성물을 첨가한 사료를 암의 예방을 목적으로 또는 위암으로 진단되거나, 위암 발병 위험이 있는 것으로 확인된 반려동물 또는 가축에게 제공할 수 있다. 상기 조성물의 원료인 혼합 균주 또는 혼합 파라바이오틱스는 종래 공지된 사료 첨가제 또는 사료와 병용하여 사용할 수 있고, 또한 공지된 사료 첨가제 또는 사료에 첨가되는 각종 부형제들도 포함될 수 있다. 상기 조성물에는 동물사료에 통상적으로 사용되는 영양제, 방부제, 보존제, 항생제, 비타민 등의 미량 영양성분 등이 더 포함될 수 있다. 상기 영양제, 방부제, 보존제, 항생제, 미량 영양 성분 등은 해당 기술 분야에서 통상의 지식을 가진 당업자가 통상적으로 사료에 첨가하는 함량으로 임의 선택하여 사용할 수 있다. The feed to which the composition is added may be provided to companion animals or livestock that are diagnosed with gastric cancer or are identified as having a risk of developing gastric cancer for the purpose of preventing cancer. Mixed strains or mixed parabiotics, which are raw materials of the composition, may be used in combination with conventionally known feed additives or feeds, and may also include various excipients added to known feed additives or feeds. The composition may further include trace nutrients such as nutrients, preservatives, preservatives, antibiotics, and vitamins commonly used in animal feed. The nutrients, preservatives, preservatives, antibiotics, trace nutrients, etc. may be arbitrarily selected and used by those skilled in the art in an amount commonly added to feed.
본 발명은 또 다른 양태로, 가열 사멸(Heat-killed)한 균체를 혼합하는 단계; 를 포함하며, 상기 균체는 비피도박테리움 비피덤 MG731(Bi. bifidum MG731, 수탁번호: KCTC13452BP), 락토바실루스 루테리 MG5346(L. reuteri MG5346, 수탁번호: KCTC14507BP) 및 락토바실루스 람노수스 MG5200(L. rhamnosus MG5200, 수탁번호: KCTC14424BP)인 것인, 위암의 예방, 개선 또는 치료용 조성물의 제조방법에 관한 것이다.In another aspect of the present invention, mixing heat-killed cells; Including, the cell body is Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP), it relates to a method for preparing a composition for preventing, improving or treating gastric cancer.
상기 가열 사멸 과정은 유산균 배양물을 바람직하게는 70℃ 내지 130℃ 온도에서 10분 내지 60분간 열처리할 수 있고 더욱 바람직하게는 90℃ 내지 110℃에서 20분 내지 40분간 열처리하는 것일 수 있다.The heat killing process may be a heat treatment of the lactic acid bacteria culture, preferably at a temperature of 70 ° C. to 130 ° C. for 10 minutes to 60 minutes, more preferably at 90 ° C. to 110 ° C. for 20 minutes to 40 minutes.
상기 조성물의 제조방법은 가열 사멸한 균체를 동결건조하여 분말화하는 단계를 더 포함할 수 있다. 상기 사멸한 균체는 동결건조 전에 트레할로즈, 말토덱스트린, 전분 및 탈지분유 등의 동결보호제로 코팅될 수도 있다. The method for preparing the composition may further include lyophilizing the heat-killed cells to powder. The dead cells may be coated with cryoprotectants such as trehalose, maltodextrin, starch and skim milk powder before lyophilization.
상기 분말화한 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200를 1:1 내지 2:1 내지 2 세포수 비로 혼합하거나, 비피도박테리움 비피덤 MG731, 락토바실루스 루테리 MG5346 및 락토바실루스 람노수스 MG5200를 1:1 내지 2:1 내지 2 세포수 비로 혼합 후 가열 사멸한 후 분말화할 수 있다.The powdered Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 were mixed at a cell count ratio of 1:1 to 2:1 to 2, or Bifidobacterium bifidum MG731 and Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 may be mixed at a cell number ratio of 1:1 to 2:1 to 2, killed by heating, and then pulverized.
이하 실시예 또는 실험예를 통하여 본 발명을 더욱 상세하게 설명하기로 한다. 이들 실시예 또는 실험예는 단지 본 발명을 예시하기 위한 것으로 본 발명의 범위가 이들에 의해 제한되는 것으로 해석되지는 않는다.The present invention will be described in more detail through examples or experimental examples below. These examples or experimental examples are only for exemplifying the present invention, and the scope of the present invention is not construed as being limited thereto.
실시예 1: 항종양 효과를 나타내는 파라바이오틱스 선별Example 1: Selection of parabiotics exhibiting antitumor effects
인간 위암 세포 이종이식 동물모델을 통해 가열 사멸된 균주의 항종양 효능을 평가하기 위해 하기 방법으로 실험군을 구성하였다.In order to evaluate the antitumor efficacy of the heat-killed strain through human gastric cancer cell xenograft animal model, an experimental group was formed in the following manner.
파라바이오틱스 준비 Preparing Parabiotics
실험에 사용된 균주는 ㈜메디오젠(제천, 한국)에서 제공받아 사용하였다(표 1). The strains used in the experiment were provided by Mediogen Co., Ltd. (Jecheon, Korea) and used (Table 1).
Fermented food
Fermented food
표 1의 균주를 각각 MRS 배지에 접종하여 37℃에서 18시간 배양 후 원심분리(5,000 × g, 4℃, 5분)하고 균체를 증류수로 3회 세척하였다. 세척한 균체를 멸균 증류수를 첨가하여 부유액을 제조한 후 100℃에서 30분간 열처리를 진행하였다. 그 다음 -80℃에서 급속 동결건조 및 분쇄과정을 거쳐 파라바이오틱스 분말을 수득하고 실험에 사용할 때까지 냉장 보관하였다. Each of the strains in Table 1 was inoculated into MRS medium, incubated at 37 ° C for 18 hours, centrifuged (5,000 × g, 4 ° C, 5 minutes), and the cells were washed three times with distilled water. After adding sterile distilled water to the washed cells to prepare a suspension, heat treatment was performed at 100 ° C. for 30 minutes. Then, parabiotics powder was obtained through rapid lyophilization and grinding at -80 ° C and stored in a refrigerator until use in experiments.
세포배양cell culture
인간 위암 MKN1 세포는 한국 세포주 은행(서울, 한국)에서 구입하였다. MKN1 세포를 1% 페니실린/스트렙토마이신 및 10% 불활성화된 소태아 혈청이 보충된 RPMI 1640(Roswell Park Memorial Institute Medium 1640)에서 배양한 다음 5% CO2, 37℃ 조건에서 인큐베이션하였다.Human gastric cancer MKN1 cells were purchased from the Korean Cell Line Bank (Seoul, Korea). MKN1 cells were cultured in RPMI 1640 (Roswell Park Memorial Institute Medium 1640) supplemented with 1% penicillin/streptomycin and 10% inactivated fetal bovine serum and then incubated at 5% CO 2 , 37°C.
세포독성 분석Cytotoxicity assay
가열 사멸된 균주의 인간 위암 MKN1 세포에 대한 세포독성 효과를 분석하였다.The cytotoxic effect of the heat-killed strain on human gastric cancer MKN1 cells was analyzed.
준비한 11종의 파라바이오틱스를 각 1×109 cells/mL로 MKN1 세포에 24시간 처리하고 MTT 분석을 사용해 세포 생존율을 정량화 그래프를 도 1에 나타냈다. 도 1을 살펴보면, 파라바이오틱스를 처리한 MKN1 세포의 생존이 유의하게 감소했으며, 비피도박테리움 비피덤(B. bifidum) MG731, 락토바실루스 루테리(L. reuteri) MG5346 및 락토바실루스 람노수스(L. rhamnosus) MG5200을 처리한 세포의 경우 각각 25.77%, 57.33% 및 56.84%의 낮은 세포 생존율을 나타내 다른 균주와 비교하여 MKN1 세포에 대한 높은 세포독성 효과를 보였다.MKN1 cells were treated with each of the 11 types of parabiotics prepared at 1×10 9 cells/mL for 24 hours, and cell viability was quantified using an MTT assay. A graph is shown in FIG. 1 . Referring to Figure 1, the survival of MKN1 cells treated with parabiotics was significantly reduced, Bifidobacterium bifidum ( B. bifidum ) MG731, Lactobacillus reuteri ( L. reuteri ) MG5346 and Lactobacillus rhamnosus ( L rhamnosus ) MG5200-treated cells showed low cell viability of 25.77%, 57.33% and 56.84%, respectively, showing high cytotoxic effect on MKN1 cells compared to other strains.
세포자멸사 분석Apoptosis assay
가열 사멸된 균주의 인간 위암 MKN1 세포에 대한 세포자멸사(Apoptosis) 효과를 분석하였다.The apoptosis effect of the heat-killed strain on human gastric cancer MKN1 cells was analyzed.
준비한 11종의 파라바이오틱스를 MKN1 세포에 24시간 1×109 cells/mL로 처리하고 유세포분석법을 이용한 결과를 도 2에 나타냈다. Annexin V-FITC 및 PI 염색 사분면(a)에서 확인되는 초기 세포자멸(%) 및 후기 세포자멸(%) 백분율의 합을 총 세포자멸(%)로 정의하고 정량화하였다(b). 도 2(b)를 살펴보면, 11종의 파라바이오틱스는 대조군(4.6%)보다 유의하게 높은 세포자멸 효과를 보였으며, 그 중 비피도박테리움 비피덤(B. bifidum) MG731, 락토바실루스 루테리(L. reuteri) MG5346, 락토바실루스 람노수스(L. rhamnosus) MG316 및 락토바실루스 람노수스(L. rhamnosus) MG5200이 각각 13.3%, 24.6%, 13.4% 및 11.4%의 높은 세포자멸 유도 효과를 나타냈다.The prepared 11 parabiotics were treated with MKN1 cells at 1×10 9 cells/mL for 24 hours, and the results using flow cytometry are shown in FIG. 2 . The sum of the percentages of early apoptosis (%) and late apoptosis (%) found in the Annexin V-FITC and PI staining quadrants (a) was defined as total apoptosis (%) and quantified (b). Looking at Figure 2 (b), 11 parabiotics showed a significantly higher apoptotic effect than the control group (4.6%), among which Bifidobacterium bifidum ( B. bifidum ) MG731, Lactobacillus reuteri ( L. reuteri ) MG5346, L. rhamnosus MG316 and Lactobacillus rhamnosus MG5200 showed high apoptosis inducing effects of 13.3%, 24.6%, 13.4% and 11.4%, respectively.
in-vivo in-vivo 실험군 구성Composition of experimental group
인간 위암 MKN1 세포에 대한 세포독성 및 세포자멸 유도에 높은 효과를 보인 비피도박테리움 비피덤(B. bifidum) MG731, 락토바실루스 루테리(L. reuteri) MG5346 및 락토바실루스 람노수스(L. rhamnosus) MG5200를 혼합한 3MIX 파라바이오틱스 투여군을 위암 이종이식 동물모델에 대한 실험군으로 구성하였다. Bifidobacterium bifidum ( B. bifidum ) MG731, L. reuteri ( L. reuteri ) MG5346 and L. rhamnosus ( L. rhamnosus ) MG5200 showing high effects on cytotoxicity and apoptosis induction for human gastric cancer MKN1 cells 3MIX parabiotics administration group mixed with was composed of an experimental group for gastric cancer xenograft animal models.
음용수 투여군을 대조군(Control)으로 하고 비피도박테리움 비피덤(B. bifidum) MG731, 락토바실루스 루테리(L. reuteri) MG5346 및 락토바실루스 람노수스(L. rhamnosus) MG5200를 동일한 비율로 혼합하여 1 × 109 CFU/mouse 농도로 투여한 실험군 1(3Mix-1) 및 3 × 109 CFU/mouse 농도로 투여한 실험군 2(3Mix-3)로 구성하여 농도별 투여에 따른 항종양 효과 분석에 이용하였다.The drinking water administration group was used as a control group, and Bifidobacterium bifidum ( B. bifidum ) MG731, Lactobacillus reuteri ( L. reuteri ) MG5346 and Lactobacillus rhamnosus ( L. rhamnosus ) MG5200 were mixed in equal proportions to obtain 1 × It was composed of experimental group 1 (3Mix-1) administered at a concentration of 10 9 CFU/mouse and experimental group 2 (3Mix-3) administered at a concentration of 3 × 10 9 CFU/mouse, and was used to analyze the antitumor effect according to administration by concentration. .
실시예 2: 3MIX 파라바이오틱스의 항위암 효능Example 2: Anti-gastric cancer efficacy of 3MIX parabiotics
2-1. 3MIX 파라바이오틱스의 항종양 효능2-1. Anti-tumor efficacy of 3MIX parabiotics
동물 실험은 덕성여자대학교 동물관리 및 이용위원회(허가번호:2021-011-015)의 승인을 받고 진행하였다. Animal experiments were conducted with the approval of the Animal Care and Use Committee of Duksung Women's University (permit number: 2021-011-015).
BALB/c 랫드(5주령 암컷)는 라온바이오(서울, 한국)에서 구입하였다. 랫드를 병원균이 없는 통제된 환경(45 ± 5% 습도 및 23-27°C, 12시간 낮/12시간 야간 주기)에서 표준 실험실 사료와 물의 임의로 제공하며 실험 전 일주일 동안 적응시켰다. 인간 위암 MKN1 세포(5 × 106 cells/mouse)를 랫드 오른쪽 뒷다리 옆의 등으로 피하 주사한 다음 하기 표 2의 3개 그룹에 무작위로 할당하였다.BALB/c rats (5-week-old females) were purchased from Raon Bio (Seoul, Korea). Rats were acclimatized for one week prior to the experiment in a controlled, pathogen-free environment (45 ± 5% humidity and 23-27 °C, 12-h day/12-h night cycle) with standard laboratory chow and water ad libitum. Human gastric cancer MKN1 cells (5 × 10 6 cells/mouse) were subcutaneously injected into the back of the right hind leg of rats, and then randomly assigned to the three groups shown in Table 2 below.
(1:1:1 혼합, 총 1 × 109 CFU/mouse)MG731 + MG5346 + MG5200
(1:1:1 mix, total 1 × 10 9 CFU/mouse)
(1:1:1 혼합, 총 3 × 109 CFU/mouse)MG731 + MG5346 + MG5200
(1:1:1 mix, total 3 × 10 9 CFU/mouse)
3주간 대조군에게는 음용수 0.1 mL를 매일 경구투여 하였으며, 실험군 1 및 실험군 2는 음용수에 용해된 3Mix-1 및 3Mix-3을 각각 매일 경구투여 하였다.For 3 weeks, 0.1 mL of drinking water was orally administered to the control group daily, and 3Mix-1 and 3Mix-3 dissolved in drinking water were orally administered to
표준 캘리퍼스를 사용하여 이틀 간격으로 종양을 확인하고 측정하였다. 종양 부피는 [종양 길이(mm) × 종양 너비(mm)2]/2로 계산하였다. 종양 부피가 2000 mm3에 도달하였을 때, 랫드를 안락사시키고 종양을 수확하였다.Tumors were identified and measured every two days using standard calipers. Tumor volume was calculated as [tumor length (mm) x tumor width (mm)2]/2. When the tumor volume reached 2000 mm 3 , the rats were euthanized and the tumors harvested.
수확한 종양의 외형을 촬영해 비교한 도 3을 살펴보면 대조군 대비 3MIX 파라바이오틱스를 투여받은 실험군에서 종양의 크기의 현저히 감소되어 있음을 육안으로 확인할 수 있다.Looking at Figure 3, which compares the appearance of the harvested tumor by photographing it, it can be seen with the naked eye that the size of the tumor is significantly reduced in the experimental group receiving 3MIX parabiotics compared to the control group.
구체적인 비교를 위해 랫드 3개 그룹에서 수집한 종양의 부피 및 무게를 측정하여 도 4에 나타냈다. 도 4a에서 보는 바와 같이, 종양의 부피가 급격히 증가한 대조군과 비교하여 3MIX 파라바이오틱스를 투여한 실험군은 종양의 성장을 유의하게 억제하는 효과를 보였다.For specific comparison, the volume and weight of tumors collected from three groups of rats were measured and shown in FIG. 4 . As shown in Figure 4a, compared to the control group in which the volume of the tumor increased rapidly, the experimental group administered with 3MIX parabiotics showed an effect of significantly inhibiting tumor growth.
구체적으로 살펴보면, 음용수만 투여받은 대조군은 투여 5일차부터 종양의 성장이 급격히 증가하여 투여 19일 차에 종양의 부피가 318 ± 17.14 mm3을 기록한 반면, 3MIX 파라바이오틱스를 투여받은 실헌군 1 및 실험군 2는 투여 19일 차에 종양의 부피가 각각 177 ± 27.09mm3 및 122 ± 30.00mm3으로 종양의 부피가 대조군 대비 각각 45% 및 62%로 나타나 종양의 성장이 탁월하게 억제되었음을 확인하였다. 특히, 실험군 2는 투여 초기부터 종양의 성장이 유의하게 억제되었으며 3Mix-3을 5회 경구 투여했을 때부터 대조군 대비 종양의 성장이 27% 이상 감소된 것을 확인하였다.Specifically, in the control group, which received only drinking water, tumor growth increased rapidly from the 5th day of administration, and the tumor volume recorded 318 ± 17.14 mm 3 on the 19th day of administration, whereas in the 3MIX parabiotics-administered
종양 조직의 무게를 측정하여 나타낸 도 4b를 살펴보면 대조군의 종양 무게는 78.12 ±13.31 mg으로 기록괸 반면, 실험군 1은 44.22 ± 10.08 mg, 실험군 2는 36.32 ± 6.18 mg으로 나타나 실험군 2의 경우 대조군 대비 종양의 무게가 절반에 미치지 않았다. Looking at FIG. 4B, which shows the weight of tumor tissue measured, the tumor weight of the control group was recorded as 78.12 ± 13.31 mg, whereas the
한편, 3MIX 파라바이오틱스의 경구 투여가 랫드의 체중 변화에 영향을 미치는지 확인하기 위해 실험 기간 동안 2일 간격으로 체중을 측정한 결과를 도 4c에 나타냈다. 이를 살펴보면 경구 투여가 끝난 19일차까지 대조군 및 실험군 간의 체중 변화는 유의적인 차이를 나타내지 않는 것을 확인하였다.On the other hand, in order to confirm whether oral administration of 3MIX parabiotics affects the weight change of rats, the results of measuring the body weight every 2 days during the experimental period are shown in FIG. 4c. Looking at this, it was confirmed that the weight change between the control group and the experimental group did not show a significant difference until the 19th day after oral administration was completed.
2-2. 3MIX 파라바이오틱스의 세포자멸 신호 단백질 발현 분석2-2. Analysis of apoptosis signal protein expression of 3MIX parabiotics
3MIX 파라바이오틱스가 인간 위암 MKN1 세포를 이종이식한 동물모델에서 세포자멸 표적 단백질의 발현에 미치는 영향을 웨스턴 블롯 분석을 통해 확인하였다.The effect of 3MIX parabiotics on the expression of apoptosis target proteins in an animal model in which human gastric cancer MKN1 cells were xenotransplanted was confirmed through Western blot analysis.
AKT-p53 신호 전달 기작은 암세포의 증식 조절과 세포자멸에 관여하며, 암세포의 세포자멸을 촉진시키는 Bax 및 Bak과 같은 다운스트림 전사인자들을 활성화시키는 역할을 한다.The AKT-p53 signaling mechanism is involved in cancer cell proliferation regulation and apoptosis, and plays a role in activating downstream transcription factors such as Bax and Bak that promote cancer cell apoptosis.
도 5를 살펴보면 p-AKT/AKT 발현량(도 5a)은 대조군(Control)에 비해 실험군 1(3Mix-1) 및 실험군 2(3Mix-3) 모두 감소 효과를 나타냈다. p53/GAPDH 발현량(도 5b)은 대조군에 비하여 실험군 1(3Mix-1) 및 실험군 2(3Mix-3)에서 각각 1.70 및 2.48배로 증가하였으며, Bax/GAPDH 발현량(도 5c)은 대조군에 비해 실험군 1(3Mix-1) 및 실험군 2(3Mix-3)에서 각각 1.53 및 2.14배로 유의적으로 증가하였다. 또한 Bak/GAPDH 발현량(도 5d)은 대조군에 비해 실험군 1(3Mix-1) 및 실험군 2(3Mix-3)에서 각각 1.17 및 2.49배 증가하여 3MIX 파라바이오틱스의 투여에 의해 암세포의 세포자멸이 촉진된 것을 확인하였다.Referring to FIG. 5, the p-AKT/AKT expression level (FIG. 5a) showed a decreasing effect in both experimental group 1 (3Mix-1) and experimental group 2 (3Mix-3) compared to the control group. The p53/GAPDH expression level (Fig. 5b) increased 1.70 and 2.48 times in Experimental Group 1 (3Mix-1) and Experimental Group 2 (3Mix-3), respectively, compared to the control group, and the Bax/GAPDH expression level (Fig. 5c) was higher than that of the control group. It increased significantly by 1.53 and 2.14 times in Experimental Group 1 (3Mix-1) and Experimental Group 2 (3Mix-3), respectively. In addition, the amount of Bak/GAPDH expression (Fig. 5d) increased by 1.17 and 2.49 times in Experimental Group 1 (3Mix-1) and Experimental Group 2 (3Mix-3), respectively, compared to the control group. confirmed to be stimulated.
Caspase(Cysteine aspartic acid proteases)는 세포자멸을 조절하는 주요한 조절인자로서 세포내에서 불활성 형태이지만 분절되며 활성화되고 PARP 및 DNA 단편화 인자 등의 단백질을 분해하여 세포자멸을 유도한다.Caspase (Cysteine aspartic acid proteases), as a major regulator of apoptosis, is an inactive form in cells, but is cleaved and activated, and induces apoptosis by degrading proteins such as PARP and DNA fragmentation factors.
내인성 세포자멸 기전에 관여하는 활성화된 caspase 발현량을 확인하여 도 6a에 나타내고 이를 정량화하여 b~d에 나타냈다.The amount of activated caspase expression involved in the endogenous apoptosis mechanism was confirmed and shown in FIG. 6a and quantified and shown in b to d.
도 6b의 cleaved caspase-9/caspase-9 발현량은 대조군에 비하여 실험군 1(3Mix-1) 및 실험군 2(3Mix-3)에서 각각 1.70 및 2.09배 증가하였고, 도 6c의 caspase-3의 활성화 수준도 대조군에 비해 실험군 1 및 실험군 2 모두 1.5배 이상 증가하였다. 또한 도 6d의 Cleaved PARP/PARP의 발현량은 대조군에 비해 실험군 1(3Mix-1) 및 실험군 2(3Mix-3)에서 각각 1.73 및 1.78배 증가하여, 3MIX 파라바이오틱스 투여에 의한 세포자멸 촉진 기능이 현저히 증가하여 암세포의 세포자멸을 유도해 항종양 효과를 나타내었음을 확인하였다.The expression level of cleaved caspase-9/caspase-9 in FIG. 6b increased by 1.70 and 2.09 times in experimental group 1 (3Mix-1) and experimental group 2 (3Mix-3), respectively, compared to the control group, and the activation level of caspase-3 in FIG. 6c Compared to the control group, both
2-3. 종양 조직의 면역조직화학 검사2-3. Immunohistochemical examination of tumor tissue
인간 위암 MKN1 세포를 이종이식한 동물모델에서 회수된 종양조직에서 3MIX 파라바이오틱스가 세포자멸에 관여하는 특정 항원에 대한 발현을 확인하기 위해 면역조직화학적 분석(IHC)을 시행하여 도 7에 그 결과를 나타냈다.Immunohistochemical analysis (IHC) was performed to confirm the expression of specific antigens involved in apoptosis by 3MIX parabiotics in tumor tissue recovered from an animal model in which human gastric cancer MKN1 cells were xenotransplanted, and the results are shown in FIG. showed
도 7에서 보는 바와 같이 p-AKT 발현량이 대조군에 비해 3MIX 파라바이오틱스를 경구투여한 실험군1 및 실험군 2에서 모두 감소한 것을 확인할 수 있다. P53, Bax, cleaved caspase-9, cleaved caspase-3 및 cleaved PARP 발현량은 대조군에 비해 실험군1 및 실험군 2에서 모두 증가하였으며 특히 실험군 2(3Mix-3)에서 대량 분포하고 있다.As shown in FIG. 7, it can be seen that the expression level of p-AKT was decreased in both
상기 웨스턴 블롯 및 IHC의 결과를 통해 3Mix 파라바이오틱스가 암세포 사멸을 유도하여 항종양 효과를 나타낼 수 있는 것으로 확인하였다.Through the results of the Western blot and IHC, it was confirmed that 3Mix parabiotics can exhibit antitumor effects by inducing cancer cell death.
Claims (11)
Heat-killed Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), heat-killed Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and heat-killed Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP) comprising a mixed strain or a culture thereof, a pharmaceutical composition for preventing or treating gastric cancer.
The pharmaceutical composition for preventing or treating gastric cancer according to claim 1, wherein the heat killing is performed at a temperature of 70°C to 130°C for 10 minutes to 60 minutes.
The method of claim 1, wherein the Bifidobacterium bifidum MG731, Lactobacillus reuteri MG5346 and Lactobacillus rhamnosus MG5200 are included in a cell number ratio of 1: 1 to 2: 1 to 2, for preventing or treating gastric cancer. pharmaceutical composition.
Heat-killed Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), heat-killed Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and heat-killed Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP) containing a mixed strain or a culture thereof, a health functional food composition for preventing or improving gastric cancer.
Heat-killed Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), heat-killed Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and heat-killed Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP) comprising a mixed strain or a culture thereof, preventing or improving a feed additive composition for gastric cancer.
Mixing heat-killed cells; Including, the cell body is Bifidobacterium bifidum MG731 ( Bi. bifidum MG731, accession number: KCTC13452BP), Lactobacillus reuteri MG5346 ( L. reuteri MG5346, accession number: KCTC14507BP) and Lactobacillus rhamnosus MG5200 ( L. rhamnosus MG5200, accession number: KCTC14424BP), a method for producing a composition for preventing, improving or treating gastric cancer.
상기 가열 사멸한 균체 혼합물을 동결건조하여 분말화하는 단계; 를 더 포함하는, 위암의 예방, 개선 또는 치료용 조성물의 제조방법.
According to claim 9,
Freeze-drying the heat-killed cell mixture to powder; Further comprising a method for producing a composition for preventing, improving or treating gastric cancer.
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KR102040117B1 (en) * | 2018-05-11 | 2019-11-05 | 주식회사 지놈앤컴퍼니 | Bifidobacterium bifidum MG731 and composition for preventing or treating cancers comprising the same |
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KR102040117B1 (en) * | 2018-05-11 | 2019-11-05 | 주식회사 지놈앤컴퍼니 | Bifidobacterium bifidum MG731 and composition for preventing or treating cancers comprising the same |
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Microorganisms, 10, 533, pp.1-11, 2022-02-28 * |
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