KR102261589B1 - Composition for improving anticancer efficacy of sorafenib containing polygonum cuspidatum extract as an active ingredient and extracting method thereof - Google Patents
Composition for improving anticancer efficacy of sorafenib containing polygonum cuspidatum extract as an active ingredient and extracting method thereof Download PDFInfo
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- KR102261589B1 KR102261589B1 KR1020190133074A KR20190133074A KR102261589B1 KR 102261589 B1 KR102261589 B1 KR 102261589B1 KR 1020190133074 A KR1020190133074 A KR 1020190133074A KR 20190133074 A KR20190133074 A KR 20190133074A KR 102261589 B1 KR102261589 B1 KR 102261589B1
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- sorafenib
- extract
- culture
- saccharomyces
- lactobacillus
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Abstract
본 발명은 호장근 추출물을 포함하는 소라페니브 (sorafenib)의 암치료 효과 증강용 조성물에 관한 것으로, 소라페니브와 병용 투여하는 경우, 호장근 추출물과 소라페니브를 각각 단독 투여한 경우에 비하여 암세포 성장 저해 효과가 현저히 우수하고, 또한 소라페니브의 사용량을 기존의 적정 처리 농도보다 저농도로 줄일 수 있어 항암제 내성에 따른 문제점을 극복할 수 있다.The present invention relates to a composition for enhancing the cancer treatment effect of sorafenib, comprising an extract of sorafenib, and when administered in combination with sorafenib, cancer cells compared to when the extract of sorafenib and sorafenib were administered alone. The growth inhibitory effect is remarkably excellent, and the amount of sorafenib used can be reduced to a lower concentration than the conventional appropriate treatment concentration, thereby overcoming the problems caused by anticancer drug resistance.
Description
본 발명은 호장근 (polygonum cuspidatum) 추출물을 포함하는 소라페니브 (sorafenib)의 암 치료 효과 증강용 조성물에 관한 것으로, 보다 구체적으로는 호장근 추출물을 유효성분으로 포함하는 소라페니브의 간암 치료 효과 증강용 조성물 또는 소라페니브와 함께 병용 투여할 수 있는 새로운 항암 보조제에 관한 것이다.The present invention relates to a composition for enhancing the cancer treatment effect of sorafenib, including a polygonum cuspidatum extract, and more specifically, the liver cancer treatment effect of sorafenib containing the sorafenib extract as an active ingredient. It relates to a novel anticancer adjuvant that can be administered in combination with a composition for enhancement or sorafenib.
현재 암치료율을 높이기 위해 환자의 특성에 따라 여러 약물을 혼합하여 사용하는 개인 맞춤형 병용 요법이 여러 국가에서 연구되고 있으며, 한국에서도 서울 아산병원에서 급성 백혈병 치료에 기존의 항암제와 글리벡을 병용 투여하여 완치율을 높이고 있음을 보고하였다.In order to increase the cancer treatment rate, a personalized combination therapy using a combination of several drugs according to the characteristics of the patient is being studied in several countries. In Korea, the cure rate is achieved by administering the existing anticancer drug and Gleevec in combination for the treatment of acute leukemia at Asan Hospital in Seoul. reported to be increasing.
제2세대 표적 항암제는 기존의 1세대 화학 항암제의 부작용을 극복하고자 개발된 암 특이적 유전자 돌연변이를 표적화하고 제어하는 특수한 항암제이다. 제2세대 표적항암제인 소라페니브 [Sorafenib, 넥사바(Nexavar)®]는, 약 50% 이상의 간암, 신장암, 갑상선암 환자에게서 공통적으로 활성화되는 세포성장 신호체계 Ras-Raf-Mek-Erk 및 신생혈관작용을 제어함으로써 암세포의 성장을 억제하는 사멸기전을 가지고 있다. 간암 치료에서 소라페니브는 인체의 정상 세포 및 조직에 독성이 없이 암세포만을 선택적으로 제어할 수 있으나, 의료비가 매우 높다는 단점이 있다. 소라페니브의 경우, 간암 환자의 평균 생존율을 약 3개월 연장시킨다고 알려져 있으나, 종양 성장을 촉진하는 유전자 및 세포 신호전달 체계의 재활성으로 인해, 장기 투여시 소라페니브의 치료효과 제한성과 소라페니브 내성이 나타난다고 보고되었다.Second-generation targeted anticancer drugs are special anticancer drugs that target and control cancer-specific gene mutations developed to overcome the side effects of existing first-generation chemical anticancer drugs. The second-generation targeted anticancer drug, Sorafenib [Sorafenib, Nexavar ® ], is a cell growth signaling system that is commonly activated in more than 50% of liver, kidney, and thyroid cancer patients, including Ras-Raf-Mek-Erk and neovascularization. It has an apoptosis mechanism that inhibits the growth of cancer cells by controlling the action. In the treatment of liver cancer, sorafenib can selectively control cancer cells without toxicity to normal cells and tissues of the human body, but has a disadvantage in that the medical cost is very high. In the case of sorafenib, it is known that it prolongs the average survival rate of liver cancer patients by about 3 months. However, due to the reactivity of genes and cell signaling systems that promote tumor growth, the therapeutic effect of sorafenib is limited and sorafenib is limited in long-term administration. B resistance has been reported.
최근에는 소라페니브 (Sorafenib) 저항성 극복을 통한 치료효과 개선을 위해 기존의 1세대 항암제와 2세대 표적항암제를 이용한 결합 치료기술이 개발되고 있다. 현재 대부분의 기술이 임상시험 중에 있으나, 세포독성을 유발하는 항암제의 과다사용으로 부작용이 심하다고 알려지고 있다. 따라서, 소라페니브 치료효과 개선을 위한 결합 치료기술은 부작용을 최소화할 수 있는 소재로의 변화가 필요한 시점이라 할 수 있다. 따라서, 표적항암제의 사용을 줄이면서 효과를 증대시키고 항암제 저항성을 극복할 수 있는 연구가 천연물에서 유래한 추출물 또는 정제 분리된 물질을 중심으로 이루어지고 있다.Recently, in order to improve the therapeutic effect by overcoming Sorafenib resistance, a combined treatment technology using the existing first-generation anticancer agent and the second-generation targeted anticancer agent is being developed. Currently, most of the technologies are in clinical trials, but it is known that the side effects are severe due to the excessive use of anticancer drugs that cause cytotoxicity. Therefore, the combination therapy technology for improving the therapeutic effect of sorafenib can be said to be the time when it is necessary to change to a material that can minimize side effects. Therefore, research capable of increasing the effect while reducing the use of the target anticancer agent and overcoming the anticancer drug resistance is focused on extracts or purified and separated substances derived from natural products.
한편, 호장근 (Polygonum cuspidatum)은 동아시아권에 널리 분포하는 천연식물로 전통 중국 약초에 사용된다. 호장근은 페놀성분이 풍부하며 무월경, 관절통, 황달, 농양, 화상 및 타박상 치료에 효과가 있음이 보고되어 있으며 (Lin et al., 2012), 호장근의 주요 활성 성분은 에피카테킨 (epicatechin) 및 레스베라트롤 (resveratrol) 등을 함유하고 있다고 보고되어 있다.On the other hand, Polygonum cuspidatum is a natural plant widely distributed in East Asia and is used in traditional Chinese herbal medicine. It has been reported to be effective in the treatment of amenorrhea, arthralgia, jaundice, abscesses, burns and bruises (Lin et al., 2012), and its main active ingredients are epicatechin and resveratrol. (resveratrol) has been reported to contain.
현재까지 호장근에 의한 2세대 표적항암제의 간암세포 성장억제 강화 및 치료보조제로서의 가능성에 대한 연구는 보고된 바 없다. 이에 본 발명자들은 호장근 추출물이 소라페니브의 항암효과를 증가시킬 수 있는지 간암세포 및 간암세포 (SK-HEP-1, HepG2, PLC/PRF5)를 주입한 동물모델을 이용해 조사한 결과 호장근 추출물은 소라페니브의 항암효과를 유효한 수준으로 증가시키는 것을 확인하였으며, 특히, 간암세포 (SK-HEP-1)를 주입한 동물모델에서 생물전환 호장근 추출물과 소라페니브를 병행 투여한 결과 간암조직의 성장이 약 75%까지 억제됨을 확인하고, 또한 저농도의 소라페니브의 항암효과를 크게 증가시킬 수 있음을 확인하여 본 발명을 완성하였다.To date, there have been no reports of studies on the potential of second-generation targeted anticancer drugs to enhance the growth inhibition of hepatocarcinoma cells and as a therapeutic adjuvant. Accordingly, the present inventors investigated whether the rhizome extract can increase the anticancer effect of sorafenib using an animal model injected with liver cancer cells and liver cancer cells (SK-HEP-1, HepG2, PLC/PRF5). It was confirmed that the anticancer effect of sorafenib was increased to an effective level, and in particular, in an animal model injected with liver cancer cells (SK-HEP-1), as a result of concurrent administration of bioconverted hojang root extract and sorafenib, The present invention was completed by confirming that growth was inhibited by about 75%, and also by confirming that the anticancer effect of sorafenib at a low concentration could be greatly increased.
본 발명은 상기와 같은 문제를 해결하기 위해, 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물을 제공하는 것을 목적으로 한다.In order to solve the above problems, the present invention provides a composition for enhancing the therapeutic effect of cancer, comprising an extract of polygonum cuspidatum as an active ingredient, and administering it in combination with sorafenib. The purpose.
또한 본 발명은 상기와 같은 문제를 해결하기 위해, 호장근 추출물을 유효성분으로 포함하고, 소라페니브의 암 세포 성장 억제 효과를 증진시키는 것을 특징으로 하는, 항암 보조제를 제공하는 것을 목적으로 한다.In addition, in order to solve the above problems, an object of the present invention is to provide an anti-cancer adjuvant, which comprises a rhizome extract as an active ingredient, and enhances the cancer cell growth inhibitory effect of sorafenib.
상기한 과제를 해결하기 위하여, 본 발명은 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물을 제공한다.In order to solve the above problems, the present invention provides a composition for enhancing the therapeutic effect of cancer comprising an extract of polygonum cuspidatum as an active ingredient, and characterized in that it is administered in combination with sorafenib.
또한, 본 발명은 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 개선 효과 증강용 건강기능성식품 조성물을 제공한다.In addition, the present invention provides a functional health food composition for enhancing cancer improvement effect, comprising an extract of polygonum cuspidatum as an active ingredient, and characterized in that it is administered in combination with sorafenib.
또한, 본 발명은 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)의 암 세포 성장 억제 효과를 증진시키는 것을 특징으로 하는, 항암 보조제를 제공한다.In addition, the present invention provides an anticancer adjuvant, comprising an extract of polygonum cuspidatum as an active ingredient, and enhancing the cancer cell growth inhibitory effect of sorafenib.
마지막으로, (1) 해조류 추출물을 사카로마이세스를 접종하여 1차 배양 후, 락토바실러스, 스트렙토코커스, 바실러스 및 로도슈도모나스로 구성된 군에서 선택된 하나 이상의 균주를 접종하고 2차 배양하여 배양물을 얻는 단계; (2) 상기 (1)의 배양물에 올리브 잎 추출물 및 현미배아분말을 첨가한 후, 사카로마이세스, 락토바실러스, 스트렙토코커스, 바실러스 및 로도슈도모나스로 구성된 군에서 선택된 하나 이상의 균주를 접종하고 배양하여 배양물을 얻는 단계; 및 (3) 호장근 추출물에 상기 (1) 또는 (2)의 배양물을 접종하고 배양하는 단계를 포함하는, 호장근 추출물을 유효성분으로 포함하고, 소라페니브와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물의 제조방법을 제공한다.Finally, (1) after the primary culture by inoculating the seaweed extract with Saccharomyces, one or more strains selected from the group consisting of Lactobacillus, Streptococcus, Bacillus and Rhodopseudomonas are inoculated and secondary culture to obtain a culture step; (2) After adding olive leaf extract and brown rice germ powder to the culture of (1) above, Saccharomyces, Lactobacillus, Streptococcus, Bacillus and one or more strains selected from the group consisting of Rhodopseudomonas are inoculated and cultured to obtain a culture; And (3) comprising the step of inoculating and culturing the culture of (1) or (2) in the rhododendron extract as an active ingredient, characterized in that it is administered in combination with sorafenib, Provided is a method for preparing a composition for enhancing the therapeutic effect of cancer.
본 발명은 호장근 추출물을 유효성분으로 포함하는 소라페니브의 암 치료 효과 증강용 조성물에 관한 것으로, 상기 호장근 추출물을 소라페니브와 병용 투여하는 경우, 호장근 추출물과 소라페니브를 각각 단독 투여한 경우에 비하여 암세포 성장 저해 효과가 현저히 우수하고, 또한 소라페니브의 사용량을 기존의 적정 처리 농도보다 저농도로 줄일 수 있어 항암제 내성에 따른 문제점을 극복할 수 있어 항암 보조제로 활용될 수 있다.The present invention relates to a composition for enhancing the therapeutic effect of sorafenib for cancer treatment, comprising the extract of sorafenib as an active ingredient. When the extract of sorafenib is administered in combination with sorafenib, the extract of sorafenib and sorafenib are administered alone. Compared to the first case, the cancer cell growth inhibitory effect is significantly superior, and the amount of sorafenib can be reduced to a lower concentration than the conventional appropriate treatment concentration, thereby overcoming the problems caused by anticancer drug resistance and thus can be used as an anticancer adjuvant.
도 1은 생물전환용 호장근 추출물의 간암세포 성장 저해 효과를 확인한 도이다.
도 2는 해조류 배양 원균 생물전환된 호장근과 소라페니브의 간암세포 성장억제 효과를 확인한 도이다.
도 3은 2차배양균 생물전환 호장근과 소라페니브의 간암세포 성장억제 효과를 확인한 도이다.
도 4는 동물모델에서 생물전환된 호장근 추출물과 소라페니브의 병행투여에 의한 간암의 성장억제 효과를 확인한 도이다.1 is a view confirming the liver cancer cell growth inhibitory effect of the extract for bioconversion Hojanggeun.
2 is a view confirming the hepatocellular growth inhibitory effect of algae culture progenitor bioconverted hojanggeun and sorafenib.
3 is a view confirming the liver cancer cell growth inhibitory effect of the secondary cultured bioconverted hojang-geun and sorafenib.
4 is a view confirming the growth inhibitory effect of liver cancer by the parallel administration of the bioconverted hojanggeun extract and sorafenib in an animal model.
본 발명은 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a composition for enhancing the therapeutic effect of cancer, comprising an extract of polygonum cuspidatum as an active ingredient, and characterized in that it is administered in combination with sorafenib.
본 발명의 일 실시예에 있어서, 본 발명의 조성물의 암 치료 효과 증강에서 암은 간암, 신장암, 갑상선암, 폐암, 악성 흑색종 및 대장암으로 이루어진 군으로부터 선택된 어느 1종인 것을 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, in enhancing the cancer treatment effect of the composition of the present invention, the cancer may be any one selected from the group consisting of liver cancer, kidney cancer, thyroid cancer, lung cancer, malignant melanoma and colorectal cancer. However, the present invention is not limited thereto.
본 발명의 일 실시예에 있어서, 본 발명의 조성물이 소라페니브와 병용 투여시 소라페니브와 별도로, 동시에, 또는 순차로 병용 투여되는 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, when the composition of the present invention is administered in combination with sorafenib, it may be characterized in that it is administered in combination with sorafenib separately, simultaneously, or sequentially, but is not limited thereto.
본 발명의 일 실시예에 있어서, 본 발명의 조성물은 호장근 추출물:소라페니브의 투여 용량비가 중량비로 1:1 내지 50:1인 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, the composition of the present invention may be characterized in that the administration dose ratio of rhododendron extract: sorafenib is 1:1 to 50:1 by weight, but is not limited thereto.
또한, 본 발명은 호장근 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 개선 효과 증강용 건강기능성식품 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a health functional food composition for enhancing cancer improvement effect, comprising an extract of rhododendron as an active ingredient, and characterized in that it is administered in combination with sorafenib.
또한, 본 발명은 호장근 추출물을 유효성분으로 포함하는, 항암 보조제를 제공하는 것을 목적으로 한다.In addition, it is an object of the present invention to provide an anticancer adjuvant, comprising the extract of hojanggeun as an active ingredient.
본 발명의 일 실시예에 있어서, 본 발명의 항암 보조제는 항암제의 암 세포 성장 억제 효과를 증진시키는 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, the anticancer adjuvant of the present invention may be characterized by enhancing the cancer cell growth inhibitory effect of the anticancer agent, but is not limited thereto.
본 발명의 일 실시예에 있어서, 본 발명의 항암 보조제는 소라페니브 (sorafenib)의 암 세포 성장 억제 효과를 증진시키는 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, the anticancer adjuvant of the present invention may be characterized in that it enhances the cancer cell growth inhibitory effect of sorafenib, but is not limited thereto.
본 발명의 일 실시예에 있어서, 본 발명의 항암 보조제는 항암 보조제는 소라페니브와 병용 투여시 소라페니브와 별도로, 동시에, 또는 순차로 병용 투여되는 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, the anticancer adjuvant of the present invention may be characterized in that when the anticancer adjuvant is administered in combination with sorafenib, it may be administered in combination with sorafenib separately, simultaneously, or sequentially, but is not limited thereto.
마지막으로, 본 발명은 (1) 해조류 추출물을 사카로마이세스를 접종하여 1차 배양 후, 락토바실러스, 스트렙토코커스, 바실러스 및 로도슈도모나스로 구성된 군에서 선택된 하나 이상의 균주를 접종하고 2차 배양하여 배양물을 얻는 단계; (2) 상기 (1)의 배양물에 올리브 잎 추출물 및 현미배아분말을 첨가한 후, 사카로마이세스, 락토바실러스, 스트렙토코커스, 바실러스 및 로도슈도모나스로 구성된 군에서 선택된 하나 이상의 균주를 접종하고 배양하여 배양물을 얻는 단계; 및 (3) 호장근 추출물에 상기 (1) 또는 (2)의 배양물을 접종하고 배양하는 단계를 포함하는, 호장근 추출물을 유효성분으로 포함하고, 소라페니브와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물의 제조방법을 제공하는 것을 목적으로 한다.Finally, the present invention provides (1) inoculating the seaweed extract with Saccharomyces and then culturing first, then inoculating one or more strains selected from the group consisting of Lactobacillus, Streptococcus, Bacillus and Rhodopseudomonas, followed by secondary culture to inoculate obtaining water; (2) After adding olive leaf extract and brown rice germ powder to the culture of (1) above, Saccharomyces, Lactobacillus, Streptococcus, Bacillus and one or more strains selected from the group consisting of Rhodopseudomonas are inoculated and cultured to obtain a culture; And (3) comprising the step of inoculating and culturing the culture of (1) or (2) in the rhododendron extract as an active ingredient, characterized in that it is administered in combination with sorafenib, An object of the present invention is to provide a method for preparing a composition for enhancing the therapeutic effect of cancer.
본 발명의 일 실시예에 있어서, 사카로마이세스는 사카로마이세스 세레비지애 (Saccharomyces cerevisiae), 사카로마이세스 엘립소이데우스 (Saccharomyces ellipsoideus) 및 사카로마이세스 코레아누스 (Saccharomyces coreanus) 중 어느 하나 이고, 락토바실러스는 락토바실러스 아시도필루스 (Lactobacillus acidophilus), 락토바실러스 불가리쿠스 (Lactobacillus bulgaricus) 및 락토바실러스 카세이 (Lactobacillus casei) 중 어느 하나 이며, 스트렙토코커스는 스트렙토코커스 써모필러스 (Streptococcus thermophilus)이고, 바실러스는 바실러스 리체니포르미스 (Bacillus licheniformis), 바실러스 서브틸리스 (Bacillus subtilis) 및 바실러스 아밀로리퀴파시엔스 (Bacillus amyloliquefaciens) 중 어느 하나 이며, 로도슈도모나스는 로도슈도모나스 캡술레이트 (Rhodopseudomonas capsulate)인 것을 특징으로 할 수 있으나 이에 한정되는 것은 아니다.In one embodiment of the present invention, Saccharomyces is Saccharomyces cerevisiae ( Saccharomyces cerevisiae ), Saccharomyces ellipsoideus ( Saccharomyces ellipsoideus ) and Saccharomyces coreanus ( Saccharomyces coreanus ) Any one, Lactobacillus acidophilus ( Lactobacillus acidophilus ) , Lactobacillus bulgaricus ( Lactobacillus bulgaricus ) and Any one of Lactobacillus casei , Streptococcus is Streptococcus thermophilus , Bacillus is Bacillus licheniformis , Bacillus subtilis and Bacillus amyloliquefaciens ( Bacillus amyloliquefaciens ) It is any one, and Rhodopseudomonas Rhodopseudomonas capsulate ( Rhodopseudomonas capsulate ) It may be characterized in that it is, but is not limited thereto.
이하, 첨부된 도면을 참조하여 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현 예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허 청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다.Hereinafter, the present invention will be described in detail as an embodiment of the present invention with reference to the accompanying drawings. However, the following embodiments are presented as examples of the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description may be omitted and , the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
또한, 본 명세서에서 사용되는 용어 (terminology)들은 본 발명의 바람직한 실시 예를 적절히 표현하기 위해 사용된 용어들로서, 이는 사용자, 운용자의 의도 또는 본 발명이 속하는 분야의 관례 등에 따라 달라질 수 있다. 따라서 본 용어들에 대한 정의는 본 명세서 전반에 걸친 내용을 토대로 내려져야 할 것이다. 명세서 전체에서, 어떤 부분이 어떤 구성요소를 “포함”한다고 할 때, 이는 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성 요소를 더 포함할 수 있는 것을 의미한다.In addition, terms used in this specification are terms used to properly express preferred embodiments of the present invention, which may vary depending on the intention of a user or operator or customs in the field to which the present invention belongs. Therefore, definitions of these terms should be made based on the content throughout this specification. Throughout the specification, when a part "includes" a certain element, it means that other elements may be further included, rather than excluding other elements, unless otherwise stated.
본 명세서 전체에 걸쳐, 특정 물질의 농도를 나타내기 위하여 사용되는 '%'는 별도의 언급이 없는 경우, 고체/고체는 (w/w) %, 고체/액체는 (w/v) %, 그리고 액체/액체는 (v/v) %이다.Throughout this specification, '%' used to indicate the concentration of a specific substance is (w/w) % for solid/solid, (w/v) % for solid/liquid, and Liquid/liquid is (v/v) %.
일 측면에서, 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물에 관한 것이다.In one aspect, it relates to a composition for enhancing the therapeutic effect of cancer, comprising an extract of polygonum cuspidatum as an active ingredient, characterized in that it is administered in combination with sorafenib.
본 발명에 따른 추출물은 당업계에 공지된 추출 및 분리방법을 사용하여 천연으로부터 추출 및 분리하여 수득한 것을 사용할 수 있으며, 본 발명에서 정의된 “추출물”은 적절한 용매를 이용하여 호장근으로부터 추출한 것이며, 예를 들어, 조추출물, 극성용매 가용 추출물 또는 비극성용매 가용 추출물을 모두 포함한다. 상기 호장근으로부터 추출물을 추출하기 위한 적절한 용매로는 약학적으로 허용되는 유기용매라면 어느 것을 사용해도 무방하며, 물 또는 유기용매를 사용할 수 있으며, 이에 제한되지는 않으나, 예를 들어, 정제수, 메탄올 (methanol), 에탄올 (ethanol), 프로판올 (propanol), 이소프로판올 (isopropanol), 부탄올 (butanol) 등을 포함하는 탄소수 1 내지 4의 알코올, 아세톤 (acetone), 에테르 (ether), 벤젠 (benzene), 클로로포름 (chloroform), 에틸아세테이트 (ethyl acetate), 메틸렌클로라이드 (methylene chloride), 헥산 (hexane) 및 시클로헥산 (cyclohexane) 등의 각종 용매를 단독으로 혹은 혼합하여 사용할 수 있다. 추출 방법으로는 열수추출법, 냉침추출법, 환류냉각추출법, 용매추출법, 수증기증류법, 초음파추출법, 용출법, 압착법 등의 방법 중 어느 하나를 선택하여 사용할 수 있다. 또한, 목적하는 추출물은 추가로 통상의 분획 공정을 수행할 수도 있으며, 통상의 정제 방법을 이용하여 정제될 수도 있다. The extract according to the present invention may be obtained by extraction and separation from nature using extraction and separation methods known in the art, and the "extract" as defined in the present invention is extracted from rhizome using an appropriate solvent. , for example, include all crude extracts, polar solvent-soluble extracts, or non-polar solvent-soluble extracts. As a suitable solvent for extracting the extract from the rhizome, any pharmaceutically acceptable organic solvent may be used, and water or an organic solvent may be used, but is not limited thereto, for example, purified water, methanol (methanol), ethanol (ethanol), propanol (propanol), isopropanol (isopropanol), alcohol having 1 to 4 carbon atoms, including butanol (butanol), acetone (acetone), ether (ether), benzene (benzene), chloroform Various solvents such as (chloroform), ethyl acetate, methylene chloride, hexane and cyclohexane may be used alone or in combination. As the extraction method, any one of methods such as hot water extraction, cold extraction, reflux cooling extraction, solvent extraction, steam distillation, ultrasonic extraction, elution, and compression may be selected and used. In addition, the desired extract may be further subjected to a conventional fractionation process, and may be purified using a conventional purification method.
본 발명의 추출물의 제조방법에는 제한이 없으며, 공지되어 있는 어떠한 방법도 이용될 수 있다. 예를 들면, 본 발명의 조성물에 포함되는 추출물은 상기한 열수 추출 또는 용매 추출법으로 추출된 1차 추출물을, 감압 증류 및 동결 건조 또는 분무 건조 등과 같은 추가적인 과정에 의해 분말상태로 제조할 수 있다. 또한 상기 1차 추출물을 실리카겔 컬럼 크로마토그래피 (silica gel column chromatography), 박층 크로마토그래피 (thin layer chromatography), 고성능 액체 크로마토그래피 (high performance liquid chromatography) 등과 같은 다양한 크로마토그래피를 이용하여 추가로 정제된 분획을 얻을 수도 있다. 따라서 본 발명에 있어서 추출물은 추출, 분획 또는 정제의 각 단계에서 얻어지는 모든 추출액, 분리된 화합물, 분획 및 정제물, 그들의 희석액, 농축액 또는 건조물을 모두 포함하는 개념이다.There is no limitation on the method for preparing the extract of the present invention, and any known method may be used. For example, the extract included in the composition of the present invention may be prepared in a powder state by an additional process such as distillation under reduced pressure and freeze-drying or spray-drying the primary extract extracted by the hot water extraction or solvent extraction method described above. In addition, the first extract was further purified using various chromatography methods such as silica gel column chromatography, thin layer chromatography, high performance liquid chromatography, etc. you may get Therefore, in the present invention, the extract is a concept including all extracts, separated compounds, fractions and purified substances obtained in each step of extraction, fractionation or purification, and dilutions, concentrates or dried products thereof.
본 발명의 암 치료 효과 증강용 조성물이 약학적 조성물인 경우, 유효성분 이외에 보조제 (adjuvant)를 추가로 포함할 수 있다. 상기 보조제는 당해 기술분야에 알려진 것이라면 어느 것이나 제한 없이 사용할 수 있으나, 예를 들어 프로인트 (Freund)의 완전 보조제 또는 불완전 보조제를 더 포함하여 그 면역성을 증가시킬 수 있다. When the composition for enhancing the cancer treatment effect of the present invention is a pharmaceutical composition, it may further include an adjuvant in addition to the active ingredient. The adjuvant can be used without limitation as long as it is known in the art, for example, Freund's complete adjuvant or incomplete adjuvant can be further included to increase the immunity thereof.
본 발명에 따른 “약학적 조성물”은 유효성분을 약학적으로 허용된 담체에 혼입시킨 형태로 제조될 수 있다. 여기서, 약학적으로 허용된 담체는 제약 분야에서 통상 사용되는 담체, 부형제 및 희석제를 포함한다. 본 발명의 약학적 조성물에 이용할 수 있는 약학적으로 허용된 담체는 이들로 제한되는 것은 아니지만, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The “pharmaceutical composition” according to the present invention may be prepared in a form in which the active ingredient is incorporated into a pharmaceutically acceptable carrier. Here, the pharmaceutically acceptable carrier includes carriers, excipients and diluents commonly used in the pharmaceutical field. Pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present invention include, but are not limited to, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin , calcium phosphate, calcium silicate, cellulose, methyl cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
본 발명의 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀전, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition of the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, or sterile injection solutions according to conventional methods, respectively. have.
제제화할 경우에는 통상 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 그러한 고형 제제는 유효성분에 적어도 하나 이상의 부형제, 예를 들면 전분, 칼슘 카르보네이트, 수크로스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 일반적으로 사용되는 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수용성용제, 현탁제, 유제, 동결건조 제제 및 좌제가 포함된다. 비수용성용제, 현탁제로는 프로필렌 글리콜, 폴리에틸렌 글리콜, 올리브유와 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (witepsol), 트윈 (tween) 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.In the case of formulation, it may be prepared using a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, and a surfactant commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and such solid preparations include at least one excipient in the active ingredient, for example, starch, calcium carbonate, sucrose, lactose, gelatin. It can be prepared by mixing and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used diluents, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. can Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As the base of the suppository, witepsol, tween 61, cacao butter, laurin fat, glycerogelatin, and the like can be used.
본 발명에 따른 약학적 조성물은 개체에 다양한 경로로 투여될 수 있다. 투여의 모든 방식이 예상될 수 있는데, 예를 들면 경구, 정맥, 근육, 피하, 복강내 주사에 의해 투여될 수 있다.The pharmaceutical composition according to the present invention may be administered to an individual by various routes. Any mode of administration can be envisaged, for example, by oral, intravenous, intramuscular, subcutaneous, intraperitoneal injection.
상기 약학적 조성물은 다양한 경구 또는 비경구 투여 형태로 제형화될 수 있다.The pharmaceutical composition may be formulated in various oral or parenteral dosage forms.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경질, 연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제 등이 있는데, 이들 제형은 유효성분 이외에 희석제 (예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제 (예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 추가로 포함할 수 있다. 또한, 상기 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 트라가칸스, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제 및 감미제를 함유할 수 있다. 상기 제형은 통상적인 혼합, 과립화 또는 코팅 방법에 의해 제조될 수 있다.Formulations for oral administration include, for example, tablets, pills, hard, soft capsules, solutions, suspensions, emulsifiers, syrups, granules, etc., and these formulations include diluents (eg, lactose, dextrose, water crose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg, silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). In addition, the tablet may contain a binder such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid. or disintegrants such as sodium salts thereof or effervescent mixtures and/or absorbents, coloring, flavoring and sweetening agents. The formulation may be prepared by conventional mixing, granulating or coating methods.
또한, 비경구 투여용 제형의 대표적인 것은 주사용 제제이며, 주사용 제제의 용매로서 물, 링거액, 등장성 생리식염수 또는 현탁액을 들 수 있다. 상기 주사용 제제의 멸균 고정 오일은 용매 또는 현탁 매질로서 사용할 수있으며 모노-, 디-글리세라이드를 포함하여 어떠한 무자극성 고정오일도 이러한 목적으로 사용될 수 있다.In addition, representative formulations for parenteral administration are injection formulations, and water, Ringer's solution, isotonic physiological saline, or suspension can be exemplified as a solvent for the injection formulation. The sterile, fixed oil of the injectable preparation can be used as a solvent or suspending medium, and any non-irritating fixed oil including mono- and di-glycerides can be used for this purpose.
또한, 상기 주사용 제제는 올레산과 같은 지방산을 사용할 수 있다.In addition, the injection preparation may use a fatty acid such as oleic acid.
일 측면에서, 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 소라페니브 (sorafenib)와의 병용 투여를 특징으로 하는, 암 개선 효과 증강용 건강기능성식품 조성물에 관한 것이다.In one aspect, it relates to a functional health food composition comprising an extract of polygonum cuspidatum as an active ingredient, characterized in that it is administered in combination with sorafenib, and for enhancing the effect of improving cancer.
본 발명의 “건강기능성식품 조성물”은 유효성분인 호장근 추출물을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다."Health functional food composition" of the present invention may contain various flavoring agents or natural carbohydrates as additional ingredients, like a conventional food composition, in addition to containing an active ingredient, Hojanggeun extract.
상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨,소르비톨, 에리트리톨 등의 당알코올이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 본 발명의 식품 조성물은 상기 약학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등이 있다.Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The above-mentioned flavoring agents can advantageously use natural flavoring agents (Taumatine), stevia extract (eg rebaudioside A, glycyrrhizine, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.). The food composition of the present invention may be formulated in the same manner as the pharmaceutical composition and used as a functional food or added to various foods. Foods to which the composition of the present invention can be added include, for example, beverages, meat, chocolate, foods, confectionery, pizza, ramen, other noodles, gums, candy, ice cream, alcoholic beverages, vitamin complexes and health supplements. There is this.
또한 상기 식품 조성물은 유효성분인 추출물 외에 여러 가지 영양제, 비타민, 광물 (전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제 (치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명의 식품 조성물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다.In addition, the food composition includes various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, colorants and thickeners (cheese, chocolate, etc.), pectic acid and its salts, Alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may be contained. In addition, the food composition of the present invention may contain natural fruit juice and pulp for the production of fruit juice beverages and vegetable beverages.
본 발명의 건강기능성식품 조성물은, 정제,캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공될 수 있다. 본 발명에서 건강기능성식품 조성물이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다. 본 발명의 건강기능성식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다. 상기 '식품 첨가물 공전'에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨 제제, 면류첨가알칼리제, 보존료 제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다. 예를 들어, 정제 형태의 건강 기능성 식품은 본 발명의 유효성분을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강 기능성 식품은 필요에 따라 교미제 등을 함유할 수도 있다. 캅셀 형태의 건강 기능성 식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 본 발명의 유효성분을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다. 환 형태의 건강 기능성 식품은 본 발명의 유효성분과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다. 과립 형태의 건강 기능성 식품은 본 발명의 유효성분의 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다.The health functional food composition of the present invention may be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, and the like. In the present invention, the term "health functional food composition" refers to food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and contains nutrients for the structure and function of the human body. It refers to ingestion for the purpose of obtaining useful effects for health purposes such as regulation or physiological action. The health functional food of the present invention may contain normal food additives, and unless otherwise specified, whether it is suitable as a food additive is related to the item according to the general rules and general test method of food additives approved by the Food and Drug Administration. It is judged according to the standards and standards. The items listed in the 'Food Additives Codex' include, for example, chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; natural additives such as persimmon pigment, licorice extract, crystalline cellulose, high pigment, and guar gum; Mixed preparations, such as a sodium L-glutamate preparation, a noodle-added alkali agent, a preservative preparation, and a tar dye preparation, etc. are mentioned. For example, the health functional food in the form of a tablet is granulated in a conventional way by mixing the active ingredient of the present invention with an excipient, binder, disintegrant and other additives in a conventional manner, and then compression-molded by putting a lubricant, etc., or The mixture can be compression molded directly. In addition, the health functional food in the form of tablets may contain a corrosive agent or the like, if necessary. Among health functional foods in the form of capsules, hard capsules can be prepared by filling a mixture of the active ingredient of the present invention with additives such as excipients in ordinary hard capsules, and soft capsules include the active ingredient of the present invention with additives such as excipients. It can be prepared by filling a mixture mixed with a capsule base such as gelatin. The soft capsules may contain a plasticizer such as glycerin or sorbitol, a colorant, a preservative, and the like, if necessary. A health functional food in the form of a ring can be prepared by molding a mixture of the active ingredient of the present invention with an excipient, a binder, a disintegrant, etc. by a conventionally known method, and can be coated with sucrose or other peeling agent if necessary, Alternatively, the surface may be coated with a material such as starch or talc. The health functional food in the form of granules can be prepared in a granular form by a conventionally known method by mixing a mixture of the active ingredient excipients, binders, disintegrants, etc. of the present invention, and may contain flavoring agents, flavoring agents, etc. can
일 측면에서, 호장근 (polygonum cuspidatum) 추출물을 유효성분으로 포함하고, 항암 보조제에 관한 것이다.In one aspect, it relates to an anticancer adjuvant, including an extract of polygonum cuspidatum as an active ingredient.
본 발명의 용어, “항암 보조제”는 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제로서, 그 자체로는 항암활성을 나타내지 않으나 항암제와 함께 사용될 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다. 또한, 농도의존적인 항암활성을 나타내는 제제를 그 자체로는 항암활성을 나타내지 않은 수준으로 항암제와 함께 사용할 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다. As used herein, the term “anticancer adjuvant” refers to an agent capable of improving, enhancing, or enhancing the anticancer effect of an anticancer agent, which by itself does not exhibit anticancer activity, but when used together with an anticancer agent, improves, improves the anticancer effect of the anticancer agent Or it may be an agent capable of augmenting. In addition, when an agent exhibiting concentration-dependent anticancer activity is used together with an anticancer agent at a level that does not exhibit anticancer activity by itself, it may be an agent capable of improving, enhancing or enhancing the anticancer effect of the anticancer agent.
항암 보조제의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 항암 보조제는 목적하는 바에 따라 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 경구 투여, 비 내 투여, 폐 내 투여, 직장 내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 상기 항암 보조제는 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.The administration route of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, oral administration, intranasal administration, intrapulmonary administration, or rectal administration according to the purpose, but is not limited thereto. does not In addition, the anti-cancer adjuvant may be administered by any device capable of transporting an active substance to a target cell.
본 발명의 용어, “항암제 내성 (drug-resistance)”은 항암제 치료 요법에 대하여 극히 낮은 감수성을 나타내어 상기 치료 요법에 의하여 암의 증세가 호전, 완화, 경감 또는 치료증상을 나타내지 않는 증상을 말한다. 항암제 내성은 암이 특정 항암제 치료 요법에 대하여 처음부터 내성을 가질 수 있고, 최초에는 내성을 나타내지 않았으나 긴 시간의 치료로 인하여 암세포의 성질이 변하여 동일한 치료제에 대해 더 이상 감수성을 나타내지 않게 되어 나타날 수 있다.As used herein, the term "anticancer drug resistance (drug-resistance)" refers to a symptom that exhibits extremely low sensitivity to an anticancer drug treatment regimen, and thus the symptoms of cancer are improved, alleviated, alleviated, or do not exhibit therapeutic symptoms by the treatment regimen. Anticancer drug resistance is that a cancer can have resistance from the beginning to a specific anticancer drug treatment regimen, and although it did not initially show resistance, the properties of cancer cells change due to long-term treatment and it can appear that it is no longer sensitive to the same therapeutic agent. .
이하, 실시예를 통하여 본 발명을 보다 자세히 설명한다. 다만, 상기 실시예 및 실험예는 본 발명에 대한 예시로 제시되는 것으로, 당업자에게 주지 저명한 기술 또는 구성에 대한 구체적인 설명이 본 발명의 요지를 불필요하게 흐릴 수 있다고 판단되는 경우에는 그 상세한 설명을 생략할 수 있고, 이에 의해 본 발명이 제한되지는 않는다. 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다. Hereinafter, the present invention will be described in more detail through examples. However, the above embodiments and experimental examples are presented as examples for the present invention, and when it is determined that detailed descriptions of well-known techniques or configurations known to those skilled in the art may unnecessarily obscure the gist of the present invention, the detailed description thereof will be omitted. , and the present invention is not limited thereby. Various modifications and applications of the present invention are possible within the scope of equivalents interpreted therefrom and the description of the claims to be described later.
실시예 1. 재료 및 방법Example 1. Materials and Methods
1.1 실험재료1.1 Experimental Materials
본 실험에 사용한 cell culture plate는 SPL사의 제품을 사용하였으며, 세포 생존률 분석을 위한 크리스탈바이올렛 (crystal violet) solution은 Sigma aldrich korea 제품을 이용하였다. The cell culture plate used in this experiment was a product of SPL, and a crystal violet solution for cell viability analysis was a product of Sigma aldrich Korea.
1.2 호장근 추출물의 제조1.2 Preparation of rhizome extract
건조된 호장근 500 g을 5 L의 증류수 (D.W.; distilled water)에 100 ℃에서 2시간 추출하였다. 30분 휴지 후, 5 L의 D.W.를 추가하여 100 ℃에서 3시간 추출 후, 추출한 시료를 1시간 가량 휴지시킨 후, 여과하여 200 mL까지 농축하여 수득하였다.500 g of dried rhizomes was extracted with 5 L of distilled water (D.W.; distilled water) at 100° C. for 2 hours. After resting for 30 minutes, 5 L of D.W. was added, extracted at 100 °C for 3 hours, and the extracted sample was rested for about 1 hour, filtered and concentrated to 200 mL.
실시예 2. 기능성 신소재를 활용한 호장근의 생물전환Example 2. Biotransformation of hojang-geun using a new functional material
2.1 락토바실러스 플란타륨 (2.1 Lactobacillus plantarum ( Lactobacillus plantarumLactobacillus plantarum )을 이용한 액상발효) using liquid fermentation
건조된 호장근을 2 ~ 3cm로 절단하여 용매 DW에 넣고 압력상태에서 100℃로 약 4시간 동안 추출·농축하였다. 그 후, 호장근 농축액을 10배 희석하여 MRS배지를 넣고 Auto clave에서 125℃로 15분간 멸균시켜 액상배지를 만들었다. 락토바실러스 플란타륨 (Lactobacillus plantarum) (1.0x1010 cfu/g)를 MRS 액체배지에서 28℃, 24시간동안 배양하고, 멸균된 액상배지에 락토바실러스 플란타륨 (Lactobacillus plantarum) (1.0x1010 cfu/g)를 접종하여 쉐이킹 인큐베이터에서 28℃, 100rpm 으로 10일간 생물전환 시켰다.The dried rhizomes were cut into 2-3 cm pieces, put in solvent DW, and extracted and concentrated at 100° C. under pressure for about 4 hours. After that, 10 times dilution of the H. janggeun concentrate was put into MRS medium, and sterilized at 125° C. in an autoclave for 15 minutes to make a liquid medium. Lactobacillus plantarum ( Lactobacillus plantarum ) (1.0x10 10 cfu/g) was cultured in MRS liquid medium at 28 ° C. for 24 hours, and Lactobacillus plantarum ) (1.0x10 10 cfu) in sterilized liquid medium /g) was inoculated and bioconverted for 10 days at 28°C and 100rpm in a shaking incubator.
2.2 단계적 공서배양 배양액을 이용한 액상발효2.2 Liquid fermentation using step-by-step co-culture medium
2.2-1 실험 방법2.2-1 Experimental method
항균 활성을 가진 호장근의 섬유소 분해와 유효성분 추출 그리고 자체적 항염 기능을 보강하기 위해 단일 균주가 아닌 하기의 단계적 공서 배양을 통해 호장근 생물전환을 시도하였다.In order to decompose the fibrin, extract active ingredients, and reinforce its anti-inflammatory function, the bioconversion of the rhododendron with antibacterial activity was attempted through the following step-by-step co-culture rather than a single strain.
2.2-2 해조류의 추출 및 회수2.2-2 Extraction and recovery of seaweed
해조류 중 톳과 다시마 50 g을 적당한 크기로 절단 및 수세한 다음, 20배액 정제수에서 10시간 이상 침지하여 알긴 등을 용출 제거하였다. 그 후, 정제수 또는 80% 알코올 (Alcohol) 1500 ㎖를 추출용매로 사용하여 80℃에서 2 ~ 10시간 추출하였다.Among seaweeds, 50 g of seaweed and kelp were cut into appropriate sizes and washed, and then immersed in 20-fold purified water for 10 hours or more to elute and remove algin. Thereafter, using 1500 ml of purified water or 80% alcohol as an extraction solvent, extraction was performed at 80° C. for 2 to 10 hours.
추출물을 여과하고, 진공농축 과정을 통하여 정제수 또는 알코올 (Alcohol)을 분리 회수하고, 1차 추출 및 용매 회수과정을 통하여 300 ㎖의 1차 추출물을 수득하였다. 2차 추출과정으로 정제수 700㎖를 투입하여 90°c에서 3시간 추출 한 후, 여과하고 진공 농축하여 300㎖의 2차 추출물을 수득하였다.The extract was filtered, purified water or alcohol was separated and recovered through vacuum concentration, and 300 ml of the primary extract was obtained through primary extraction and solvent recovery. As a secondary extraction process, 700 ml of purified water was added, extracted at 90°C for 3 hours, filtered and concentrated in vacuo to obtain 300 ml of a secondary extract.
2.2-3 올리브 잎의 추출 및 회수2.2-3 Extraction and recovery of olive leaves
건조 올리브 잎 50 g을 절단하여 50 ~ 80% 알코올 (Alcohol) 용매 2000 ㎖를 투입 후 70 ~ 100℃ 에서 3 ~ 12시간 추출하였다. 그 후, 추출물을 진공 농축하여 용매 제거 후, 450 ㎖의 1차 추출액을 수득하고, 2차 추출과정으로 정제수 1000 ㎖ 투입하고 90℃에서 3시간 추출하였다. 추출물을 550 ㎖ 볼륨으로 진공농축하고, 여과하여, 잔여 알코올 (Alcohol)을 회수 및 제거한 다음 1차 추출물과 혼합하여 1000 ㎖로 제조하였다.50 g of dried olive leaves were cut, 2000 ml of a 50 to 80% alcohol solvent was added, and then extracted at 70 to 100° C. for 3 to 12 hours. After that, the extract was concentrated in vacuo to remove the solvent, to obtain 450 ml of a primary extract, 1000 ml of purified water was added as a secondary extraction process, and extracted at 90° C. for 3 hours. The extract was concentrated in vacuo to a volume of 550 ml, filtered to recover and remove residual alcohol, and then mixed with the primary extract to prepare 1000 ml.
2.2-4 해조류 배양 원균과 2차 배양균 생성을 위한 단계적 공서배양 발효 과정2.2-4 Step-by-step co-culture fermentation process for the production of seaweed culture progenitors and secondary cultures
상기 (2)의 1차 및 2차 추출물 각 300 ㎖ 용액과 정제수 400 ㎖, 알코올당 15 g, 과당 5 g을 혼합하여 1000 ㎖ 로 조제한 다음, 121℃ 로 30분 이상 멸균하였다. 효모균주 사카로마이세스 (Saccharomyces spp.) 균종을 접종하고, 25℃ ~ 37℃에서 2 ~ 3일 간 1차 배양 후, 다시 락토바실러스 (Lactobacillus spp.), 스트렙토코커스 (Streptococcus sp.), 바실러스 (Bacillus spp.) 및 로도슈도모나스 (Rhodopseudomonas sp.)를 15℃ ~ 30℃로 10 ~ 30일 간 2차 공서배양 하였다 (해조류 배양 원균). 300 ml of each of the primary and secondary extracts of (2), 400 ml of purified water, 15 g of alcohol, and 5 g of fructose were mixed to prepare 1000 ml, and then sterilized at 121° C. for 30 minutes or more. Yeast strain Saccharomyces ( Saccharomyces spp. ) is inoculated, and after primary culture at 25 ℃ ~ 37 ℃ for 2-3 days, again Lactobacillus ( Lactobacillus spp. ), Streptococcus sp., Bacillus ( Bacillus spp.) and Rhodopseudomonas sp . were secondary co-cultured at 15° C. to 30° C. for 10 to 30 days (seaweed culture progenitors).
위의 배양물에 상기 (3)의 추출물 1000 ㎖과 현미배아분말 200 g을 투입하여 15℃ ~ 25℃에서 10일 간 공서배양 하였다 (2차 배양균). 배양 완료 후 Filter press에 여과하여 발효물을 제조하였다. 이때 공서배양을 위해 사용한 균주는 사카로마이세스로는 사카로마이세스 세레비지애 (Saccharomyces cerevisiae), 사카로마이세스 엘립소이데우스 (Saccharomyces ellipsoideus) 또는 사카로마이세스 코레아누스 (Saccharomyces coreanus)을 사용하였고, 스트렙토코커스 속 균주로는 스트렙토코커스 써모필러스 (Streptococcus thermophilus)을 사용하였으며, 로도슈도모나스 균주로는 로도슈도모나스 캡술레이트 (Rhodopseudomonas capsulate)을 사용하였다. 또한, 바실러스 속 균주로는 바실러스 리체니포르미스 (Bacillus licheniformis), 바실러스 서브틸리스 (Bacillus subtilis), 바실러스 아밀로리퀴파시엔스 (Bacillus amyloliquefaciens)를 사용하였고, 락토바실러스 속 균주로는 락토바실러스 아시도필루스 (Lactobacillus acidophilus), 락토바실러스 불가리쿠스 (Lactobacillus bulgaricus), 락토바실러스 카세이 (Lactobacillus casei) 을 사용하였다.1000 ml of the extract of (3) and 200 g of brown rice embryo powder were added to the above culture, and co-cultured at 15° C. to 25° C. for 10 days (secondary culture). After completion of the culture, the fermented product was prepared by filtration through a filter press. At this time, the strain used for co-culture is Saccharomyces as Saccharomyces cerevisiae ( Saccharomyces cerevisiae ), Saccharomyces ellipsoideus ( Saccharomyces ellipsoideus ) or Saccharomyces coreanus ( Saccharomyces coreanus ) was used, Streptococcus thermophilus was used as a Streptococcus sp. strain, and Rhodopseudomonas capsulate was used as a Rhodopseudomonas strain. ) was used. In addition, as the Bacillus sp. strain, Bacillus licheniformis , Bacillus subtilis , Bacillus amyloliquefaciens was used, and as the Lactobacillus sp. strain, Lactobacillus acido was used. Pylus ( Lactobacillus acidophilus ) , Lactobacillus bulgaricus , Lactobacillus casei ( Lactobacillus casei ) was used.
2.3 해조류 배양 원균을 이용한 액상발효2.3 Liquid fermentation using seaweed culture progenitors
건조된 호장근을 2 ~ 3cm로 절단하여 용매 DW에 넣고 압력상태에서 100℃로 약 4시간 동안 추출 및 농축하여 호장근 농축액을 10배 희석하여 LB배지를 넣고 Auto clave에서 125℃로 15분간 멸균시켜 액상배지를 만들었다. 해조류 배양 원균 배양액 (1.0x1010 cfu/g)을 LB 액체배지에서 28℃, 24시간동안 배양하였다. 멸균된 액상배지에 해조류 배양 원균 배양액 (1.0x1010 cfu/g)을 접종하여 쉐이킹 인큐베이터에서 28℃, 100rpm 으로 10일간 생물전환 시켰다.Cut the dried rhizomes into 2 ~ 3 cm, put them in solvent DW, extract and concentrate at 100℃ under pressure for about 4 hours, dilute the rhizome concentrate 10 times, put LB medium, and sterilize at 125℃ in an auto clave for 15 minutes. to make a liquid medium. The seaweed culture broth (1.0x10 10 cfu/g) was cultured in LB broth at 28° C. for 24 hours. The sterilized liquid medium was inoculated with the algae culture source culture medium (1.0x10 10 cfu/g) and bioconverted in a shaking incubator at 28° C., 100 rpm for 10 days.
2.4 2차배양균을 이용한 액상발효2.4 Liquid fermentation using secondary culture bacteria
건조된 호장근을 2 ~ 3cm로 절단하여 용매 DW에 넣고 압력상태에서 100℃로 약 4시간 동안 추출 및 농축하여 호장근 농축액을 10배 희석하여 LB배지를 넣고 Auto clave에서 125℃로 15분간 멸균시켜 액상배지를 만들었다. 2차 배양균 배양액(1.0x1010 cfu/g)을 LB 액체배지에서 28℃, 24시간동안 배양하였다. 멸균된 액상배지에 2차 배양균 배양액 (1.0x1010 cfu/g)을 접종하여 쉐이킹 인큐베이터에서 28℃, 100rpm 으로 10일간 생물전환 시켰다.Cut the dried rhizomes into 2 ~ 3 cm, put them in solvent DW, extract and concentrate at 100℃ under pressure for about 4 hours, dilute the rhizome concentrate 10 times, put LB medium, and sterilize at 125℃ in an auto clave for 15 minutes. to make a liquid medium. The secondary culture medium (1.0x10 10 cfu/g) was cultured in LB liquid medium at 28° C. for 24 hours. The secondary culture medium (1.0x10 10 cfu/g) was inoculated into the sterilized liquid medium and bioconverted in a shaking incubator at 28°C, 100rpm for 10 days.
실시예 3. 간암세포 배양 및 간암세포 생존율 분석Example 3. Hepatocarcinoma cell culture and liver cancer cell viability analysis
3.1 실험방법3.1 Experimental method
(1) 3종의 간암 세포주 (HepG2, SK-Hep-1, PLC/PRF5)는 한국세포주은행 (서울대학교 의과대학)에서 구입하였다. 세포배양에 필요한 FBS (fetal bovine serum)은 ATCC사의 제품을 사용하였다. 각각의 암세포는 heat inactivated FBS 10%와 penicillin/streptomycin을 첨가한 DMEM 배지에서 37℃, 5% CO2 의 Incubator에서 배양하였다.(1) Three types of liver cancer cell lines (HepG2, SK-Hep-1, PLC/PRF5) were purchased from the Korea Cell Line Bank (Seoul National University College of Medicine). For the fetal bovine serum (FBS) required for cell culture, ATCC's product was used. Each cancer cell was cultured in a DMEM medium supplemented with heat inactivated FBS 10% and penicillin/streptomycin at 37° C. and 5% CO 2 in an incubator.
(2) 세포 생존율 측정은 크리스탈바이올렛 (crystal violet) (Sigma aldrich) solution을 이용하여 측정하였다. 각각의 암세포는 96 well plate에 3 x 105/ml로 well 당 0.1ml씩 분주하여 24 시간 동안 plate에 안정화 시킨 후 대조군에는 DMSO (dimethylsurfoxide), 실험군 (생물전환 호장근 추출물, 소라페니브, 생물전환 호장근 추출물과 소라페니브 병행처리)에 적절한 약물을 처리하였다. 각각의 약물은 DMSO (dimethylsurfoxide)를 이용하여 녹였으며, 세포에 처리할 경우 최종 약물의 농도가 생물전환 호장근 추출물 12 ug/ml, 소라페니브 2 uM가 되도록 처리하였다. 약물을 처리한 세포는 2일 또는 3일 간 37℃와 5% CO2 조건에서 배양하였다. 배양된 세포는 PBS를 이용해 세척 후 4% Paraformaldehyde solution에서 10분 간 고정과정을 거쳤으며, 최종적으로 0.5% 크리스탈바이올렛 (crystal violet) solution을 이용하여 10분 간 염색을 진행하였다. 염색된 세포를 하루 동안 실온에서 건조한 후 1% SDS (sodium dodecyl sulfate) solution을 이용하여 녹였으며, 세포성장률을 정량화하기 위해 absorbance reader를 이용하여 570nm의 흡광도로 분석하였다.(2) Cell viability was measured using a crystal violet (Sigma aldrich) solution. Each cancer cell was aliquoted at 3 x 10 5 /ml in a 96-well plate at 0.1 ml per well and stabilized on the plate for 24 hours. In the control group, DMSO (dimethylsurfoxide), the experimental group (bioconversion rhizome extract, sorafenib, An appropriate drug was treated with the converted rhododendron extract and sorafenib). Each drug was dissolved using DMSO (dimethylsurfoxide), and when the cells were treated, the final drug concentrations were 12 ug/ml of bioconverted rhododendron extract and 2 uM of sorafenib. The drug-treated cells were cultured at 37° C. and 5% CO 2 conditions for 2 or 3 days. The cultured cells were washed with PBS, fixed in 4% Paraformaldehyde solution for 10 minutes, and finally stained with 0.5% crystal violet solution for 10 minutes. The stained cells were dried at room temperature for one day and dissolved using 1% SDS (sodium dodecyl sulfate) solution, and the absorbance was analyzed using an absorbance reader at 570 nm to quantify the cell growth rate.
3.2 호장근 추출물의 간암세포 성장 저해 효과3.2 Hepatocarcinoma cell growth inhibitory effect of Hojang-geun extract
생물전환용 호장근 추출물은 50, 100, 200, 300, 400 ug/ml농도로 48시간 동안 처리하였으며, 세포성장율의 분석은 크리스탈바이올렛 (Crystal violet) 기법을 통해 분석하였다. 그 결과, 도 1에 나타낸 바와 같이, 호장근 추출물에 의한 간암세포 (HepG2, SK-HEP-1, PLC/PRF5)의 성장이 억제되는 것을 확인하였다. 상기 결과에서 100 ug/ml 이상 농도의 호장근 추출물에 의해 간암세포의 성장이 농도 의존적으로 억제되는 것을 확인하였다.The extract for bioconversion was treated at concentrations of 50, 100, 200, 300, and 400 ug/ml for 48 hours, and the cell growth rate was analyzed using the Crystal violet technique. As a result, as shown in FIG. 1 , it was confirmed that the growth of hepatocellular carcinoma cells (HepG2, SK-HEP-1, PLC/PRF5) was inhibited by the H. janggeun extract. From the above results, it was confirmed that the growth of hepatocellular carcinoma was inhibited in a concentration-dependent manner by the H. janggeun extract at a concentration of 100 ug/ml or more.
3.3 해조류 배양 원균 호장근과 소라페니브의 간암세포 성장억제 효과3.3 Hepatocarcinoma cell growth inhibitory effect of seaweed culture progenitor hojang-geun and sorafenib
3종의 간암세포는 ①대조군, ②소라페니브 (4uM), ③해조류 배양 원균 호장근 (400 ug/ml), ④소라페니브 (4uM)와 해조류 배양 원균 호장근 (400 ug/ml)의 병행처리 군으로 나누었으며, 각 물질은 간암세포에 2일 간 처리한 후 세포생존율을 분석하였다. The 3 types of hepatocellular carcinoma cells were: ① control group, ② sorafenib (4uM), ③ seaweed culture progenitor hojanggun (400 ug/ml), ④ sorafenib (4uM) and algae culture progenitor hojanggun (400 ug/ml). They were divided into parallel treatment groups, and each substance was treated with liver cancer cells for 2 days, and then cell viability was analyzed.
그 결과 도 2에 나타낸 바와 같이, 해조류 배양 원균 호장근 (400 ug/ml)에 의해 간암세포 (SK-HEP-1, HepG2, PLC/PRF5)의 성장이 억제되지 않는 것을 확인하였으며, 더욱이 소라페니브 (넥사바, 4uM)에 의해 간암세포의 성장저해가 나타나지 않는다는 것을 확인하였다. 하지만 소라페니브 (4uM)와 해조류 배양 원균 호장근 (400 ug/ml)을 병행투여한 결과 3종의 간암세포 모두에서 약 20~30% 정도 간암세포의 성장이 억제되는 것을 확인하였다. 상기 실험결과를 통해 생물전환된 호장근 추출물과 소라페니브의 병행투여에 의해 간암세포 성장억제 효과가 있음을 확인하였다.As a result, as shown in FIG. 2, it was confirmed that the growth of hepatocellular carcinoma cells (SK-HEP-1, HepG2, PLC/PRF5) was not inhibited by seaweed culture progenitor Hojang-geun (400 ug/ml). It was confirmed that no inhibition of the growth of liver cancer cells was observed by B (Nexavar, 4uM). However, as a result of concurrent administration of sorafenib (4uM) and seaweed-cultured progenitor hojanggeun (400 ug/ml), it was confirmed that the growth of hepatocellular carcinoma cells was inhibited by about 20-30% in all three types of hepatocellular carcinoma cells. Through the above experimental results, it was confirmed that the liver cancer cell growth inhibitory effect was obtained by concurrent administration of the bioconverted hojang-geun extract and sorafenib.
3.4 2차배양균 호장근과 소라페니브의 간암세포 성장억제 효과3.4 Hepatocarcinoma cell growth inhibitory effect of secondary cultured hojang-geun and sorafenib
2종의 간암세포 (HepG2, PLC/PRF5)는 ①대조군, ②소라페니브 (2uM), ③2차배양균 호장근 (12 ug/ml), ④소라페니브 (2uM)와 2차배양균 호장근 (12 ug/ml)의 병행처리 군으로 나누었으며, 각 물질은 간암세포에 48 시간 동안 처리한 후 세포생존율을 분석하였다. The two types of hepatocellular carcinoma cells (HepG2, PLC/PRF5) were: ① control group, ② sorafenib (2uM), ③ secondary cultured bacteria Hojanggeun (12 ug/ml), ④ sorafenib (2uM) and secondary cultured bacteria. It was divided into a parallel treatment group of long root (12 ug/ml), and each substance was treated with liver cancer cells for 48 hours, and then the cell viability was analyzed.
그 결과 도 3에 나타낸 바와 같이, 2차배양균 호장근 (12 ug/ml)과 소라페니브 (2 uM)를 단독으로 처리하였을 경우에는 간암세포 (HepG2, PLC/PRF5)의 성장 억제 효과가 크지 않은 것을 확인하였다. 하지만, 소라페니브 (2uM)와 2차배양균 호장근 (12 ug/ml)을 병행처리한 결과 2종의 간암세포 모두에서 약 40-50% 정도 간암세포 성장이 억제되는 것을 확인하였다. 상기 결과를 통해 저농도의 2차배양균 생물전환된 호장근 추출물과 소라페니브의 병행투여에 의해 간암세포 성장억제 효과가 나타난다는 것을 확인하였다.As a result, as shown in FIG. 3 , when the secondary cultured hojanggeun (12 ug/ml) and sorafenib (2 uM) were treated alone, the growth inhibitory effect of hepatocellular carcinoma cells (HepG2, PLC/PRF5) was reduced. It was confirmed that it was not large. However, as a result of parallel treatment with sorafenib (2uM) and the secondary cultured hojanggeun (12 ug/ml), it was confirmed that the growth of hepatocellular carcinoma was inhibited by about 40-50% in both types of hepatocellular carcinoma cells. Through the above results, it was confirmed that the hepatocellular growth inhibitory effect appeared by the parallel administration of the low-concentration secondary cultured bioconverted hojang-geun extract and sorafenib.
실시예 4. 동물실험 및 이종이식 모델Example 4. Animal experiments and xenograft model
4.1 실험방법4.1 Experimental method
동물실험을 위한 실험용 생쥐는 수컷의 NCr athymic nude mice (4 ~ 5주령)를 이용하였으며, 동물은 Charles River (Shin-Yokohama, Japan)사로부터 구입하였다. 인간유래 간암 세포주 (SK-HEP-1)를 3X106세포수 만큼 NCr athymic nude mice의 옆구리 피하조직에 주입하였다. 종양이 적절한 크기로 자랄 수 있도록 동물을 3주 간 사육하였으며, 종양의 크기가 300 mm3가 되었을 때부터 대조군 (Vehicle, n=7), 소라페니브 단독처리군 (Sorafenib, n=7), 생물전환 호장근 추출물 단독처리군 (P.C, n=7), 생물전환 호장근 추출물과 소라페니브 병행투여군 (P.C+Sorafenib, n=7)으로 실험군을 나누어 약물투여를 시작하였다. For animal experiments, male NCr athymic nude mice (4 to 5 weeks of age) were used as experimental mice, and animals were purchased from Charles River (Shin-Yokohama, Japan). A human-derived liver cancer cell line (SK-HEP-1) was injected into the subcutaneous tissue of the flank of NCr athymic nude mice as much as 3X10 6 cells. The animals were bred for 3 weeks so that the tumors could grow to an appropriate size, and when the tumor size reached 300 mm 3 , the control group (Vehicle, n=7), the sorafenib alone group (Sorafenib, n=7), The drug administration was started by dividing the experimental group into a group treated with bioconverted rhododendron extract alone (PC, n=7), and a group treated with bioconverted rhododendron extract and sorafenib in combination (P.C+Sorafenib, n=7).
약물투여는 복강 내 주사를 통해 투여하였으며, 주입되는 용액의 전체양은 200 ul로 하였고, 약물 투여기간은 총 10일 간 투여하였다. 종양의 크기 (볼륨)는 약물투여 후 매일 caliper를 이용하여 측정하였다. 종양의 크기 (부피)는 아래 수식을 이용하여 계산되었다. [Volume = ab2/2; a = 최대 넓이, b = 직교 넓이]Drug administration was administered through intraperitoneal injection, the total amount of the injected solution was 200 ul, and the drug administration period was a total of 10 days. The size (volume) of the tumor was measured using a caliper every day after drug administration. The size (volume) of the tumor was calculated using the formula below. [Volume = ab 2 /2; a = maximum area, b = orthogonal area]
4.2 생물전환 호장근 추출물 (2차배양균 호장근)과 소라페니브 병행투여에 의한 간암의 성장억제 효과4.2 Growth inhibitory effect of liver cancer by concurrent administration of bioconverted hojang-geun extract (secondary culture bacterium hojang-geun) and sorafenib
인간유래 간암세포주 (SK-HEP-1)를 피하조직에 이식한 동물 종양모델을 이용하였으며, 종양의 크기가 300 mm3 정도 되었을 때 동물을 각 7마리씩 4그룹 (①대조군, ②소라페니브, ③생물전환 호장근 추출물, ④소라페니브와 생물전환 호장근 추출물 병행투여 군)으로 암맹분류 하였다. 분류된 4그룹의 실험용 쥐에게 생물전환 호장근 추출물 (50 mg/kg)과 소라페니브 (10 mg/kg)를 표시한 농도로 10일 간 복강 내 주사를 통해 투여하였다. An animal tumor model in which a human-derived liver cancer cell line (SK-HEP-1) was transplanted into the subcutaneous tissue was used. When the size of the tumor was about 300 mm 3 , 7 animals each were divided into 4 groups (① control group, ② sorafenib, ③ Bioconverted Hojang-geun extract, ④ Sorafenib and bioconverted Hojang-geun extract group) were classified as dark. Bioconverted rhododendron extract (50 mg/kg) and sorafenib (10 mg/kg) were administered intraperitoneally for 10 days at the indicated concentrations to the classified 4 groups of rats.
그 결과 도 4에서와 같이, 생물전환 호장근 추출물 (50 mg/kg)과 소라페니브 (10 mg/kg)를 단독으로 처리하였을 경우에는 대조군에 비해 SK-HEP-1세포 유래 간암조직의 성장이 약 5~10% 정도 억제되는 것을 확인하였으나, 소라페니브 (10 mg/kg)와 생물전환 호장근 추출물 (50 mg/kg)을 병행 투여한 결과 간암조직의 성장이 약 75% 정도 억제되는 것을 확인하였다. As a result, as shown in FIG. 4, when bioconverted hojang root extract (50 mg/kg) and sorafenib (10 mg/kg) were treated alone, the growth of SK-HEP-1 cell-derived liver cancer tissue compared to the control group It was confirmed that this drug was inhibited by about 5-10%, but as a result of concurrent administration of sorafenib (10 mg/kg) and bioconverting rhizome extract (50 mg/kg), the growth of liver cancer tissue was inhibited by about 75%. confirmed that.
따라서, 본 결과를 통해 생물전환된 호장근 추출물과 소라페니브의 병행투여가 간암성장 저해에 효과적이라는 것을 동물실험을 통해 확인하였으며, 더욱이, 본 결과를 통해 생물전환된 호장근이 저농도의 소라페니브 (10 mg/kg)의 항암효과를 증가시킬 수 있다는 것을 확인하여 본 발명을 완성하였다.Therefore, through this result, it was confirmed through animal experiments that the parallel administration of the bioconverted rhododendron extract and sorafenib was effective in inhibiting the growth of liver cancer. The present invention was completed by confirming that it was possible to increase the anticancer effect of B (10 mg/kg).
이제까지 본 발명에 대하여 그 바람직한 실시예들을 중심으로 살펴보았다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 청구범위에 나타나 있으며, 그와 동등한 범위내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.So far, with respect to the present invention, the preferred embodiments have been looked at. Those of ordinary skill in the art to which the present invention pertains will understand that the present invention can be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments are to be considered in an illustrative rather than a restrictive sense. The scope of the present invention is indicated in the claims rather than in the foregoing description, and all differences within the scope equivalent thereto should be construed as being included in the present invention.
Claims (13)
(2) 상기 (1)의 배양물에 올리브 잎 추출물 및 현미배아분말을 첨가한 후, 사카로마이세스, 락토바실러스, 스트렙토코커스, 바실러스 및 로도슈도모나스로 구성된 군에서 선택된 하나 이상의 균주를 접종하고 배양하여 배양물을 얻는 단계; 및
(3) 호장근 추출물에 상기 (1) 또는 (2)의 배양물을 접종하고 배양하는 단계를 포함하는,
호장근 추출물을 유효성분으로 포함하고, 소라페니브와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물의 제조방법.(1) inoculating the seaweed extract with Saccharomyces to obtain a culture by inoculating one or more strains selected from the group consisting of Lactobacillus, Streptococcus, Bacillus and Rhodopseudomonas, followed by primary culture and secondary culture;
(2) After adding the olive leaf extract and brown rice germ powder to the culture of (1), Saccharomyces, Lactobacillus, Streptococcus, Bacillus and one or more strains selected from the group consisting of Rhodopseudomonas are inoculated and cultured to obtain a culture; and
(3) comprising the step of inoculating and culturing the culture of (1) or (2) in the Hojanggeun extract,
A method for producing a composition for enhancing the therapeutic effect of cancer, comprising the extract of rhododendron as an active ingredient, and administering it in combination with sorafenib.
상기 사카로마이세스는 사카로마이세스 세레비지애 (Saccharomyces cerevisiae), 사카로마이세스 엘립소이데우스 (Saccharomyces ellipsoideus) 및 사카로마이세스 코레아누스 (Saccharomyces coreanus) 중 어느 하나 이고,
상기 락토바실러스는 락토바실러스 아시도필루스 (Lactobacillus acidophilus), 락토바실러스 불가리쿠스 (Lactobacillus bulgaricus) 및 락토바실러스 카세이 (Lactobacillus casei) 중 어느 하나 이며,
상기 스트렙토코커스는 스트렙토코커스 써모필러스 (Streptococcus thermophilus)이고,
상기 바실러스는 바실러스 리체니포르미스 (Bacillus licheniformis), 바실러스 서브틸리스 (Bacillus subtilis) 및 바실러스 아밀로리퀴파시엔스 (Bacillus amyloliquefaciens) 중 어느 하나 이며,
상기 로도슈도모나스는 로도슈도모나스 캡술레이트 (Rhodopseudomonas capsulate)인 것을 특징으로 하는,
호장근 추출물을 유효성분으로 포함하고, 소라페니브와의 병용 투여를 특징으로 하는, 암 치료 효과 증강용 조성물의 제조방법.13. The method of claim 12,
The Saccharomyces is Saccharomyces cerevisiae ( Saccharomyces cerevisiae ), Saccharomyces ellipsoideus ( Saccharomyces ellipsoideus ) And Saccharomyces coreanus ( Saccharomyces coreanus ) Any one,
The Lactobacillus is Lactobacillus acidophilus ( Lactobacillus acidophilus ) , Lactobacillus bulgaricus ( Lactobacillus bulgaricus ) and Lactobacillus casei ( Lactobacillus casei ) is any one,
The Streptococcus is Streptococcus thermophilus ,
The Bacillus is Bacillus licheniformis ( Bacillus licheniformis ) , Bacillus subtilis ( Bacillus subtilis ) and Bacillus amyloliquefaciens ( Bacillus amyloliquefaciens ) is any one,
The Rhodopseudomonas is characterized in that the Rhodopseudomonas capsulate ( Rhodopseudomonas capsulate ),
A method for producing a composition for enhancing the therapeutic effect of cancer, comprising the extract of rhododendron as an active ingredient, characterized in that it is administered in combination with sorafenib.
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