KR20120124151A - Composition for inhibition of multidrug resistance containing an extract of Morus alba L. - Google Patents
Composition for inhibition of multidrug resistance containing an extract of Morus alba L. Download PDFInfo
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- KR20120124151A KR20120124151A KR1020110041860A KR20110041860A KR20120124151A KR 20120124151 A KR20120124151 A KR 20120124151A KR 1020110041860 A KR1020110041860 A KR 1020110041860A KR 20110041860 A KR20110041860 A KR 20110041860A KR 20120124151 A KR20120124151 A KR 20120124151A
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- South Korea
- Prior art keywords
- extract
- composition
- cancer
- anticancer
- multidrug resistance
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Abstract
Description
본 발명은 다중약물내성 (multidrug resistance, MDR) 억제능이 매우 뛰어난 상백피 (Morus alba L.)추출물을 유효성분으로 포함하는 다중약물내성 억제용 조성물에 관한 것이다.
The present invention relates to a composition for inhibiting multi-drug resistance, comprising as an active ingredient, Morus alba L. extract having excellent multidrug resistance (MDR) inhibition.
현재까지 암을 치료하기 위한 외과적 요법, 방사선 요법, 화학적 요법 등과 같은 다양한 치료방법이 연구되고 있으나, 아직까지 암의 완전 치료에는 이르지 못하고 있는 실정이다.Until now, various treatment methods such as surgical therapy, radiation therapy, and chemotherapy for the treatment of cancer have been studied, but the situation has not been reached until the full treatment of cancer.
이중, 외과적 요법과 방사선 요법은 암 발생의 초기 단계에서 유용한 방법이기 때문에 초기에 감지하기가 힘든 암의 경우에는 화학적 요법에 대한 의존도가 점차 증가하고 있으며, 상기 화학적 요법은 50년 이상의 역사를 가지고 있고, 현재까지 수백여 종의 항암제가 개발되어 임상에서 사용되어 왔으나, 임상적으로 만족할만한 효과를 얻는 경우는 아직 많지 않다.Surgical and radiation therapy is a useful method in the early stages of cancer development, and cancers that are difficult to detect early on are increasingly dependent on chemotherapy, which has a history of more than 50 years. Hundreds of anticancer drugs have been developed and used in the clinic until now, but there are not many cases of obtaining clinically satisfactory effects.
항암화학요법 (Chemotherapy)은 가장 효과적인 암환자 치료 방법 중의 하나로 잘 알려져 있으나, 항암제의 지속적 투여는 항암화학요법의 실패를 초래하는 원인으로 지적되어 오고 있다. 이는 세포가 항암제에 내성을 획득하게 되기 때문이며, 한 항암제에 내성을 획득하면 구조가 서로 다른 항암제에 대해서도 내성을 획득하는 것으로 알려져 있다. 이와 같이 암세포가 항암제 구조에 상관없이 비 특이적인 내성을 획득하는 것을 "다중약물내성 (다약제 내성, Multidrug Resistance: MDR)"이라 한다 (Gottesman et al., Nat Rev Cancer 2:48-58, 2002; Ambudkar et al.,Oncogene 22:7468-85, 2003). 이러한 암세포의 MDR 획득은 항암화학요법 실패의 가장 큰 원인 중 하나로 잘 알려져 있다. 항암제 내성은 크게 2가지로 분류될 수 있는데 하나는 약물에 세포내로 유입이 되지 못해 생기는 것이고, 또 다른 하나는 암세포 자체가 유전적 (genetic) 또는 후생유전적 (epigenetic) 변화에 의해 항암제에 대한 감수성이 떨어져 나타날 수 있는 것이다.Chemotherapy is well known as one of the most effective cancer treatment methods, but continuous administration of anticancer drugs has been pointed out as a cause of failure of chemotherapy. This is because cells acquire resistance to anticancer drugs, and if the resistance to one anticancer agent is obtained, resistance to anticancer drugs having different structures is known. As such, cancer cells acquire non-specific resistance regardless of the anticancer structure is referred to as "multidrug resistance (MDR)" (Gottesman et al., Nat Rev Cancer 2: 48-58, 2002). Ambudkar et al., Oncogene 22: 7468-85, 2003). MDR acquisition of these cancer cells is well known as one of the biggest causes of chemotherapy failure. Anticancer drug resistance can be broadly classified into two types, one is due to inflow of drugs into cells, and the other is that cancer cells themselves are susceptible to anticancer drugs due to genetic or epigenetic changes. This can appear apart.
암세포가 MDR을 획득하는 기전을 자세하게 살펴보면 크게 5가지 정도로 나눌 수 있다. 첫째, ATP-의존적 수송체와 같은 유출 펌프 (efflux pump)를 이용하여 세포 내 약물을 세포 외로 쉽게 유출시켜 세포 내 유효약물 농도보다 낮은 농도로 유지하여 내성을 유발하거나, 둘째, 약물 수송체 또는 엔도사이토시스를 통한 약물 유입 감소로 인하여 세포 내 유효약물농도가 유지되지 못해 내성이 발생하거나, 셋째, 세포 내로 유입된 약물의 대사를 촉진/불활성화시켜 약물내성을 유도하거나, 넷째, 약물에 의한 DNA 손상을 복구할 수 있는 시스템의 활성화로 약물의 작용을 무력화하여 내성을 발현시키거나, 다섯째, 약물에 의해 유도되는 세포사멸 (Apoptosis)을 억제할 수 있는 방어 체계 (NF-kB 신호전달과정 활성화, 세라마이드 농도 감소 등)의 활성화로 인하여 내성을 유발할 수 있다.Looking at the mechanism by which cancer cells acquire MDR in detail can be divided into five categories. First, efflux pumps, such as ATP-dependent transporters, can be used to easily drain intracellular drugs out of the cell to keep them at concentrations lower than the effective drug concentrations in the cell to induce resistance, or second, drug transporters or endo Tolerance occurs because the effective drug concentration in the cell is not maintained due to the reduction of drug inflow through cytosis. Third, the drug resistance is induced by promoting / inactivating the metabolism of the drug introduced into the cell. Activation of a system capable of repairing damage to neutralize the action of the drug to express resistance, or fifth, to activate a defense system (NF-kB signaling process activation, which can inhibit apoptosis induced by the drug, Resistance may be induced due to activation of ceramide concentrations, etc.).
이 중에서 약물 유출 펌프 과발현에 의한 암세포의 MDR 획득은 효과적인 치료를 위해 항암제를 고용량 투여해야 하는 문제를 발생하게 하고, 기존 항암제의 가장 큰 문제점인 골수 독성 (bone marrow toxicity)을 야기할 수 있다. 즉 항암화학요법제를 투여할 경우 암세포가 유출 펌프 과발현에 의해 내성을 획득하였을 경우 암세포는 항암제를 효과적으로 세포 외로 유출시켜 생존할 수 있으나, 골수에서는 유출 펌프 발현이 적어 항암제에 감수성이 높아져 세포사멸이 일어나고 골수 독성이 증가될 수 있다. 따라서 내성 발현에서 유출 펌프 과발현에 의한 내성이 가장 심각하고, 항암화학요법을 이용하여 암을 성공적으로 극복하기 위해서는 이를 극복할 수 있는 유출 펌프를 효과적으로 제어할 수 있거나, 유출 펌프에 상관없이 항암효과를 나타낼 수 있는 기술의 개발이 반드시 필요하다고 할 수 있다 (Gottesman et al., Nat Rev Cancer 2:48-58, 2002; Friedenberg et al., Cancer 106:830-8, 2006; Seiden et al., Gynecol Oncol 86:302-10, 2002).Among these, MDR acquisition of cancer cells by drug outflow pump overexpression may cause a problem of high doses of anticancer drugs for effective treatment, and may cause bone marrow toxicity, which is the biggest problem of conventional anticancer drugs. In other words, when the anticancer chemotherapeutic agent is administered and the cancer cells acquire resistance by overexpression of the effusion pump, the cancer cells can effectively survive by effluxing the anticancer agent to the outside of the cell, but in the bone marrow, the expression of the effusion pump is low, so the susceptibility to the anticancer agent is high, resulting in cell death. And bone marrow toxicity may be increased. Therefore, resistance by effusion pump overexpression is most severe in the expression of resistance, and in order to successfully overcome cancer using chemotherapy, it is possible to effectively control the effusion pump that can overcome it, or to have anticancer effects regardless of the effusion pump. It is imperative that the development of techniques that can be demonstrated (Gottesman et al., Nat Rev Cancer 2: 48-58, 2002; Friedenberg et al., Cancer 106: 830-8, 2006; Seiden et al., Gynecol) Oncol 86: 302-10, 2002).
약물 유출 펌프는 아미노산 염기서열 및 구조적 특징 등을 비교해 보면 ATP-결합 카세트 (ATP-binding cassette; ABC) 수송체 패밀리에 속하는 막단백질 (membrane protein)이다. 지금까지 사람에서 48개의 ABC 유전자가 확인되었고, 7개의 아형 (subfamily; ABCA-ABCG)으로 구분되고 있다. 이 중에서 약물수송과 관련된 ABC 수송체는 MDR1, MRP (multidrug-resistant protein)1~7, BSEP/SPGP, MXR/BCRP/ABC-P 등이 있다. 상기 약물수송 ABC 수송체는 약물의 구조와 상관없이 비특이적으로 세포내의 약물을 세포 외로 유출시키는 역할을 하며, 이는 MDR 발현에 가장 중요하게 작용하는 것으로 잘 알려져 있다 (Endicott et al., Annu Rev Biochem 58:137-71, 1989; Ambudkar et al., Annu Rev Pharmacol Toxicol 39:361-98, 1999; Gottesman et al., Nat Rev Cancer 2:48-58, 2002).The drug outflow pump is a membrane protein belonging to the ATP-binding cassette (ABC) transporter family by comparing amino acid sequences and structural features. To date, 48 ABC genes have been identified in humans and classified into seven subfamily (ABCA-ABCG). Among these, ABC transporters related to drug transport include MDR1, MRP (multidrug-resistant protein) 1-7, BSEP / SPGP, MXR / BCRP / ABC-P. The drug transporter ABC transporter is known to play a role in non-specifically outflow of intracellular drugs regardless of the structure of the drug, which is most important for MDR expression (Endicott et al., Annu Rev Biochem 58 : 137-71, 1989; Ambudkar et al., Annu Rev Pharmacol Toxicol 39: 361-98, 1999; Gottesman et al., Nat Rev Cancer 2: 48-58, 2002).
약물수송 ABC 수송체 중에서 가장 잘 알려져 있는 것은 ABCB1 (또는 MDR1) 유전자의 산물인 P-당단백질 (P-gp)이다. P-gp는 170 KDa의 12개의 막통과 도메인 (transmembrane domain)과 2개의 ATP 결합 부위를 가지고 있는 막 단백질로서 대부분의 항암제 (빈카 알카로이드 (vinca alkaloids), 택솔 (taxol), 에토포시드 (etoposide) 등)를 기질로 하여 세포 외로 유출하는 기능을 수행한다. P-gp의 막투과 도메인에 소수성의 약물 (중성 또는 양이온성 약물)이 결합하면 두 분자의 ATP가 가수분해하면서 P-gp의 형태적 변화가 유도되어 세포 외로 약물이 배출되게 된다 (Ambudkar et al., Annu Rev Pharmacol Toxicol 39:361-98, 1999). 따라서 P-gp의 넓은 범위의 기질 특이성 (broad substrate specificity)은 약물결합부위인 막투과 도메인의 다양한 약물과 결합할 수 있는 다형성 때문인 것으로 생각된다. 이와 더불어, MRP1 (multidrug-resistance-associated protein 1; ABCC1)도 MDR 발현에 중요하게 작용한다. MRP1은 주로 중성 또는 음이온성의 소수성 약물 및 글루타치온과 결합된 약물과 주로 결합하고 이를 배출하는 기능을 하고 있다 (Gottesman et al., Nat Rev Cancer 2:48-58, 2002).The best known among drug transport ABC transporters is P-glycoprotein (P-gp), a product of the ABCB1 (or MDR1) gene. P-gp is a membrane protein with 12 transmembrane domains of 170 KDa and two ATP binding sites. Most anti-cancer drugs (vinca alkaloids, taxol, etoposide) Etc.) as a substrate to perform the function of outflowing to the cell. Binding of hydrophobic drugs (neutral or cationic drugs) to the transmembrane domain of P-gp causes hydrolysis of the two molecules of ATP, leading to morphological changes of P-gp resulting in the release of the drug extracellularly (Ambudkar et al. , Annu Rev Pharmacol Toxicol 39: 361-98, 1999). Therefore, the broad substrate specificity of P-gp is thought to be due to the polymorphism that can bind to various drugs of the transmembrane domain, which is a drug binding site. In addition, MRP1 (multidrug-resistance-associated
화학요법제 치료 후에 암세포에서의 P-gp 발현 증가는 크게 두 가지 모델로 설명이 된다. 첫 번째로 모델은 "선택 및 과잉증식 모델(selection and expansion model)"로서 약 20년 전에 제안되었다. 즉, 암이 발생하면서 P-gp를 많이 발현하는 세포와 적게 발현하는 세포가 공존하게 되는데 화학요법제 치료과정에서 P-gp를 적게 발현하는 세포는 죽고, 대신 많이 발현하는 세포가 살아남는 "선택 (selection)" 과정을 거치게 되고 이후 P-gp 과발현 세포들이 "과잉증식 (expansion)"하여 항암제에 내성을 나타내는 과정으로 설명이 된다 (Goldie & Coldman, Cancer Res 44:3643-53, 1984). 두 번째 모델은 화학요법제가 직접 MDR1 유전자를 활성화 시켜 P-gp를 과발현 시키고 이를 통해 약물내성이 발현된다는 "활성화 모델 (activation model)"이다 (Abolhoda et al., Clin Cancer Res 19995:3352-6, 1999).Increased P-gp expression in cancer cells after chemotherapy treatment is largely explained by two models. First, the model was proposed about 20 years ago as a "selection and expansion model." In other words, as the cancer develops, cells expressing P-gp and cells expressing less coexist, while cells expressing less P-gp die during chemotherapy treatment. selection) and then P-gp overexpressing cells "expansion" to explain the anti-cancer resistance (Goldie & Coldman, Cancer Res 44: 3643-53, 1984). The second model is an "activation model" in which chemotherapeutic agents directly activate the MDR1 gene to overexpress P-gp and thereby express drug resistance (Abolhoda et al., Clin Cancer Res 19995: 3352-6, 1999).
최근 암 치료 효과를 증진시키기 위해 P-gp와 같은 배출펌프의 작용을 저해할 수 있는 물질을 개발하여 기존 항암제와 병용 투여함으로써 항암제에 대한 내성을 감소시키고, 항암제의 용량도 줄여 약에 대한 부작용을 감소시키는 방향으로의 연구가 활발하게 진행되고 있다. 이러한 내성 저해물질은 다약제 내성역전제 (MDR reversing agent), 화학감작제 (chemosensitizer) 또는 다약제 내성조절제 (MDR modulator)라 한다. 가장 먼저 개발된 다약제 내성역전제는 P-gp 억제제로 베라파밀 (verapamil)이며, 그 후 다양한 물질들이 많이 개발되어 사용되어 왔으나 세포독성으로 인한 다른 부작용이 발생하여 문제되고 있다. 또한 다중약물내성에 관한 특허를 살펴보면, 이미다졸 화합물 (대한민국 등록특허 제 0330698호, 0349500호), 크로몬 화합물 (대한민국 등록특허 제0580743호, 대한민국 공개특허 제2005-0034024호), 퀴놀린 화합물 (대한민국 등록특허 제0639163호, 대한민국 공개특허 제2006-0093554호), 피페라진-2,5-디온 화합물 (대한민국 공개특허 제1998-7000978, 제1998-700972호), 한국산 자생식물 중 번행초, 조릿대풀, 석송, 큰개불알풀 및 약모밀에 의한 항암제 감수성 증가 (대한민국 공개특허 제2006-0124453호), MDR 억제용 P-당단백질 170에 대한 백신 (대한민국 공개특허 제2006-0125676호) 및 MDR생성물에 대한 항체 (대한민국 공개특허 제1995-7000938호) 등이 있다. Recently, in order to enhance the effect of cancer treatment, we developed a substance that can inhibit the action of an exhaust pump such as P-gp and co-administer it with existing anticancer drugs to reduce the resistance to anticancer drugs, and reduce the dose of anticancer drugs to reduce the side effects of drugs. There is an active research in the direction of reducing. Such resistance inhibitors are called MDR reversing agents, chemosensitizers or MDR modulators. The first-developed multi-drug resistant inverter is verapamil as a P-gp inhibitor, and various substances have been developed and used since then, but other side effects due to cytotoxicity have occurred. In addition, looking at the patent on multi-drug resistance, imidazole compound (Korea Patent No. 0330698, 0349500), Chromone compound (Korea Patent No. 0580743, Korea Patent Publication No. 2005-0034024), quinoline compound (Korea) Korean Patent No. 0639163, Korean Laid-Open Patent Publication No. 2006-0093554), piperazine-2,5-dione compound (Korean Patent Publication No. 1998-7000978, 1998-700972), hungry vinegar, botanic herb among Korean native plants, Increasing anticancer drug susceptibility by trachea, larvae and vulgaris (Korean Patent No. 2006-0124453), vaccine against PDR glycoprotein 170 for MDR inhibition (Korean Patent No. 2006-0125676) and antibodies against MDR products (Korean Unexamined Patent Publication No. 195-7000938).
한편 상백피 (Morus alba L.) 는 뽕나무과의 뽕나무 (Morus alba L.) 또는 동속 식물의 뿌리껍질로 만든 약재로, 생김새는 반관상 또는 띠 모양을 이루고 가끔 가늘게 세로로 잘라져 있다. 바깥 면은 백색 또는 황갈색을 띠며 주피가 붙어 있는 것은 주피가 황갈색이고 떨어지기 쉬우며 가는 세로주름이 많으며 적갈색을 띤 피목이 있다. 가로로 자른 면은 흰색 또는 엷은 갈색이고 섬유성이며 안쪽 면은 어두운 황갈색이고 평탄하다. 다른 이름으로 상근백피(桑根白皮), 백상피(白桑皮)가 있으며 열매를 심이라고 한다. 상백피는 폐열로 인한 해수, 천식을 치료하며 이뇨 작용이 있다. 급성신우염, 허약성부종에 쓰이고 혈압강하 작용이 있으며 코피와 각혈에도 사용한다. 또한 유행성 간염 등에도 쓰인다. 약리작용은 진해, 이뇨, 혈압강하, 진정, 진통, 해열, 진경, 항균작용 등이 보고되었다. 그러나 상백피의 생리활성으로서 다중약물내성 억제제로서의 연구 결과는 보고되어 있지 않다. Morus alba L., on the other hand, is a medicinal herb made from the mulberry of Morus alba L. or the same plant's root bark. The appearance is semi-tubular or band-shaped, sometimes thinly and vertically cut. The outer surface is white or yellowish brown, and attached to the main skin is the main skin is yellowish brown, easy to fall off, and there are many fine vertical wrinkles, and the reddish brownish skin. The side cut horizontally is white or light brown, fibrous, and the inner side is dark yellow brown and flat. Another name is erectus baekpi (桑根 白皮), white baekpi (白 桑皮) and the fruit is called sim. Epidermis pelvis treats seawater and asthma caused by waste heat and has diuretic effect. It is used for acute pyelonephritis and fragile edema and has a blood pressure-lowering effect. It is also used for epidemic hepatitis. Pharmacological action is reported by Jinhae, diuresis, lowering blood pressure, sedation, analgesic, fever, jingyeong, antibacterial action. However, the results of research as a multidrug resistance inhibitor as a bioactive activity of the epidermis are not reported.
이에, 본 발명자들은 항암화학요법의 가장 큰 실패요인인 MDR 현상을 극복하고, 세포독성으로 인한 다른 부작용을 방지하기 위하여 천연물 (식물 및 생약)로부터 새로운 다중약물내성 억제용 조성물을 연구하던 중, 상백피 추출물이 P-당단백질 (P-glycoprotein)발현을 억제하고, MDR1 유전자의 발현을 억제하여 다중약물내성 암세포주에서 항암제에 대한 민감도를 높여주는 것을 확인함으로써 본 발명을 완성하였다.
Thus, the present inventors while studying a new multi-drug resistance inhibiting composition from natural products (plants and herbs) in order to overcome the MDR phenomenon which is the biggest failure of chemotherapy and prevent other side effects due to cytotoxicity, The present invention was completed by confirming that the extract inhibits P-glycoprotein expression and inhibits the expression of the MDR1 gene to increase the sensitivity to anticancer drugs in multi-drug resistant cancer cell lines.
본 발명의 목적은 항암화학요법의 문제점인 다중약물내성을 극복하기 위하여, 다중약물내성 암세포주에서 항암제에 대한 민감도를 높여주는 다중약물내성 억제용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for inhibiting multi-drug resistance to increase the sensitivity to anti-cancer drugs in multi-drug resistant cancer cell lines, in order to overcome the multi-drug resistance of the chemotherapy.
본 발명의 또 다른 목적은 항암화학요법의 문제점인 다중약물내성을 극복하기 위하여 다중약물내성 암세포주에서 항암제에 대한 민감도를 높여주는 항암제 보조용 약학적 조성물을 제공하는 것이다. It is another object of the present invention to provide a pharmaceutical composition for adjuvant anticancer drugs that increases the sensitivity to anticancer drugs in multidrug resistant cancer cell lines in order to overcome the multidrug resistance that is a problem of chemotherapy.
본 발명의 또 다른 목적은 항암화학요법의 문제점인 다중약물내성을 극복하기 위하여 다중약물내성 암세포주에서 항암제에 대한 민감도를 높여주는 항암제 보조용 식품학적 조성물을 제공하는 것이다.
Another object of the present invention to provide a pharmaceutical composition for adjuvant anticancer agent to increase the sensitivity to anticancer agents in multi-drug resistant cancer cell line in order to overcome the multi-drug resistance of the chemotherapy.
상기 과제를 해결하기 위해 본 발명은 상백피 추출물을 유효성분으로 포함하는 다중약물 내성 억제용 조성물을 제공한다. In order to solve the above problems, the present invention provides a composition for inhibiting multi-drug resistance, which comprises an extract of lettuce extract as an active ingredient.
또한 본 발명은 상백피 추출물을 유효성분으로 포함하는 항암 보조용 약학적 조성물을 제공한다. In another aspect, the present invention provides an anticancer adjuvant pharmaceutical composition comprising an extract of lettuce extract as an active ingredient.
또한 본 발명은 상백피 추출물을 유효성분으로 포함하는 항암 보조용 식품학적 조성물을 제공한다.
In another aspect, the present invention provides an anticancer adjuvant composition comprising an extract of lettuce extract as an active ingredient.
본 발명의 조성물은 항암제에 내성을 나타내는 다중약물내성 (Multidrug resistance, MDR) 세포에서 P-당단백질 (P-glycoprotein)에 의한 다중약물내성 억제 활성이 매우 우수하여 항암 약물 내성을 가진 암환자의 치료에 사용될 수 있는 조성물로 개발될 수 있다.
The composition of the present invention is very excellent in multidrug resistance inhibitory activity by P-glycoprotein in multidrug resistance (MDR) cells that are resistant to anticancer drugs, thereby treating cancer patients with anticancer drug resistance. It can be developed into a composition that can be used in.
도 1은 정상 암세포인 KB 세포주와 다중약물내성 암세포인 KB/VB20 세포주 및 대조군으로 A549 세포주와 Caco-2 세포주에서 MDR1의 발현 여부를 확인한 그림이다.
도 2은 상백피 추출물의 Rhodamine 123 assay 결과이다.
도 3는 상백피 추출물이 P-당단백질 (P-glycoprotein)의 발현에 미치는 영향을 분석한 그림이다.
도 4는 상백피 추출물이 MDR1의 유전자 발현에 미치는 영향을 분석한 그림이다.
도 5은 상백피 추출물이 YB-1 유전자 발현에 미치는 영향을 분석한 그림이다.
도 6은 상백피 추출물이 다중약물내성 암세포에서 항암제인 빈블라스틴 (vinblastine)의 민감도에 미치는 영향을 분석한 그림이다. 1 is a diagram confirming the expression of MDR1 in A549 cell line and Caco-2 cell line as a normal cancer cell KB cell line and multi-drug resistant cancer cell KB / VB20 cell line and control group.
Figure 2 shows the results of Rhodamine 123 assay of the extract of lettuce.
Figure 3 is an analysis of the effect of the extract of P. erythropoietin on the expression of P-glycoprotein.
Figure 4 is a figure analyzing the effect of the extract of M. vulgaris on the gene expression of MDR1.
Figure 5 is a figure analyzing the effect of the baekpipi extract on YB-1 gene expression.
Figure 6 is an analysis of the effect of the extract of baekhyeolpi on the sensitivity of the anticancer drug vinblastine (multiblast-resistant cancer cells).
이하 본 발명에 대하여 보다 상세히 설명한다. Hereinafter, the present invention will be described in more detail.
본 발명은, 상백피 추출물을 유효성분으로 포함하는 다중약물 내성 억제용 조성물을 제공한다. The present invention provides a composition for inhibiting multi-drug resistance, which comprises an extract of lettuce extract as an active ingredient.
또한 본 발명은 상백피 추출물을 유효성분으로 포함하는 항암 보조용 약학적 조성물을 제공한다. In another aspect, the present invention provides an anticancer adjuvant pharmaceutical composition comprising an extract of lettuce extract as an active ingredient.
또한 본 발명은 상백피 추출물을 유효성분으로 포함하는 항암 보조용 식품학적 조성물을 제공한다. In another aspect, the present invention provides an anticancer adjuvant composition comprising an extract of lettuce extract as an active ingredient.
본 발명의 상백피 추출물은 하기와 같이 수득될 수 있다. The lettuce extract of the present invention can be obtained as follows.
상백피 (Morus alba L.)을 물로 세척하여 이물질을 제거한 후 그늘에서 건조하고 분쇄한다. 상백피는 재배한 것 또는 시판되는 것 등 제한 없이 사용할 수 있다. 분쇄된 상백피에 적당한 양의 용매를 첨가하여 완전히 침지되도록 한다. 추출용매로는 물, 탄소수 1내지 4의 저급 알코올 또는 이들의 혼합용매로부터 선택된 용매가 바람직하며, 보다 바람직하게는80% 에탄올이다. 다음 상기에서 얻은 상백피 추출물을 여과한 후 감압 농축하여 최종 추출물을 수득한다. Morus alba L. is washed with water to remove debris, dried in the shade and crushed. Morus bark can be used without limitation, such as cultivated or commercially available. Appropriate amount of solvent is added to the ground chlorophyll to ensure complete immersion. The extraction solvent is preferably a solvent selected from water, a lower alcohol having 1 to 4 carbon atoms or a mixed solvent thereof, more preferably 80% ethanol. Next, the extract obtained from the above extracts was filtered and concentrated under reduced pressure to obtain a final extract.
본 명세서에서 사용되는 용어 " 다중약물내성 (multidrug resistance)"는 세포 특히 특정 질병 유발 세포가 매우 다른 화학 구조를 갖는 다양한 약물들 또는 화합물들에 대해 내성을 갖는 특성을 의미한다. 본 발명의 바람직한 구현예에 따르면, 상기 다중약물내성은 P-당단백질 (P-glycoprotein)에 의한 다중약물내성이다.As used herein, the term "multidrug resistance" refers to the property that cells, especially certain disease causing cells, are resistant to various drugs or compounds with very different chemical structures. According to a preferred embodiment of the present invention, the multi-drug resistance is multi-drug resistance by P-glycoprotein.
본 명세서에서 사용되는 용어 "P-당단백질 (P-glycoprotein)"은 ATP-결합 카세트 (ATP-binding cassette, ABC)를 갖는 세포막에 존재하는 수송단백질 (transporter protein)의 일종을 의미하고, 상기 P-당단백질은 약물과 결합하여 ATP를 에너지원으로 사용하는 능동적 수송 기작에 약물을 세포 밖으로 방출시켜 세포에 약물내성을 부여한다. 특히, 암세포에서 발현되는 P-당단백질은 항암 약물에 대한 내성을 증가시켜 항암치료 효능을 현저히 떨어뜨리는 것으로 알려져 있다.As used herein, the term "P-glycoprotein" refers to a kind of transporter protein present in a cell membrane having an ATP-binding cassette (ABC), and said P-glycoprotein. Glycoproteins bind drugs and release drugs out of the cell, giving them drug resistance to active transport mechanisms that use ATP as an energy source. In particular, P-glycoproteins expressed in cancer cells are known to increase resistance to anticancer drugs, thereby significantly reducing anticancer efficacy.
본 발명의 다중약물내성을 나타내는 약물은 예를 들어, 빈카 알카로이드 (vinca alkaloids) 계열의 빈블라스틴 (vinblastine), 빈크리스틴 (vincristine) 및 나벨빈 (navelbine); 탁산스 (taxanes) 계열의 파클리탁셀 (paclitaxel;TAX), 탁소테르 (taxotere); 안트라사이클린 (anthracyclines) 계열의 독소루비신 (doxorubicin), 다우노루비신 (daunorubicin), 에피루비신 (epirubicin) 및 이다루비신 (idarubicin); 에피포도필로톡신 (epipodophyllotoxins) 계열 약물인 에토포시드 (etoposide) 및 테니포시드 (teniposide); 콜히친 (colchicine), 미톡산트론 (mitoxantrone), 닥티노마이신 (dactinomycin), 토포테칸 (topotecan), 트리메트렉스산 (trimetrexate), 미트라마이신 (mithramycin), 미토마이신 C (mitomycin C)의 기타 약물을 포함하지만, 이에 한정되지 않는다.Drugs exhibiting multidrug resistance of the present invention include, for example, vinblastine, vincristine and navelbine of the vinca alkaloids family; Paclitaxel (TAX) of the taxanes family, taxotere; Doxorubicin, daunorubicin, epirubicin and idarubicin of the anthracyclines family; Epipodophyllotoxins family drugs etoposide and teniposide; Other drugs such as colchicine, mitoxantrone, dactinomycin, topotecan, trimetrexate, mithramycin, mitomycin C Including but not limited to.
본 발명의 조성물의 상기 다중약물내성 억제 효능은 암 세포에서의 다중약물내성 억제 효능인 것을 특징으로 한다.The multidrug resistance inhibitory effect of the composition of the present invention is characterized in that the multi-drug resistance inhibitory effect in cancer cells.
상기 암세포에서의 암은 예를 들어, 구강암 (oral cancer), 위암 (stomach cancer), 폐암 (lung cancer), 유방암 (breast cancer), 난소암 (ovarian cancer), 간암 (liver cancer), 기관지암 (bronchogenic cancer), 비인두암 (nasopharyngeal cancer), 후두암 (laryngeal cancer), 췌장암 (pancreatic cancer), 방광암 (bladder cancer), 대장암 (colon cancer), 자궁경부암 (uterine cervical cancer), 뇌암 (brain cancer), 전립선암 (prostate cancer), 골암 (bone cancer), 피부암 (skin cancer), 갑상선암 (thymus cancer), 부갑상선암 (parathyroid cancer), 신장암 (renal cancer) 또는 요관암을 포함하지만, 이에 한정되지 않는다. Cancer in the cancer cells may be, for example, oral cancer, stomach cancer, lung cancer, breast cancer, ovarian cancer, liver cancer, bronchial cancer ( bronchogenic cancer, nasopharyngeal cancer, laryngeal cancer, pancreatic cancer, bladder cancer, colon cancer, uterine cervical cancer, brain cancer, Prostate cancer, bone cancer, skin cancer, thymus cancer, thymus cancer, parathyroid cancer, renal cancer or ureter cancer.
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물의 유효량은 본 발명의 조성물 총 중량에 대하여 상기 상백피 추출물인 유효성분을 0.001 내지 50 중량%로 포함하는 것을 특징으로 한다. 또한, 본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물은 상기 유효성분에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 함유할 수 있다. 또한 단독으로 또는 타약학적 활성 화합물, 예를 들어, 당업계에 잘 알려진 항암제들, 즉, 빈블라스틴 (vinblastine), 아드리아마이신 (adriamycin), 사이클로포스파마이드 (cyclophosphamide), 5-FU, 암사크린 (amsacrine), 도노마이신 (daunomycin), 탁솔 (taxol) 등의 기존 항암제들과의 결합뿐만 아니라 적당한 조합으로 기존 항암제에 대한 다중약물내성을 갖는 암세포의 성장을 억제하기 위한 항암 보조제로 사용될 수 있다.The effective amount of the multi-drug resistant composition of the present invention and the anticancer agent-assisted composition is characterized in that it comprises 0.001 to 50% by weight of the active ingredient of the lettuce extract, based on the total weight of the composition of the present invention. In addition, the composition for suppressing multiple drug resistance and the composition for assisting an anticancer agent according to the present invention may further contain one or more active ingredients which exhibit the same or similar functions in addition to the above-mentioned effective ingredients. Also alone or as a pharmacologically active compound, for example, anticancer agents well known in the art, ie vinblastine, adriamycin, cyclophosphamide, 5-FU, amsacrine It can be used as an anticancer adjuvant for inhibiting the growth of cancer cells having multidrug resistance to existing anticancer agents as well as binding to existing anticancer agents such as amsacrine, daunomycin, and taxol.
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물에 포함되는 유효성분 화합물의 농도는 치료 목적, 환자의 상태, 필요기간 등을 고려하여 결정할 수 있으며 특정 범위의 농도로 한정되지 않는다. The concentration of the active ingredient compound included in the multi-drug resistant composition and the anticancer adjuvant composition of the present invention may be determined in consideration of the purpose of treatment, the condition of the patient, the period of time required, etc., and is not limited to a specific range of concentration.
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물은 투여를 위해서 상기 기재한 유효성분 이외에 추가로 약제학적으로 허용 가능한 담체를 1종 이상 포함하여 제조할 수 있다. 본 발명의 약학적 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다. The composition for inhibiting multi-drug resistance of the present invention and the composition for adjuvant anticancer agent may be prepared by additionally containing one or more pharmaceutically acceptable carriers in addition to the above-described active ingredients for administration. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 약학적 조성물의 경구 투여량은 바람직하게는 1일 당 0.001-100 mg/kg(체중)이다.Suitable dosages of the multi-drug resistant composition of this invention and the anticancer adjuvant composition are formulated with the method of administration, mode of administration, age, weight, sex, morbidity, food, time of administration, route of administration, rate of excretion and response of the patient. It can be prescribed in various ways by the same factors. On the other hand, the oral dosage of the pharmaceutical composition of the present invention is preferably 0.001-100 mg / kg (body weight) per day.
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 정맥 내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. 본 발명의 약학적 조성물은 적용되는 질환의 종류에 따라, 투여 경로가 결정되는 것이 바람직하다.The multi-drug resistant composition and anticancer adjuvant composition of the present invention may be administered orally or parenterally, and when administered parenterally, may be administered by intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, or the like. have. It is preferable that the route of administration of the pharmaceutical composition of the present invention is determined according to the type of the disease to be applied.
본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다. The composition for inhibiting multi-drug resistance of the present invention and the composition for adjuvant anticancer agent may be prepared by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those skilled in the art. Can be prepared in unit dose form or incorporated into a multi-dose container. The formulations may be in the form of solutions, suspensions or emulsions in oils or aqueous media, or in the form of excipients, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
또한 본 발명의 다중약물내성 억제용 조성물 및 항암제 보조용 조성물은 식품학적으로 허용되는 담체와 함께 식품 조성물로 제공될 수 있다. In addition, the composition for inhibiting multi-drug resistance of the present invention and the composition for adjuvant anticancer agent may be provided as a food composition together with a food acceptable carrier.
본 발명에 따른 식품 조성물은 상기 약제학적 조성물과 동일한 방식으로 제제화되어 기능성 식품으로 이용하거나, 각종 식품에 첨가할 수 있다. 본 발명의 조성물을 첨가할 수 있는 식품으로는 예를 들어, 음료류, 육류, 초콜릿, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류, 알코올 음료류, 비타민 복합제, 건강보조식품류 등이 있다.The food composition according to the present invention can be formulated in the same manner as the above 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, ice creams, alcoholic beverages, vitamin complexes, health supplements, and the like. .
식품 또는 음료 중의 상백피 추출물의 양은 전체 식품 중량의 0.01 내지 15 중량%로 가할 수 있으며, 건강 기능성 음료 조성물은 100㎖를 기준으로 0.02 내지 10g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.The amount of lettuce extract in the food or beverage may be added at 0.01 to 15% by weight of the total food weight, the health functional beverage composition may be added in a ratio of 0.02 to 10g, preferably 0.3 to 1g based on 100ml.
본 발명의 식품 조성물은 유효성분인 상백피 추출물을 함유하는 것 외에 통상의 식품 조성물과 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올이다. 상술한 향미제는 천연 향미제 (타우마틴), 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제 (사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. The food composition of the present invention may contain, as an additional ingredient, various flavors or natural carbohydrates, as well as ordinary food compositions, in addition to the extract of an extract of an active ingredient. 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 conventional sugars such as polysaccharides such as dextrin, cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. The aforementioned flavoring agents can advantageously be used natural flavoring agents (tautin), stevia extracts (for example rebaudioside A, glycyrzin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.).
또한 상기 식품 조성물은 상백피 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 주스 및 과일 주스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition, the food composition is a variety of nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavoring agents, colorants and neutralizing agents (such as cheese, chocolate), pectic acid and salts thereof, alginic acid Salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonation agents used in carbonated drinks, and the like. In addition, the food composition of the present invention may contain natural fruit juice and fruit flesh for the production of fruit juice beverages and vegetable beverages.
본 발명의 유효성분인 상백피 추출물은 천연물질로서 독성 및 부작용은 거의 없으므로 장기간 복용 시에도 안심하고 사용할 수 있다.
As an active ingredient of the present invention, baekbaekpi extract is a natural substance with little toxicity and side effects, so can be used with confidence even in long-term use.
이하 본 발명을 실시예에 의해 상세히 설명한다. 하기 실시예는 본 발명을 예시하기 위 한 것일 뿐 본 발명이 하기 실시예에 의해 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail by way of examples. The following examples are only intended to illustrate the invention and the invention is not limited by the following examples.
실험예Experimental Example 1. 한약재 추출물의 제조 1. Preparation of Herbal Extracts
상백피를 100g 정량 후 80 % 에탄올을 가하여 30분 동안 2회에 걸쳐 초음파진동을 이용하여 획득하였다. 다시 추출액은 지름 185mm 종이여과지 (Whatman, Maidstone, England)를 이용하여 감압 여과 하였다. 그 후 감압 농축기 (Eyela, Japan)를 사용하여 농축한 다음, 동결 건조기 (Freezedryer, Matsushita, Japan)로 동결 건조하여 얻은 분말을 DMSO에 녹여 vortexing한 후 원심분리하여 녹지 않은 물질은 제거한 후 실험에 사용하였다.
After weighing 100g of baekryepi, 80% ethanol was added and obtained by ultrasonic vibration twice over 30 minutes. The extract was filtered under reduced pressure using a 185 mm diameter paper filter (Whatman, Maidstone, England). After concentrating using a vacuum concentrator (Eyela, Japan), and then freeze-dried (Freezedryer, Matsushita, Japan), the powder obtained by dissolving in DMSO vortexing and centrifuged to remove the undissolved material used in the experiment It was.
실험예Experimental Example 2. 2. KBKB /Of VB20VB20 세포주에서 In cell lines MDR1MDR1 발현 분석 Expression analysis
실험에 사용한 사람 상피 세포주 KB는 한국 세포주 은행 (Korean Cell Line Bank, Korea)을 통하여 구입하였으며, 빈블라스틴 (vinblastine) 20nM에 저항성을 지닌 KB 세포주 (KB/VB20)는 성균관대학교 이동권 교수님께 분양 받았다. KB 세포주는 RPMI1640, KB/VB20세포주는 DMEM (Wellgene) 배지에 5% (v/v) 혈청 (heat-inactivated fetal bovine serum (Wellgene)과 1% 항생제 (antibiotic-antimycotic, (Gibco BRL))를 넣어 5% CO2가 든 37 ℃ humidified incubator에서 배양하였다. The human epithelial cell line KB used for the experiment was purchased through the Korean Cell Line Bank (Korea), and the KB cell line (KB / VB20) resistant to vinblastine 20nM was directed to Prof. Dong Kwon Lee of Sungkyunkwan University. I was sold. KBI cell line contains RPMI1640 and KB / VB20 cell line with 5% (v / v) heat-inactivated fetal bovine serum (Wellgene) and 1% antibiotic (antibiotic-antimycotic (Gibco BRL)) in DMEM (Wellgene) medium. The cells were incubated in a 37 ° C. humidified incubator with 5% CO 2 .
본 실험에 사용한 KB/VB20 세포의 MDR1 과발현 여부를 확인하기 위하여 KB 세포주, KB/KV20 세포주, 대조군으로 A549 세포주, Caco-2 세포주를 이용하여 RT-PCR을 수행하였다. 그 결과, 도 1에 나타낸 바와 같이 KB 세포주에서는 MDR1이 발현되지 않았지만. KB/VB20세포주에서는 MDR1이 과발현 되어 있는 것을 확인할 수 있었다. 따라서 이하 실험에서는 상기 KB/VB20 세포주를 다중 약물 내성 세포주로 이용하였다.
RT-PCR was performed using KB cell line, KB / KV20 cell line, A549 cell line and Caco-2 cell line as a control to confirm MDR1 overexpression of KB / VB20 cells used in this experiment. As a result, although MDR1 was not expressed in KB cell line as shown in FIG. In the KB / VB20 cell line, MDR1 was overexpressed. Therefore, in the following experiment, the KB / VB20 cell line was used as a multi-drug resistant cell line .
실험예Experimental Example
3. 3.
Rhodamine
Rhodamine 123은 P-gp에 의해 세포 안과 밖 사이를 이동할 수 있는 형광 물질로, 세포 안에 축적된 이 약물을 유세포분석기 (FACS Calibur, Becton Dickinson)를 이용하여 측정함으로써 P-gp의 발현 정도를 유추하는 지표가 된다. 즉, 세포 내에 이 물질의 축적 정도가 높으면 P-gp 발현량이 적기 때문에 세포 안으로 들어가는 양이 많아지고, 반대로 축적 정도가 낮으면 P-gp 발현량이 많아 이 물질이 세포막 바깥으로 배출된 것을 의미한다. KB와 KB/VB20 세포주 둘 다 6 well plate에 1x106 과 1.5x106 cells/well이 되도록 준비한 후 1시간 동안 약재를 전처리 한 다음 rhodamine 123 (2.5 uM)만 넣거나 P-gp 억제제의 하나인 니카르디핀 (Nicardipine, NCD, 12.5 uM)을 동시에 넣어 한 시간 더 배양하였다. 다음으로 스크래퍼를 이용하여 세포를 모아 차가운 PBS로 두 번 세척한 후, 다시 300 ml의 PBS에 부유시켜 유세포 분석을 하였다. 약재 추출물에 의한 P-gp 기능의 억제 정도는 아래 식을 이용하여 비교함으로써 측정하였다.
% of control activity = Fluorescence sample/Fluorescence control x 100% of control activity = Fluorescence sample / Fluorescence control x 100
(여기서, Fluorescence sample은 천연 추출물이나 약물 처리 후 측정한 형광 정도, Fluorescence control은 rhodamine123만을 처리 한 후 측정한 형광 정도를 나타낸다.)(Fluorescence sample is the fluorescence level measured after treatment with natural extract or drug. Fluorescence control is the fluorescence level after rhodamine123 treatment only.)
KB 세포주와 KB/VB20 세포주에서 상백피 추출물을 각각 25, 50, 100 ㎍/㎖ 농도별로 처리한 후 Rhodamine 123 assay를 하였다. 그 결과 KB 세포주에서는 농도에 따른 차이가 없었지만, KB/KV20 세포주에서는 상백피 추출물에서 농도에 따라 Rhodamine 123 물질을 세포 밖으로 배출하는 능력이 증가하는 것 이 관찰되었다 (도 2). 이를 통해 상백피 추출물이 P-gp의 기능 억제 활성이 있음을 확인할 수 있었다.
In the KB cell line and KB / VB20 cell line, the extracts were treated with 25, 50 and 100 ㎍ / mL concentrations, respectively, and then
실험예Experimental Example 4. P- 4. P- glycoproteinglycoprotein 과 and MDR1MDR1 유전자의 발현 분석 Gene expression analysis
Rhodamine 123 물질을 세포 밖으로 배출하는 능력이 단백질 단계에서 조절되는지 확인하기 위해, 약재 50 ㎍/㎖을 2시간 동안 처리 한 후 샘플을 얻어 웨스턴 블랏 (western blot)을 통해 내성억제 단백질인 P-glycoprotein을 양을 확인하였다. 그 결과 도 3에 나타낸 바와 같이, P-glycoprotein 단백질은 KB 세포주에서는 발현 되지 않았으며, 오직 KB/VB20 세포주에서만 발현되었다 (도 3A). 또한 KB/VB20 세포주에서는 대조군인 P-glycoprotein 저해제로 알려진 니카르디핀 (Nicardipine, NCD) 및 상백피 추출물을 처리한 군에서 P-glycoprotein을 억제하는 것을 관찰하였다 (도 3B). To determine if the ability to release the
또한, 상백피 추출물이 P-glycoprotein을 코딩하는 MDR1 유전자 발현 단계에도 영향을 미치는지 확인하기 위하여, 50 ㎍/㎖ 농도의 상백피 추출물을 각 세포주에 2시간 동안 처리하여 얻은 mRNA로 RT-PCR을 수행하였다. 도 4에 나타낸 바와 같이, MDR1 유전자 발현은 KB 세포주에서는 발현이 안되었으며 KB/VB20 세포주에서만 발현되었다 (도 4A) 또한, KB/VB20 세포주에서 양성대조군인 니카르디핀 및 상백피 추출물 처리군에서 MCD 유전자 발현이 억제되는 것을 확인하였다 (도 4B).
In addition, RT-PCR was performed with mRNA obtained by treating each cell line with an extract of 50 ㎍ / mL concentration for 2 hours in order to confirm whether the extracts of the epidermis extract affected the MDR1 gene expression step encoding P-glycoprotein. As shown in FIG. 4, MDR1 gene expression was not expressed in KB cell line but expressed only in KB / VB20 cell line (FIG. 4A). In addition, MCD gene in the treatment group of nicardidipine and epithelium extract, which was positive control in KB / VB20 cell line, was shown. It was confirmed that expression was suppressed (FIG. 4B).
실험예Experimental Example 5. 5. YBYB -1 단백질의 발현 분석Expression Analysis of -1 Proteins
Y-box-binding protein-1 (YB-1)은 conserved nucleic acid에 결합하는 단백질 중의 하나로 전사와 번역을 조절하고, DNA에 손상을 입었을 때 복구 시스템을 증가 시키는 등의 역할을 한다. 또한 YB-1의 타겟 유전자 중의 하나로 알려진 MDR1 유전자를 조절함으로써, P-gp의 발현을 조절하는 것으로 알려져 있다. Y-box-binding protein-1 (YB-1) is a protein that binds to conserved nucleic acid, regulates transcription and translation, and increases the repair system in the event of DNA damage. It is also known to regulate the expression of P-gp by regulating the MDR1 gene, which is known as one of the target genes of YB-1.
내성억제 기작이 P-glycoprotein 발현 조절을 조절하는 것으로 알려진 Y-box binding protein-1 (YB-1) 단백질의 발현단계를 조절하는지 western blot을 통해 확인하였다. 도 5에 나타낸 바와 같이, 양성대조군인 니카르디핀 및 상백피 추출물 처리군에서 YB-1 단백질의 발현이 감소된 것을 확인하였다.
It was confirmed by western blot whether resistance inhibition mechanism regulates the expression level of Y-box binding protein-1 (YB-1) protein, which is known to regulate P-glycoprotein expression regulation. As shown in Figure 5, it was confirmed that the expression of YB-1 protein in the positive control group nicardipine and lettuce extract treatment group was reduced.
실험예Experimental Example 6. 6. vinblastinevinblastine 에 대한 민감도 변화 분석Sensitivity change analysis for
상백피 추출물이 KB 세포주와 KB/VB20 세포주에서 항암제 중 하나인 빈블라스틴 (vinblastine)에 대한 민감도를 높여주는지 확인하기 위해 MTT assay를 통해 세포 증식도를 측정하였다. MTT assay는 MTS 혼합액 ((3-(4,5-dimethylthiazol-2-yl)-5, 3-carboxymethoxyphenyl )-2-(4-sulfophenyl)-2H-tetrazolium, inner salt)와 an electron coupling reagent (phenazine methosulfate; PMS))이 살아있는 세포의 미토콘드리아에 있는 숙신산 탈수소효소 (succinic dehydrogenase)라는 효소를 환원시켜 생성하는 수용성 포르마잔 (formazan)의 농도를 측정함으로써 생존한 세포수를 측정하는 실험이다. Cell proliferation was measured by MTT assay to determine whether the extract of E. coli increased the sensitivity to vinblastine, one of anticancer drugs, in KB and KB / VB20 cell lines. MTT assay was performed with MTS mixture ((3- (4,5-dimethylthiazol-2-yl) -5, 3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2 H -tetrazolium, inner salt) and an electron coupling reagent ( phenazine methosulfate (PMS)) is an experiment that measures the number of surviving cells by measuring the concentration of water-soluble formazan produced by reducing an enzyme called succinic dehydrogenase in the mitochondria of living cells.
상백피 추출물을 KB/VB20 세포주에 2시간 동안 전 처리 한 후, 빈블라스틴 (vinblastine)을 농도별 (0?100 nM)로 48 시간 동안 처리하여 세포증식 정도를 측정하였다. 도 6에 나타낸 바와 같이 니카르디핀 보다 상백피 추출물이 빈블라스틴의 낮은 농도에서 그 민감도를 높여주는데 효과가 있음을 보여주었다. 이를 통해 상백피 추출물이 다중약물내성 세포에서 항암제의 민감성을 높여주어, 다중약물내성 억제용 조성물로 이용될 수 있음을 확인하였다.
After the epidermis extract was pre-treated with KB / VB20 cell line for 2 hours, vinblastine was treated for 48 hours at different concentrations (0-100 nM) to measure the degree of cell proliferation. As shown in FIG. 6, it was shown that the extract of Morus alba L. on the lower concentration of vinblastine was effective in increasing its sensitivity than the nicardipine. Through this, it was confirmed that the extract of S. pellucida increased the sensitivity of the anticancer agent in multi-drug resistant cells, and thus could be used as a composition for inhibiting multi-drug resistance.
이하 본 발명의 상기 조성물을 함유하는 약학적 조성물 및 식품 조성물의 제제예를 설명하나, 본 발명은 이를 한정하고자 함이 아닌 단지 구체적으로 설명하고자 함이다.
Hereinafter, the preparation examples of the pharmaceutical composition and the food composition containing the composition of the present invention, but the present invention is not intended to limit it, only intended to explain in detail.
제제예Formulation example 1. 약학적 조성물의 제조 1. Preparation of pharmaceutical composition
1-1. 1-1. 산제의Sanje 제조 Produce
상백피 추출물2gMorus Extract 2g
유당 1g1g lactose
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above components were mixed and packed in airtight bags to prepare powders.
1-2. 정제의 제조1-2. Manufacture of tablets
상백피 추출물100mgMorus Extract 100mg
옥수수전분 100mgCorn Starch 100mg
유당 100mgLactose 100mg
스테아린산 마그네슘 2mg2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
1-3. 캡슐제의 제조1-3. Preparation of capsules
상백피 추출물100mgMorus Extract 100mg
옥수수전분 100mgCorn Starch 100mg
유당 100mgLactose 100mg
스테아린산 마그네슘 2mg2 mg magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsule was prepared by filling in gelatin capsules according to the conventional method for producing a capsule.
1-4. 주사제의 제조1-4. Injection preparation
상백피 추출물 100 ㎎100 mg of lettuce extract
만니톨 180 ㎎, Mannitol 180 mg,
Na2HPO412H2O 26 ㎎ Na2HPO412H2O 26 mg
증류수 2974 ㎎Distilled water 2974 mg
상기의 성분을 혼합한 후, 통상의 제조방법에 따라서 주사제를 제조하였다.After the above ingredients were mixed, injections were prepared according to a conventional production method.
제제예Formulation example 2. 식품 조성물의 제조 2. Preparation of Food Composition
2-1. 건강기능식품의 제조 2-1. Preparation of health functional food
상백피 추출물 100 mg100 ml of lettuce extract
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70 μg Vitamin A acetate 70 μg
비타민 E 1.0 mgVitamin E 1.0 mg
비타민 B1 0.13 mgVitamin B1 0.13 mg
비타민 B2 0.15 mgVitamin B2 0.15 mg
비타민 B6 0.5 mgVitamin B6 0.5 mg
비타민 B12 0.2 μg Vitamin B12 0.2 μg
비타민 C 10 mg
비오틴 10 μg Biotin 10 μg
니코틴산아미드 1.7 mgNicotinamide 1.7 mg
엽산 50 μg
판토텐산 칼슘 0.5 mgCalcium pantothenate 0.5 mg
무기질 혼합물 적량Mineral mixture
황산제1철 1.75 mgFerrous Sulfate 1.75 mg
산화아연 0.82 mgZinc Oxide 0.82 mg
탄산마그네슘 25.3 mgMagnesium carbonate 25.3 mg
제1인산칼륨 15 mg15 mg potassium monophosphate
제2인산칼슘 55 mgDicalcium Phosphate 55 mg
구연산칼륨 90 mgPotassium Citrate 90 mg
탄산칼슘 100 mg
염화마그네슘 24.8 mgMagnesium chloride 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
2-2. 2-2. 건강음료의Health drink 제조 Produce
상백피 추출물 100 mg100 ml of lettuce extract
비타민 C 15 g15 g of vitamin C
비타민 E(분말) 100 gVitamin E (powder) 100 g
젖산철 19.75 g19.75 g of ferrous lactate
산화아연 3.5 g3.5 g of zinc oxide
니코틴산아미드 3.5 gNicotinic acid amide 3.5 g
비타민 A 0.2 gVitamin A 0.2 g
비타민 B1 0.25 gVitamin B1 0.25 g
비타민 B2 0.3gVitamin B2 0.3g
물 정량Water quantification
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85 ℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2 l 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다.The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The solution thus prepared was filtered and sterilized in a sterilized 2 liter container, It is used in the production of the health beverage composition of the invention.
상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.
Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
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KR20210082574A (en) * | 2019-12-26 | 2021-07-06 | 동의대학교 산학협력단 | Cancer preventive and therapeutic composition comprising Mori Cortex Radicis extract and Adenophoratriphylla var. japonica Hara extract |
WO2021187905A1 (en) * | 2020-03-20 | 2021-09-23 | ㈜송헌알앤디 | Pharmaceutical composition for cancer and resistant cancer comprising trichosanthes kirilowii maxim, dictamnus dasycarpus turcz and morus alba l. |
CN114767669A (en) * | 2022-05-20 | 2022-07-22 | 湖南省中医药研究院 | P-gp inhibitor and extraction method and application thereof |
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KR100902094B1 (en) * | 2007-08-07 | 2009-06-09 | 한국생명공학연구원 | Pharmaceutical composition for the prevention and treatment of cancers containings extracts, fractions and isolated 2?arylbenzofuran compounds of Mori Cortex Radicis as an active ingredient |
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KR20210082574A (en) * | 2019-12-26 | 2021-07-06 | 동의대학교 산학협력단 | Cancer preventive and therapeutic composition comprising Mori Cortex Radicis extract and Adenophoratriphylla var. japonica Hara extract |
WO2021187905A1 (en) * | 2020-03-20 | 2021-09-23 | ㈜송헌알앤디 | Pharmaceutical composition for cancer and resistant cancer comprising trichosanthes kirilowii maxim, dictamnus dasycarpus turcz and morus alba l. |
KR20210117802A (en) * | 2020-03-20 | 2021-09-29 | (주)송헌알앤디 | composition anticancer and inhibition of multidrug resistance comprising extract of Trichosanthes kirilowii Maxim, Dictamnus dasycarpus Turcz. and Morus alba L. |
CN114767669A (en) * | 2022-05-20 | 2022-07-22 | 湖南省中医药研究院 | P-gp inhibitor and extraction method and application thereof |
CN114767669B (en) * | 2022-05-20 | 2023-07-04 | 湖南省中医药研究院 | P-gp inhibitor and extraction method and application thereof |
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