KR20190036172A - Composition for preventing or treating cancer comprising anti-cancer agents and nonsteroidal antiinflammatory drugs - Google Patents
Composition for preventing or treating cancer comprising anti-cancer agents and nonsteroidal antiinflammatory drugs Download PDFInfo
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- KR20190036172A KR20190036172A KR1020170125092A KR20170125092A KR20190036172A KR 20190036172 A KR20190036172 A KR 20190036172A KR 1020170125092 A KR1020170125092 A KR 1020170125092A KR 20170125092 A KR20170125092 A KR 20170125092A KR 20190036172 A KR20190036172 A KR 20190036172A
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- South Korea
- Prior art keywords
- combination
- cancer
- sorafenib
- tamoxifen
- diclofenac
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Abstract
Description
본 발명은 항암제 및 비스테로이드성 항염증제를 병용투여하여 암을 예방 또는 치료하는 화학요법 및 이를 위한 암 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a chemotherapy for preventing or treating cancer by administering a combination of an anti-cancer agent and a non-steroidal anti-inflammatory agent, and a composition for preventing, improving or treating cancer.
현재, 암의 치료를 위해서는 수술 요법, 방사선 치료 요법 및 화학요법 등이 사용되고 있다. 이 중에서, 화학요법은 항암제를 이용하여 암을 치료하는 방법을 말한다. 오늘날에는 약 60여종의 다양한 항암제가 사용되고 있으며, 최근 암 발생 및 암 세포의 특성에 관한 지식이 많이 알려짐에 따라, 새로운 항암제 개발에 관한 연구가 활발하게 진행되고 있다. Currently, surgery, radiation therapy, and chemotherapy are used to treat cancer. Among them, chemotherapy refers to a method of treating cancer using an anticancer agent. Today, about 60 kinds of various anticancer drugs are used. Recently, as knowledge of cancer development and characteristics of cancer cells is well known, researches on the development of new anticancer drugs are being actively carried out.
항암 화학치료에 있어 많은 환자들은 항암제의 부작용에 의하여 고통을 받고 있으며, 특히 항암제의 독성으로 인하여 제한적인 투여가 이루어지고 있다. 임상에서 사용되고 있는 항암물질은 암세포뿐만 아니라 정상세포에도 영향을 미치며 투여회수가 반복되면서 치료에 실패하는 등 부작용 및 항암제 내성과 같은 문제점을 가지고 있다. 암 자체의 다양성 및 발병기전의 다양화로 인해 야기되는 기존항암제의 부작용을 극복할 수 있는 새로운 형태의 항암제 치료물질 연구가 진행되고 있으며, 항암 화학증감제와의 병용요법은 항암제의 용량을 감소시켜 부작용을 경감시킬 수 있을 뿐 아니라 기존 항암제와 다른 타겟에 작용함으로써 항암활성을 증가시킬 수 있는 장점이 있다.Many patients in cancer chemotherapy suffer from the side effects of anticancer drugs, especially because of the toxicity of anticancer drugs. The anticancer substances used in clinical use have effects such as side effects and anticancer drug resistance, such as failure to treat the cancer cells as well as normal cells as well as repeated administration. A new type of anticancer drug that can overcome the side effects of conventional anticancer drugs caused by the diversity of the cancer itself and the pathogenesis of the disease is under study and the combination therapy with the anticancer chemotherapeutic agent reduces the dose of the anticancer drug, But also has the advantage of increasing the anticancer activity by acting on a different target than the conventional anticancer drug.
한편, 항암화학요법제의 타겟으로 알려져 있는 기전 중에 오토파지(autophagy)가 있다. 오토파지는 이중막을 가진 오토파고솜이 세포 내에 불필요한 소기관이나 단백질을 포식하여 리소좀을 통해 분해시키는 과정이며, 정상적으로 작동하지 않을 경우 세포의 항상성이 깨져 다양한 질병을 일으키는 원인이 된다. 또한 암세포는 저산소, 항암화학요법, 방사선조사와 같은 스트레스 상황에서 오토파지의 활성이 크게 증가되는 것이 관찰되었고 높아진 오토파지 활성을 통해 암세포는 항암약물에 대한 저항성을 가지게 된다. 따라서 오토파지를 억제하는 약물을 항암제와 병용투여하게 되면 상승된 효과를 기대할 수 있으며 오토파지 억제제로 잘 알려진 클로로퀸(chloroquine)과 하이드록시클로로퀸(hydroxychloroquine)과 같은 물질은 다양한 암에서 여러 항암요법과 함께 병용 투여하는 것이 임상시험 중에 있다.On the other hand, there is autophagy in the mechanism known as the target of chemotherapy. Autophagy is a process in which double-membraneed autopagosomes digest unnecessary organelles or proteins in cells and decompose them through lysosomes. If not functioning normally, the homeostasis of cells will be broken and cause various diseases. Furthermore, the activity of autophagy was significantly increased in the cancer cells under stress conditions such as hypoxia, chemotherapy, and irradiation, and the cancer cells were resistant to the anticancer drugs by the increased autophage activity. Therefore, it is anticipated that the combination of antioxidants and antioxidants will increase the efficacy of antioxidants. Chloroquine and hydroxychloroquine, which are known as autophage inhibitors, It is in clinical trials to co-administer.
이에, 본 발명자들은 비스테로이드성 항염증제 계열의 약물들을 이용하여 오토파지를 억제함으로써 항암제의 항암활성을 증가시킬 수 있음을 확인하여 본 발명을 완성하였다.Accordingly, the inventors of the present invention completed the present invention by confirming that antitumor activity of anticancer drugs can be increased by inhibiting autophage using drugs of the non-steroidal anti-inflammatory drug family.
따라서, 본 발명의 목적은 타목시펜(tamoxifen), 소라페닙(sorafenib), 5-플루오로우라실(5-Fluorouracil) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac), 나프록센(naproxen), 아세클로페낙(aceclofenac), 프루비프로펜(flurbiprofen) 및 덱시부프로펜(dexibuprofen)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs)를 포함하는 암 예방, 개선 또는 치료용 약학적 조성물, 건강기능식품 조성물 및 건강식품 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition comprising one kind of anticancer agent selected from the group consisting of tamoxifen, sorafenib, 5-fluorouracil and paclitaxel; And one nonsteroidal antiinflammatory drug selected from the group consisting of diclofenac, naproxen, aceclofenac, flurbiprofen, and dexibuprofen. , NSAIDs), a health functional food composition and a health food composition for preventing, ameliorating or treating cancer.
상기 목적을 달성하기 위하여, 본 발명은 타목시펜(tamoxifen), 소라페닙(sorafenib), 5-플루오로우라실(5-Fluorouracil) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac), 나프록센(naproxen), 아세클로페낙(aceclofenac), 프루비프로펜(flurbiprofen) 및 덱시부프로펜(dexibuprofen)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs)를 포함하는 암 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides an anticancer agent selected from the group consisting of tamoxifen, sorafenib, 5-fluorouracil and paclitaxel; And one nonsteroidal antiinflammatory drug selected from the group consisting of diclofenac, naproxen, aceclofenac, flurbiprofen, and dexibuprofen. ; NSAIDs). ≪ / RTI >
본 발명의 일실시예에 있어서, 상기 암은 유방암, 간암, 대장암 및 폐암으로 이루어진 군으로부터 선택된 1종 이상인 것일 수 있다. In one embodiment of the present invention, the cancer may be one or more selected from the group consisting of breast cancer, liver cancer, colon cancer, and lung cancer.
또한, 본 발명은 타목시펜(tamoxifen), 소라페닙(sorafenib), 5-플루오로우라실(5-Fluorouracil) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac), 나프록센(naproxen), 아세클로페낙(aceclofenac), 프루비프로펜(flurbiprofen) 및 덱시부프로펜(dexibuprofen)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs)를 포함하는 암 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also relates to an anticancer agent selected from the group consisting of tamoxifen, sorafenib, 5-fluorouracil and paclitaxel; And one nonsteroidal antiinflammatory drug selected from the group consisting of diclofenac, naproxen, aceclofenac, flurbiprofen, and dexibuprofen. ; NSAIDs). ≪ / RTI >
또한, 본 발명은 타목시펜(tamoxifen), 소라페닙(sorafenib), 5-플루오로우라실(5-Fluorouracil) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac), 나프록센(naproxen), 아세클로페낙(aceclofenac), 프루비프로펜(flurbiprofen) 및 덱시부프로펜(dexibuprofen)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs)를 포함하는 암 예방 또는 개선용 건강식품 조성물을 제공한다.The present invention also relates to an anticancer agent selected from the group consisting of tamoxifen, sorafenib, 5-fluorouracil and paclitaxel; And one nonsteroidal antiinflammatory drug selected from the group consisting of diclofenac, naproxen, aceclofenac, flurbiprofen, and dexibuprofen. ; NSAIDs). ≪ / RTI >
본 발명에 따른 암 예방 또는 치료용 약학적 조성물은 항암제 및 비스테로이드성 항염증제를 병용함으로써, 상기 항암제 또는 비스테로이드성 항염증제를 단독으로 사용하는 경우보다 암세포의 사멸율이 증가되고, 암세포 증식율이 감소되는 상승 효과를 나타냄에 따라 암의 예방 또는 치료에 유용하게 사용될 수 있다.The pharmaceutical composition for preventing or treating cancer according to the present invention can be used in combination with an anticancer agent and a nonsteroidal antiinflammatory agent to increase the mortality rate of cancer cells and decrease the cancer cell proliferation rate when the anticancer agent or nonsteroidal antiinflammatory agent is used alone And exhibit a synergistic effect, thus being useful for preventing or treating cancer.
도 1은 타목시펜(tamoxifen; TAM) 및 다이클로페낙(diclofenac; DCF)을 단독 또는 병용처리한 후, 유방암 세포주인 MCF7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 2는 타목시펜(TAM) 및 나프록센(naproxen)을 단독 또는 병용처리한 후, 유방암 세포주인 MCF7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 3은 타목시펜(TAM) 및 아세클로페낙(aceclofenac; ace)을 단독 또는 병용처리한 후, 유방암 세포주인 MCF7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 4는 타목시펜(TAM) 및 프루비프로펜(flurbiprofen)을 단독 또는 병용처리한 후, 유방암 세포주인 MCF7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 5는 타목시펜(TAM) 및 덱시부프로펜(dexibuprofen; dexi)을 단독 또는 병용처리한 후, 유방암 세포주인 MCF7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 6은 소라페닙(sorafenib; sora) 및 아세클로페낙(ace)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 7은 소라페닙(sora) 및 다이클로페낙(DCF)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 8은 소라페닙(sora) 및 프루비프로펜(flurbiprofen; flur)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 9는 소라페닙(sora) 및 덱시부프로펜(dexi)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 10은 소라페닙(sora) 및 나프록센(naproxen; nap)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 11은 소라페닙(sora) 및 나프록센(nap)을 단독 또는 병용처리한 후, 간암 세포주인 HepG2의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 12는 소라페닙(sora) 및 다이클로페낙(DCF)을 단독 또는 병용처리한 후, 간암 세포주인 Huh7의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 13은 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 다이클로페낙(DCF)을 단독 또는 병용처리한 후, 대장암 세포주인 HCT116의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 14는 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 덱시부프로펜(dexi)을 단독 또는 병용처리한 후, 대장암 세포주인 HCT116의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 15는 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 아세클로페낙(ace)을 단독 또는 병용처리하여 48시간 후의 대장암 세포주인 HCT116의 사멸세포 비율(% of dead cell)을 확인한 결과를 나타낸 것이다.
도 16은 파클리탁셀(paclitaxel) 및 덱시부프로펜(dexi)을 단독 또는 병용처리한 후, 폐암 세포주인 A549의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.
도 17은 파클리탁셀(paclitaxel) 및 나프록센(nap)을 단독 또는 병용처리한 후, 폐암 세포주인 A549의 사멸세포 비율(% of dead cell) 및 세포 증식율(cell proliferation, %)을 확인한 결과를 나타낸 것이다.Figure 1 shows the percentage of dead cells and cell proliferation (%) of MCF7, a breast cancer cell line, after treatment with tamoxifen (TAM) and diclofenac (DCF) alone or in combination The results are as follows.
FIG. 2 shows the results of confirming% of dead cells and cell proliferation (%) of breast cancer cell line MCF7 after treatment with tamoxifen (TAM) and naproxen alone or in combination.
FIG. 3 shows the results of confirming% of dead cells and cell proliferation (%) of breast cancer cell line MCF7 after treatment of tamoxifen (TAM) and aceclofenac (ace) alone or in combination will be.
FIG. 4 shows the results of confirming% of dead cells and cell proliferation (%) of MCF7, a breast cancer cell line, after treatment of tamoxifen (TAM) and flurbiprofen alone or in combination .
FIG. 5 is a graph showing the percentage of dead cells and cell proliferation (%) of MCF7, a breast cancer cell line, after single or combined treatment of tamoxifen (TAM) and dexibuprofen (dexi) The results are shown.
FIG. 6 shows the results of confirming% of dead cell and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after sorafenib (sora) and aceclofenac (ace) .
FIG. 7 shows the results of confirming% of dead cell and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after treating sorapenib and diclofenac (DCF) alone or in combination .
8 is a graph showing the percentage of dead cells and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after single or combined treatment with sorafen and flurbiprofen The results are as follows.
FIG. 9 shows the results of confirming% of dead cells and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after treating sorapenib and sorbic acid with or without dexibuprofen (dexi) .
10 shows the results of confirming% of dead cells and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after treating sorapenib and naproxen (nap) alone or in combination .
FIG. 11 shows the results of confirming% of dead cells and cell proliferation (%) of hepatocellular carcinoma cell line HepG2 after treating sorapenib and naproxene (nap) alone or in combination .
FIG. 12 shows the results of confirming% of dead cells and cell proliferation (%) of Huh7, a liver cancer cell line, after treating sorapenib and sorafenic acid (DCF) alone or in combination .
FIG. 13 shows the percentage of dead cells and the cell proliferation rate of HCT116, a colorectal cancer cell line, after 5-fluorouracil (5-FU) and diclofenac (DCF) (cell proliferation,%).
FIG. 14 shows the percentage of dead cells of HCT116, a colon cancer cell line, and the number of cells (cells) of the cells after 5-fluorouracil (5-FU) and dexibuprophen The cell proliferation (%) was confirmed.
15 shows the results of examining the percentage of dead cells of HCT116 colon cancer cell line after 48 hours by treating 5-Fluorouracil (5-FU) and aceclofenac (ace) alone or in combination .
Figure 16 shows the results of confirming% of dead cells and cell proliferation (%) of lung cancer cell line A549 after treatment with paclitaxel and dexibupropene (dexi) alone or in combination .
FIG. 17 shows the results of confirming% of dead cells and cell proliferation (%) of lung cancer cell line A549 after treatment with paclitaxel and naprox (nap) alone or in combination.
본 발명은 항암제(anti-cancer agnets) 및 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs)를 유효성분으로 포함하는 암 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cancer comprising anti-cancer agnets and nonsteroidal antiinflammatory drugs (NSAIDs) as an active ingredient.
본 발명자들은 비스테로이드성 항염증제 계열의 약물들을 이용하여 오토파지를 억제함으로써 항암제의 항암활성을 증가시킬 수 있음을 확인하여 본 발명을 완성하였다. 구체적으로, NSAIDs는 이미 항염증 약으로서 오랜기간 사용되어온 안전성이 입증된 약물이며, 이를 항암제와 병용함으로써, 암세포 사멸율 증가 및 암세포 증식율 감소에 대한 상승 효과가 나타남을 실험적으로 입증함에 따라, 세포독성이 강한 항암제의 용량을 낮추어 독성은 경감시키면서 보다 큰 항암 효과를 기대할 수 있음을 확인하였다(실험예 1 내지 4 참조).The inventors of the present invention completed the present invention by confirming that antitumor activity of anticancer drugs can be increased by inhibiting autophage using non-steroidal anti-inflammatory drugs. Specifically, NSAIDs have already been used as anti-inflammatory drugs for a long time and have been proven to be safe. By experimentally proving that synergistic effects on cancer cell death rate and cancer cell proliferation rate decrease by combining with anti-cancer drugs, It was confirmed that the anticancer effect can be expected while lowering the dose of the strong anticancer agent and alleviating the toxicity (see Examples 1 to 4).
따라서, 본 발명은 타목시펜(tamoxifen; TAM), 소라페닙(sorafenib; sora), 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);를 포함하는 암 예방 또는 치료용 약학적 조성물을 제공함에 특징이 있다.Accordingly, the present invention provides an anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-Fluorouracil (5-FU) and paclitaxel; And one selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) The present invention is characterized by providing a pharmaceutical composition for preventing or treating cancer, which comprises a nonsteroidal antiinflammatory drug (NSAIDs).
본 발명에서의 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"란 상기 약학적 조성물의 투여에 의해 암의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.The term " prevention " in the present invention means all the actions of inhibiting or delaying the development, spread and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and " Means any action that alters the suspicion of the cancer and symptoms of the onset individual or alters it beneficially.
본 발명에 따른 상기 약학적 조성물은 타목시펜 및 다이클로페낙의 조합; 타목시펜 및 나프록센의 조합; 타목시펜 및 아세클로페낙의 조합; 타목시펜 및 프루비프로펜의 조합; 타목시펜 및 덱시부프로펜의 조합; 소라페닙 및 아세클로페낙의 조합; 소라페닙 및 다이클로페낙의 조합; 소라페닙 및 프루비프로펜의 조합; 소라페닙 및 덱시부프로펜의 조합; 소라페닙 및 나프록센의 조합; 5-플루오로우라실 및 다이클로페낙의 조합; 5-플루오로우라실 및 덱시부프로펜의 조합; 5-플루오로우라실 및 아세클로페낙의 조합; 파클리탁셀 및 덱시부프로펜의 조합; 및 파클리탁셀 및 나프록센의 조합;으로 이루어지는 군으로부터 선택되는 조합일 수 있다. 바람직하게는, 타목시펜 및 다이클로페낙의 조합; 타목시펜 및 아세클로페낙의 조합; 타목시펜 및 프루비프로펜의 조합; 타목시펜 및 덱시부프로펜의 조합; 소라페닙 및 아세클로페낙의 조합; 소라페닙 및 다이클로페낙의 조합; 소라페닙 및 프루비프로펜의 조합; 소라페닙 및 덱시부프로펜의 조합; 소라페닙 및 나프록센의 조합; 5-플루오로우라실 및 다이클로페낙의 조합; 및 파클리탁셀 및 덱시부프로펜의 조합;으로 이루어지는 군으로부터 선택되는 조합일 수 있다. 더욱 바람직하게는, 타목시펜 및 다이클로페낙의 조합; 타목시펜 및 아세클로페낙의 조합; 소라페닙 및 다이클로페낙의 조합; 소라페닙 및 프루비프로펜의 조합; 소라페닙 및 덱시부프로펜의 조합; 및 소라페닙 및 나프록센의 조합;으로 이루어지는 군으로부터 선택되는 조합일 수 있다.The pharmaceutical composition according to the present invention is a combination of tamoxifen and diclofenac; A combination of tamoxifen and naproxen; A combination of tamoxifen and aceclofenac; A combination of tamoxifen and probioprofen; A combination of tamoxifen and dexibuprofen; A combination of sorafenib and aceclofenac; A combination of sorafenib and diclofenac; A combination of sorafenib and fruviprofen; A combination of sorafenib and dexibuprofen; A combination of sorafenib and naproxen; A combination of 5-fluorouracil and diclofenac; A combination of 5-fluorouracil and dexibuprofen; A combination of 5-fluorouracil and aceclofenac; A combination of paclitaxel and dexibuprofen; And combinations of paclitaxel and < RTI ID = 0.0 > naproxen. ≪ / RTI > Preferably, a combination of tamoxifen and diclofenac; A combination of tamoxifen and aceclofenac; A combination of tamoxifen and probioprofen; A combination of tamoxifen and dexibuprofen; A combination of sorafenib and aceclofenac; A combination of sorafenib and diclofenac; A combination of sorafenib and fruviprofen; A combination of sorafenib and dexibuprofen; A combination of sorafenib and naproxen; A combination of 5-fluorouracil and diclofenac; And a combination of paclitaxel and dexibuprofen. More preferably, a combination of tamoxifen and diclofenac; A combination of tamoxifen and aceclofenac; A combination of sorafenib and diclofenac; A combination of sorafenib and fruviprofen; A combination of sorafenib and dexibuprofen; And a combination of sorapenib and naproxen.
본 발명에 따른 상기 암은 다발성 골수종, 간암, 대장암, 유방암, 자궁암, 자궁경부암, 난소암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 위암, 폐암, 췌장암, 비소세포성폐암, 간암, 식도암, 소장암, 항문부근암, 나팔관암종, 자궁내막암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 골암, 피부암, 두부암, 경부암, 피부흑색종, 안구내흑색종, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 중추신경계(central nervous system; CNS) 종양, 1차 CNS 림프종, 척수종양, 뇌간신경교종 및 뇌하수체선종으로 이루어진 그룹에서 선택되는 1종 이상의 암일 수 있다. 바람직하게는 유방암, 간암, 대장암 및 폐암으로 이루어진 군으로부터 선택된 1종 이상인 것일 수 있다. 더욱 바람직하게는 유방암 및 간암으로 이루어진 군으로부터 선택된 1종 이상인 것일 수 있다.The cancer according to the present invention may be used for the treatment of multiple myeloma, liver cancer, colon cancer, breast cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, gastric cancer, Pancreatic cancer, kidney cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, lung cancer, lung cancer, lung cancer, liver cancer, esophageal cancer, small intestine cancer, anorectal cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Cancer of the central nervous system (CNS), primary CNS lymphoma (e. G., Cervical cancer), head and neck cancer, skin cancer, , Spinal cord tumor, brainstem glioma, and pituitary adenoma. Preferably one or more selected from the group consisting of breast cancer, liver cancer, colon cancer and lung cancer. And more preferably at least one selected from the group consisting of breast cancer and liver cancer.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 암의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, Factors well known in the art and other medical disciplines including health status, type of cancer, severity, activity of the drug, sensitivity to the drug, method of administration, time of administration, route of administration and rate of release, duration of treatment, ≪ / RTI > The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. Taking all of the above factors into consideration, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학적 조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용 가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제 화할 수 있다.The pharmaceutical compositions of the present invention may include carriers, diluents, excipients, or a combination of two or more thereof commonly used in biological preparations. As used herein, the term " pharmaceutically acceptable " means that the composition is free of toxicity to cells or humans exposed to the composition. The carrier is not particularly limited as long as the composition is suitable for in vivo delivery, for example, Merck Index, 13th ed., Merck & Inc. A buffered saline solution, a buffer solution, a dextrose solution, a maltodextrin solution, glycerol, ethanol, and one or more of these components may be mixed and used, and if necessary, an antioxidant, a buffer, Conventional additives may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate into main dosage forms such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules or tablets. Further, it can be suitably formulated according to each disease or ingredient, using the method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990) in a suitable manner in the art.
본 발명의 약학적 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable additive, wherein pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate Starch glycolate, starch glycolate, starch glycolate, carnauba wax, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, sodium carboxymethylcellulose, sodium carboxymethylcellulose, sodium carboxymethylcellulose, Calcium stearate, white sugar, dextrose, sorbitol and talc may be used. The pharmaceutically acceptable additive according to the present invention is preferably included in the composition in an amount of 0.1 part by weight to 90 parts by weight, but is not limited thereto.
본 발명의 약학적 조성물은 유효성분으로서 상기 항암제 및 NSAIDs 이외에 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further comprise, as an active ingredient, an anticancer agent known in addition to the above anticancer agent and NSAIDs, and may be used in combination with other therapies known for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem cell replacement therapy, other biological therapies, immunotherapy, and the like.
본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 도세탁셀(docetaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리도테칸(iridotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include DNA alkylating agents such as mechloethamine, chlorambucil, phenylalanine, mustard, cyclophosphate, Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin cisplatin and carboplatin; The anticancer antibiotics include dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, Plicamycin, mitomycin C, and bleomycin; And plant alkaloids such as vincristine, vinblastine, docetaxel, etoposide, teniposide, topotecan, and iridotecan ), But are not limited thereto.
일 측면에서, 본 발명은 상기 약학적 조성물을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, 암을 예방 또는 치료하는 방법에 관한 것이다.In one aspect, the invention relates to a method of preventing or treating cancer, comprising administering the pharmaceutical composition to a subject in need thereof.
본 발명에서 사용되는 용어, "개체"란, 상기 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환들을 효과적으로 예방 또는 치료할 수 있다. 본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The term " individual " used in the present invention means a monkey, a horse, a sheep, a pig, a chicken, a turkey, a quail, a cat, a dog, a mouse, a rat, a rabbit Refers to all animals including guinea pigs, and the diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual. The pharmaceutical composition of the present invention can be administered in parallel with existing therapeutic agents.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 조성물의 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 본 발명의 약학적 조성물은 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥 주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성 용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물 발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.The term " administering " as used herein means providing a predetermined substance to a patient in any appropriate manner, and may be administered orally or parenterally (for example, by intravenous, subcutaneous, The dosage may vary depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and severity of the disease. Examples of the liquid preparation for oral administration of the composition of the present invention include suspensions, solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, Etc. may be included together. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. The pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).
또한, 본 발명은 타목시펜(tamoxifen; TAM), 소라페닙(sorafenib; sora), 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);를 포함하는 암 예방 또는 개선용 건강기능식품 조성물을 제공함에 특징이 있다.The present invention also relates to an anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel; And one selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) And a non-steroidal antiinflammatory drug (NSAIDs). The present invention provides a health functional food composition for preventing or ameliorating cancer.
본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술 분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 통상의 기술 분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한, 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 항암제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The term " health functional food " as used in the present invention refers to a food prepared and processed in the form of tablets, capsules, powders, granules, liquids and rings using raw materials and components having useful functions in the human body. Here, 'functional' refers to the structure and function of the human body to obtain nutritional effects and obtain useful effects for health use such as physiological action. The health functional food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and components which are usually added in the conventional technical fields. In addition, the formulation of the health functional food may also be produced without limitation as long as the formulation is recognized as a health functional food. The composition for food of the present invention can be manufactured in various forms, and unlike general pharmaceuticals, it has the advantage that there is no side effect that may occur when a drug is used for a long period of time, and is excellent in portability, Can be ingested as an adjuvant to enhance the effectiveness of anticancer drugs.
본 발명의 상기 건강기능식품 조성물은 본 발명의 항암제 및 NSAIDs를 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 이외에 식품학적으로 허용 가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.The health functional food composition of the present invention may contain the anticancer agent and the NSAIDs of the present invention as it is, or may be used together with other food or food ingredients, and may also include a food-acceptable food supplementary additive. May be suitably determined according to the intended use (prevention, health or therapeutic treatment).
본 발명의 용어, "식품보조첨가제"는 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term " food supplementary additive " of the present invention means a component which can be added to food, and it can be appropriately selected and used by those skilled in the art as added to produce health functional food of each formulation. Examples of food-aid additives include flavors such as various nutrients, vitamins, minerals (electrolytes), synthetic flavors and natural flavors, colorants and fillers, pectic acid and its salts, alginic acid and its salts, organic acids, , a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, and a carbonating agent used in a carbonated drink. However, the types of the food auxiliary additives of the present invention are not limited by these examples.
또한, 본 발명은 타목시펜(tamoxifen; TAM), 소라페닙(sorafenib; sora), 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 파클리탁셀(paclitaxel)로 이루어진 군으로부터 선택되는 1종의 항암제; 및 다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);를 포함하는 암 예방 또는 개선용 건강식품 조성물을 제공함에 특징이 있다.The present invention also relates to an anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel; And one selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) And a nonsteroidal antiinflammatory drug (NSAIDs). The present invention provides a health food composition for preventing or ameliorating cancer.
본 발명의 상기 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 상기 항암제 및 비스테로이드성 항염증제를 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 조성물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.There is no limitation on the kind of health food in which the composition of the present invention can be used. In addition, the composition comprising the anticancer agent and the non-steroidal anti-inflammatory agent of the present invention as an active ingredient may be prepared by mixing other appropriate auxiliary ingredients that may be contained in health foods and known additives according to the selection of a person skilled in the art. Examples of foods that can be added include dairy products, such as meat, sausage, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Vitamin complex, and the like, and can be prepared by adding to juice, tea, jelly, juice and the like prepared using the composition according to the present invention as a main component.
이하, 본 발명을 실시예를 통하여 더욱 상세히 설명하기로 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. These examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
<< 실시예Example > 항암제 및 > Anticancer drugs and NSAIDsNSAIDs 약물 시료 제조 Drug sample preparation
항암제 약물인 타목시펜(tamoxifen; TAM), 소라페닙(sorafenib; sora), 5-플루오로우라실(5-Fluorouracil; 5-FU) 및 파클리탁셀(paclitaxel)과 비스테로이드성항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs) 약물인 다이클로페낙(diclofenac; DCF), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)은 모두 DMSO에 용해시켜 stock을 제조하였다.The use of anticancer drugs tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel and nonsteroidal antiinflammatory drugs (NSAIDs) Diclofenac (DCF), aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) were both dissolved in DMSO to prepare stock.
NSAIDs 약물 나프록센(naproxen)은 물에 용해시켜 stock을 제조하였다.The NSAIDs drug naproxen was dissolved in water to prepare the stock.
세포 배양Cell culture
인간 유방암 세포주 MCF7, 인간 간암 세포주 HepG2 및 인간 대장암 세포주 HCT116은 37℃, 5% CO2 인큐베이터에서 10% FBS(fetal bovine serum), 1% 페니실린-스트렙토마이신(penicillin streptomycin) 및 1% 피루빈산(pyruvate)을 포함한 phenol red free Dulbecco's Modified Eagle Medium(phenol red free DMEM, HyClone BRL)을 이용하여 배양하였다. Human breast cancer cell line MCF7, human liver cancer cell line HepG2 and human colorectal cancer cell line HCT116 were cultured in a 5% CO 2 incubator at 37 占 폚 in the presence of 10% FBS (fetal bovine serum), 1% penicillin streptomycin and 1% and phenol red free Dulbecco's Modified Eagle Medium (phenol red free DMEM, HyClone BRL) containing pyruvate.
인간 폐암 세포주 A549 및 인간 간암 세포주 Huh7은 37℃, 5% CO2 인큐베이터에서 10% FBS 및 1% penicillin streptomycin을 포함한 phenol red free Roswell Park Memorial Institute medium 1640(phenol red free RPMI 1640, Gipco BRL)을 이용하여 배양하였다.Human lung cancer cell line A549 and human hepatoma cell line Huh7 were cultured in phenol red free Roswell Park Memorial Institute medium 1640 (phenol red free RPMI 1640, Gipco BRL) containing 10% FBS and 1% penicillin streptomycin in a 5% CO 2 incubator at 37 ° C And cultured.
모든 세포주는 American Type Culture Collection (Manassas, VA, USA)에서 분양받은 것을 사용하였다.All cell lines were purchased from the American Type Culture Collection (Manassas, VA, USA).
세포사멸 및 세포증식 측정 방법Methods for measuring cell death and cell proliferation
항암제와 NSAIDs의 암세포에 대한 세포사멸 및 세포증식억제 효과를 시간대별로 확인하기 위하여 HCS(High Contents Screening)를 실시하였다.HCS (High Contents Screening) was performed to confirm the cell death and cell proliferation inhibitory effects of cancer drugs and NSAIDs on cancer cells over time.
Nunc™ MicroWell™ 96-Well Optical-Bottom Plates with Polymer Base에 각 세포주 10000개/100uL의 농도로 100uL씩 plate의 가장자리 부분을 제외한 well에 seeding하고 24시간 후에 YOYO-1 염료(dye) 100nM이 포함된 배지를 이용하여 약물 농도별로 3개의 well에 상기 실시예 1의 항암제 및 NSAIDs 약물을 단독 또는 병용하여 처리하였다. 약물 처리 후 30분동안 인큐베이션(incubation)한 뒤, BioTek Cytation 3 Cell Imaging Multi-Mode Reader를 이용하여 48시간 동안 2시간 간격으로 bright field 및 GFP filter에서 10X lens를 이용하여 하나의 well에서 가운데의 4부분의 영역의 이미지를 촬영하였다. 이때, YOYO-1은 세포의 사멸 및 증식에 큰영향을 미치지 않는 염료이며, 살아있는 세포에 대해서는 투과성이 없는 세포막 불투과성(impermeable) 염료로서, 세포가 죽었을 때는 세포막 투과성이 증가하므로 YOYO-1이 세포막 내로 들어가 핵을 염색시킬 수 있기 때문에 사멸한 세포(death cell)를 판별할 수 있다. 100 uL of each cell line was seeded in wells except for the edge of the plate at a concentration of 10000 cells / 100 uL in Nunc ™ MicroWell ™ 96-Well Optical-Bottom Plates with Polymer Base. After 24 hours, 100 μM of YOYO-1 dye The anticancer agent and the NSAIDs drug of Example 1 were used alone or in combination in three wells according to the drug concentration using the medium. After incubation for 30 minutes, the cells were incubated for 48 h at 2 h intervals using a BioTek Cytation 3 Cell Imaging Multi-Mode Reader. The image of the area of the area was photographed. In this case, YOYO-1 is a dye that does not greatly affect the cell death and proliferation. It is an impermeable dye that is not permeable to living cells. When the cell is dead, YOYO-1 increases cell membrane permeability. Because it can enter the cell membrane and stain the nucleus, death cells can be identified.
Bright field에서는 모든 세포 object의 수를 카운팅(counting)하고 GFP에서 YOYO-1 positive한 세포 object의 수를 카운팅하여 전체 세포의 수 대비 죽은 세포의 비율(%)을 ‘% of dead cell’이라 정의하여 각 약물의 암세포에 대한 독성(toxicity)을 측정하였다. In the bright field, the number of all cell objects is counted, and the number of YOYO-1 positive cell objects in GFP is counted to define the percentage of dead cells to total cell number as% of dead cell The toxicity of each drug to cancer cells was measured.
또한, bright field의 각 시간대별 세포 object의 수를 시작시점 시간(0시간)의 수로 각각 나눠서 시작시점의 값을 100%로 설정하여 세포가 얼마나 증가하는지 세포증식(cell proliferation) 비율(%)을 측정하였다.The cell proliferation rate (%) is calculated by dividing the number of cell objects in each time period of the bright field by the number of start time points (0 hours) and setting the starting point value to 100% Respectively.
<< 실험예Experimental Example 1> 유방암 세포에 대한 세포독성 및 세포증식 억제 효과 1> Cytotoxicity and inhibition of cell proliferation in breast cancer cells
상기 실험예 1의 방법을 이용하여, 유방암 치료제로 알려진 타목시펜(TAM)과 NSAIDs의 병용에 따른 유방암 세포 MCF7에 대한 세포사멸 효과 및 세포증식 억제 효과를 평가하였다.Using the method of Experimental Example 1, the cytotoxic effect and cell proliferation inhibitory effect of breast cancer cell MCF7 upon the combination of tamoxifen (TAM) and NSAIDs, which are known as therapeutic agents for breast cancer, were evaluated.
타목시펜(TAM)은 10uM 농도로 처리하였으며, 다이클로페낙(DCF) 500uM, 나프록센(naproxen) 1mM 및 2mM, 아세클로페낙(ace) 500uM, 800uM 및 1000uM, 프루비프로펜(flur) 750uM 및 1000uM 및 덱시부프로펜(dexi) 3mM 및 4mM을 각각 단독으로 처리하거나 상기 타목시펜(TAM) 10uM과 병용처리하였다.Tamoxifen (TAM) was treated at a concentration of 10 uM and was treated with 500 uM diclophenac (DCF), 1 mM and 2 mM naproxen, 500 uM aceclofenac (ace), 800 uM and 1000 uM, 750 uM pruribupen and 1000 uM dexib 3mM and 4mM of propene (dexi) were each treated alone or in combination with 10uM of tamoxifen (TAM).
먼저, 도 1에 나타난 바와 같이, 타목시펜(TAM) 및 다이클로페낙(DCF)의 병용처리시 단독처리군보다 세포사멸 비율(% of dead cell)이 현저하게 증가하는 상승효과를 확인하였다.First, as shown in FIG. 1, a synergistic effect of the combination treatment of tamoxifen (TAM) and diclofenac (DCF) was observed, showing a significantly higher percentage of dead cells than the single treatment group.
타목시펜(TAM) 10uM과 나프록센(naproxen) 1mM 또는 2mM의 병용처리군에서 각 약물 단독처리군보다 세포사멸 비율(% of dead cell)은 현저하게 증가하였고, 세포증식은 유의하게 감소되었다(도 2).The percent of dead cells was significantly increased and the cell proliferation was significantly reduced (Fig. 2) in the combined treatment group of tamoxifen (TAM) 10 uM and
아세클로페낙(ace)은 500uM 및 1000uM 처리군에서 타목시펜(TAM)과의 상승작용이 나타나 유방암 세포사멸(cell death) 비율이 현저하게 증가됨이 확인되었으며, 1000uM에서는 단독처리군에서도 암세포사멸이 약간 증가하였고, 세포증식(cell proliferation)은 타목시펜 10uM 및 아세토클로페낙(ace) 1000uM 병용처리군에서 단독처리군보다 억제 효과가 비교적 증가된 것으로 나타났다(도 3).Aceclofenac (ace) showed a synergistic effect with tamoxifen (TAM) in 500 uM and 1000 uM treatment group, and the breast cancer cell death rate was remarkably increased. At 1000 uM, the cancer cell death was slightly increased even in the single treatment group, Cell proliferation showed a relatively increased inhibitory effect in the combination treatment of tamoxifen (10 uM) and acetoclophenac (ace) 1000 uM (Fig. 3).
타목시펜(TAM) 10uM 및 프루비프로펜(flur) 750uM 병용처리군에서, 약물 처리 40시간 후부터 단독처리군보다 세포사멸이 증가하였고, 프루비프로펜(flur) 1000uM을 병용처리한 군에서는 약물 처리 20시간 후부터 세포사멸이 현저하게 증가하는 것으로 나타났다(도 4). 세포증식 역시 병용처리군에서 단독처리군보다 모두 감소되었다(도 4).In the group treated with tamoxifen (TAM) 10OuM and flurbipur 750uM, the cell death was increased from 40 hours after the drug treatment, and in the group treated with 1000 μM of flurbiprofen, After 20 hours, cell death was significantly increased (FIG. 4). Cell proliferation was also reduced in the combination treatment group than in the single treatment group (Fig. 4).
타목시펜(TAM) 10uM과 덱시부프로펜(dexi) 3mM, 4mM을 병용처리했을 때 세포사멸과 세포증식의 억제 효과 모두 단독처리군보다 크게 증가되는 것을 확인하였다.(도 5)When both 10 mM of tamoxifen (TAM) and 3 mM and 4 mM of dexibuprofen (dexi) were used in combination, it was confirmed that both the cell death and the cell proliferation inhibitory effect were greatly increased compared with the single treatment group (Fig. 5)
따라서, 타목시펜(TAM)을 다이클로페낙(DCF), 나프록센(naproxen), 아세클로페낙(ace), 프루비프로펜(flur) 또는 덱시부프로펜(dexi)과 병용투여하는 경우, 두 약물의 상승작용에 의해 세포사멸 효과 또는 세포증식 억제효과가 현저하게 증가되어 유방암을 더 효과적으로 치료할 수 있음을 확인하였다.Therefore, when tamoxifen (TAM) is administered in combination with diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen or dexi, , The cell killing effect or the cell proliferation inhibitory effect was remarkably increased, and it was confirmed that breast cancer can be treated more effectively.
예practice
Yes
시간
(hr)administration
time
(hr)
투여Combined
administration
투여Combined
administration
시펜
(TAM)
10uMGrooves
Shiffen
(TAM)
10uM
<< 실험예Experimental Example 2> 간암 세포에 대한 세포독성 및 세포증식 억제 효과 2> Cytotoxicity and cell proliferation inhibitory effect on liver cancer cells
상기 실험예 1의 방법을 이용하여, 간암 치료제로 알려진 소라페닙(sora)과 NSAIDs의 병용에 따른 간암 세포 HepG2 또는 Huh7에 대한 세포사멸 효과 및 세포증식 억제 효과를 평가하였다.Using the method of Experimental Example 1, the cytotoxic effect and cell proliferation inhibitory effect of liver cancer cell HepG2 or Huh7 according to the combination of sorafenib and NSAIDs, which are known as therapeutic agents for liver cancer, were evaluated.
먼저, 간암 세포 HepG2에 대하여 소라페닙(sora)은 2.5uM 농도로 처리하였으며, 아세클로페낙(ace) 1000uM, 다이클로페낙(DCF) 100uM, 250uM 및 500uM, 프루비프로펜(flur) 1mM 및 2muM, 덱시부프로펜(dexi) 2mM 및 3mM 및 나프록센(naproxen) 500uM, 750uM, 1000uM 및 1500uM을 각각 단독으로 처리하거나 상기 소라페닙(sora) 2.5uM과 병용처리하였다. 이때, 소라페닙(sora) 2.5uM 및 다이클로페낙(DCF) 100uM 단독 또는 병용 처리군은 72시간동안 2시간 간격으로 세포사멸율 및 세포증식 정도를 측정하였다.First, sorafenib was treated at a concentration of 2.5 uM against hepatoma cell HepG2 and treated with 2.5 uM concentration of aceclofenac (aces), 100 uM of diclofenac (DCF), 250 uM and 500 uM of fluconazole, 1 uM of flurbipine and 2 uM, Sibuprophen (dexi) 2 mM and 3 mM and
도 6에 나타난 바와 같이, 소라페닙(sora) 및 아세클로페낙(ace)의 병용처리군에서 약물처리 14시간 후부터 세포사멸(cell death)이 단독처리군보다 현저하게 증가되는 상승효과를 확인하였다.As shown in FIG. 6, in the combination treatment of sorafenib (sora) and aceclofenac (ace), cell death was significantly increased after 14 hours of drug treatment than in the single treatment group.
소라페닙(sora)과 다이클로페낙(DCF) 100uM, 250uM 또는 500uM의 병용처리군 에서 각 약물 단독처리군보다 세포사멸이 현저하게 증가하였고, 세포증식은 소라페닙(sora) 2.5uM 및 다이클로페낙(DCF) 500uM 병용처리군에서 단독처리군보다 유의하게 감소되었다(도 7).In the combination treatment of sorafenib and diclofenac (DCF) at 100 uM, 250 uM or 500 uM, apoptosis was significantly higher than that of each drug alone, and cell proliferation was significantly increased in sorafenib 2.5 uM and diclofenac (DCF) treatment group (Fig. 7).
소라페닙(sora) 및 프루비프로펜(flur) 1mM 또는 2mM 병용처리군에서 단독처리군보다 세포사멸이 매우 크게 증가하였고, 프루비프로펜(flur) 1mM을 병용처리한 군에서는 약물 처리 34시간 후부터 단독처리군보다 세포증식이 더 억제되는 것으로 나타났다(도 8).In the group treated with sorafenib and sorbifen (flur) 1mM or 2mM, cell death was significantly higher than that in the single treatment group. In the group treated with 1mM of flurbiprofen, Cell proliferation was more suppressed than the single treatment group (Fig. 8).
소라페닙(sora)과 덱시부프로펜(dexi) 2mM 또는 3mM과의 병용처리군 역시 세포사멸에 대한 상승작용이 나타나 암세포에 대한 세포독성이 현저하게 증가되었고, 2mM 병용처리군에서는 단독처리군보다 세포증식이 비교적 감소된 것으로 나타났다(도 9).The combined treatment of sorafenib with 2 mM or 3 mM of dexibin (dexi) also showed a synergistic effect on apoptosis and markedly increased the cytotoxicity against cancer cells. In the 2 mM combination treatment group, Cell proliferation was relatively reduced (Fig. 9).
또한, 소라페닙(sora)과 나프록센(nap) 500uM, 750uM, 1000uM 및 1500uM과의 병용처리군 역시 세포사멸에 대한 상승작용이 나타나 암세포에 대한 세포독성이 현저하게 증가되었고 750uM 처리군을 제외한 다른 군에서는 세포증식 억제 또한 상승효과가 나타남을 확인할 수 있었다(도 10 및 11).In addition, the combined treatment of sorafenib with 500uM, 750uM, 1000uM and 1500uM of sorapenib (nap) also showed a synergistic effect on cell death, and cytotoxicity against cancer cells was remarkably increased, It was confirmed that the cell proliferation inhibition also exhibited a synergistic effect (FIGS. 10 and 11).
예practice
Yes
(hr)Time of administration
(hr)
투여Combined
administration
투여Combined
administration
페닙
(sora)
2.5uMconch
Fenip
(sora)
2.5 uM
(nap)Naproxen
(nap)
또 다른 간암 세포 Huh7에 대하여 소라페닙(sora) 5uM과 다이클로페낙(DCF) 100uM, 200uM 또는 300uM을 단독 또는 병용처리하여, 세포사멸율을 측정하였다.Another hepatocellular carcinoma Huh7 was treated with sorafenib (sora) 5 uM and diclofenac (DCF) 100 uM, 200 uM or 300 uM alone or in combination to measure the cell death rate.
그 결과, 도 12에 나타난 바와 같이, 소라페닙(sora) 및 다이클로페낙(DCF) 병용처리군 모두 단독처리군보다 세포사멸 효과가 현저하게 증가됨을 확인하였고, 특히, 300uM의 다이클로페낙(DCF) 처리군의 경우, 소라페닙(sora) 2.5uM과 병용처리한 군이 5uM과 병용처리한 경우보다 더 높은 세포사멸율을 보였다.As a result, as shown in Fig. 12, it was confirmed that the treatment with sorafenib and sorafenac (DCF) combined treatment significantly increased the cell killing effect compared with that of the single treatment group. In particular, 300 uM of diclofenac (DCF ) Treatment group showed a higher rate of apoptosis than the group treated with sorapanib (sora) 2.5 uM in combination with 5 uM.
시
예room
city
Yes
시간
(hr)administration
time
(hr)
(sora)
2.5uMSorapanib
(sora)
2.5 uM
(DCF)Diclofenac
(DCF)
(sora)
5uMSorapanib
(sora)
따라서, 소라페닙(sora)을 아세클로페낙(ace), 다이클로페낙(DCF), 프루비프 로펜(flur), 덱시부프로펜(dexi) 또는 나프록센(nap)과 병용투여하는 경우, 두 약물의 상승작용에 의해 세포사멸 효과 또는 세포증식 억제효과를 현저하게 증가시켜 간암을 더 효과적으로 치료할 수 있음을 확인하였다.Thus, when sorafenib is administered concomitantly with aceclofenac (ace), diclofenac (DCF), prubipropfen, dexibuprophen (dexi) or naproxen (nap) It was confirmed that the cell death effect or the cell proliferation inhibitory effect is remarkably increased and the liver cancer can be treated more effectively.
<< 실험예Experimental Example 3> 대장암 세포에 대한 세포독성 및 세포증식 억제 효과 3> Cytotoxicity and inhibition of cell proliferation in colon cancer cells
상기 실험예 1의 방법을 이용하여, 대장암 치료제로 알려진 5-플루오로우라실(5-FU)과 NSAIDs의 병용에 따른 대장암 세포 HCT116에 대한 세포사멸 효과 및 세포증식 억제 효과를 평가하였다.Using the method of Experimental Example 1, the cytotoxic effect and the cell proliferation inhibitory effect of 5-fluorouracil (5-FU), which is known as a therapeutic agent for colorectal cancer, and HCT116 in combination with NSAIDs were evaluated.
5-플루오로우라실(5-FU)은 3uM 농도로 처리하였으며, 다이클로페낙(DCF) 75uM, 덱시부프로펜(dexi) 3mM 및 4mM 및 나프록센(naproxen) 2mM을 각각 단독으로 처리하거나 상기 5-플루오로우라실(5-FU)과 병용처리하였다.5-Fluorouracil (5-FU) was treated at a concentration of 3 uM and treated with 75 uM of diclofenac (DCF), 3 mM dexibuprophen (dexi) and 2 mM of 4 mM and naproxen, Fluorouracil (5-FU).
그 결과, 5-플루오로우라실(5-FU) 또는 다이클로페낙(DCF)을 단독처리한 군보다 두 약물을 병용처리한 군에서 세포사멸(cell death)이 현저하게 증가되는 상승효과가 나타났으며, 세포증식 역시 병용처리군에서 더 억제되는 것을 확인하였다(도 13).As a result, there was a synergistic effect that cell death was significantly increased in the group treated with both drugs than in the group treated with 5-fluorouracil (5-FU) or diclofenac (DCF) alone And cell proliferation was further inhibited in the combination treatment group (FIG. 13).
5-플루오로우라실(5-FU)과 덱시부프로펜(dexi) 3mM 및 4mM 또는 아세클로페낙(ace) 500uM의 병용처리 역시 세포사멸이 크게 증가되는 것을 확인할 수 있었다(도 14 및 15).It was also confirmed that the combined treatment of 5-fluorouracil (5-FU) with 3 mM of dexibuprophen (dexi) and 4 mM of aceclofenac (ace)
따라서, 5-플루오로우라실(5-FU)을 다이클로페낙(DCF), 덱시부프로펜(dexi)또는 아세클로페낙(ace)과 병용투여하는 경우, 두 약물의 상승작용에 의해 세포사멸효과 또는 세포증식 억제효과가 현저하게 증가됨에 따라, 대장암을 훨씬 효과적으로 치료할 수 있음을 확인하였다.Therefore, when 5-fluorouracil (5-FU) is administered in combination with diclofenac (DCF), dexibuprofen (dexi) or aceclofenac (ace) It was confirmed that the proliferation inhibitory effect was remarkably increased, and the colon cancer could be treated more effectively.
시간
(hr)administration
time
(hr)
투여Combined
administration
투여Combined
administration
우라실
(5-FU)
3uM5-fluoro
Uracil
(5-FU)
3uM
(dexi)Dexibupropene
(dexi)
(ace)Aceclofenac
(ace)
<< 실험예Experimental Example 4> 폐암 4> Lung cancer 세포에 To the cell 대한 세포독성 및 세포증식 억제 효과 Cytotoxicity and inhibition of cell proliferation
상기 실험예 1의 방법을 이용하여, 폐암 치료제로 알려진 파클리탁셀(PAC) 및 NSAIDs를 병용처리하여 폐암 세포 A549에 대한 세포사멸 효과 및 세포증식 억제 효과를 평가하였다.Using the method of Experimental Example 1, paclitaxel (PAC) and NSAIDs known as therapeutic agents for lung cancer were co-treated to evaluate the apoptosis and cell proliferation inhibitory effect on lung cancer cell A549.
파클리탁셀(PAC)은 2.5nM 농도로 처리하였으며, 덱시부프로펜(dexi) 4mM 및 나프록센(nap) 2mM을 각각 단독으로 처리하거나 상기 파클리탁셀(PAC) 2.5nM과 병용처리하였다.Paclitaxel (PAC) was treated at a concentration of 2.5 nM and dexibuprophen (dexi) 4 mM and naproxen (nap) 2 mM were each treated alone or in combination with the paclitaxel (PAC) 2.5 nM.
그 결과, 파클리탁셀(PAC)을 덱시부프로펜(dexi) 4mM과 병용투여 했을 때 약물에 의한 세포사멸이 크게 증가하였고, 세포증식 억제 효과 역시 상승되는 것을 확인할 수 있었다(도 16).As a result, it was confirmed that when the combination of paclitaxel (PAC) and 4 mM dexibuprophen (dexi) was co-administered, the drug-induced apoptosis was significantly increased and the cell proliferation inhibitory effect was also increased (Fig. 16).
또한 파클리탁셀(PAC)과 나프록센(nap) 2mM을 병용투여 했을 때에도 세포사멸이 증가하였다(도 17).Also, cell death was increased when paclitaxel (PAC) and naproxen (nap) 2mM were administered together (Fig. 17).
따라서, 파클리탁셀(PAC)을 덱시부프로펜(dexi) 또는 나프록센(nap)과 병용투여하는 경우, 두 약물의 상승작용에 의해 세포사멸효과 또는 세포증식 억제효과가 증가됨에 따라, 대장암을 효과적으로 치료할 수 있음을 확인하였다.Therefore, when paclitaxel (PAC) is co-administered with dexibuprophen (dexi) or naproxen (nap), the cytotoxic effect or the cell proliferation inhibitory effect is increased by the synergistic action of the two drugs, Respectively.
시간
(hr)administration
time
(hr)
투여Combined
administration
투여Combined
administration
(PAC)
2.5nMPaclitaxel
(PAC)
2.5 nM
(dexi)Dexibupropene
(dexi)
(nap) Naproxen
(nap)
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 특허 청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.
Claims (8)
다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);
를 포함하는 암 예방 또는 치료용 약학적 조성물.An anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel; And
A ratio of one species selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) Nonsteroidal Antiinflammatory Drugs (NSAIDs);
Or a pharmaceutically acceptable salt thereof.
상기 약학적 조성물은 하기 조합으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 암 예방 또는 치료용 약학적 조성물:
조합 1) 타목시펜 및 다이클로페낙의 조합;
조합 2) 타목시펜 및 나프록센의 조합;
조합 3) 타목시펜 및 아세클로페낙의 조합;
조합 4) 타목시펜 및 프루비프로펜의 조합;
조합 5) 타목시펜 및 덱시부프로펜의 조합;
조합 6) 소라페닙 및 아세클로페낙의 조합;
조합 7) 소라페닙 및 다이클로페낙의 조합;
조합 8) 소라페닙 및 프루비프로펜의 조합;
조합 9) 소라페닙 및 덱시부프로펜의 조합;
조합 10) 소라페닙 및 나프록센의 조합;
조합 11) 5-플루오로우라실 및 다이클로페낙의 조합;
조합 12) 5-플루오로우라실 및 덱시부프로펜의 조합;
조합 13) 5-플루오로우라실 및 아세클로페낙의 조합;
조합 14) 파클리탁셀 및 덱시부프로펜의 조합; 및
조합 15) 파클리탁셀 및 나프록센의 조합.The method according to claim 1,
Wherein said pharmaceutical composition is selected from the group consisting of the following combinations:
Combination 1) a combination of tamoxifen and diclofenac;
Combination 2) a combination of tamoxifen and naproxen;
Combination 3) a combination of tamoxifen and aceclofenac;
Combination 4) a combination of tamoxifen and probioprofen;
Combination 5) a combination of tamoxifen and dexibuprofen;
Combination 6) a combination of sorafenib and aceclofenac;
Combination 7) a combination of sorafenib and diclofenac;
Combination 8) a combination of sorapenib and prubiprofen;
Combination 9) a combination of sorafenib and dexibuprofen;
Combination 10) a combination of sorafenib and naproxen;
Combination 11) a combination of 5-fluorouracil and diclofenac;
Combination 12) a combination of 5-fluorouracil and dexibuprofen;
Combination 13) a combination of 5-fluorouracil and aceclofenac;
Combination 14) a combination of paclitaxel and dexibuprofen; And
Combination 15) A combination of paclitaxel and naproxen.
상기 약학적 조성물은 하기 조합으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 암 예방 또는 치료용 약학적 조성물:
조합 1) 타목시펜 및 다이클로페낙의 조합;
조합 3) 타목시펜 및 아세클로페낙의 조합;
조합 4) 타목시펜 및 프루비프로펜의 조합;
조합 5) 타목시펜 및 덱시부프로펜의 조합;
조합 6) 소라페닙 및 아세클로페낙의 조합;
조합 7) 소라페닙 및 다이클로페낙의 조합;
조합 8) 소라페닙 및 프루비프로펜의 조합;
조합 9) 소라페닙 및 덱시부프로펜의 조합;
조합 10) 소라페닙 및 나프록센의 조합;
조합 11) 5-플루오로우라실 및 다이클로페낙의 조합; 및
조합 14) 파클리탁셀 및 덱시부프로펜의 조합.3. The method of claim 2,
Wherein said pharmaceutical composition is selected from the group consisting of the following combinations:
Combination 1) a combination of tamoxifen and diclofenac;
Combination 3) a combination of tamoxifen and aceclofenac;
Combination 4) a combination of tamoxifen and probioprofen;
Combination 5) a combination of tamoxifen and dexibuprofen;
Combination 6) a combination of sorafenib and aceclofenac;
Combination 7) a combination of sorafenib and diclofenac;
Combination 8) a combination of sorapenib and prubiprofen;
Combination 9) a combination of sorafenib and dexibuprofen;
Combination 10) a combination of sorafenib and naproxen;
Combination 11) a combination of 5-fluorouracil and diclofenac; And
Combination 14) Combination of paclitaxel and dexibuprofen.
상기 약학적 조성물은 하기 조합으로 이루어지는 군으로부터 선택되는 것을 특징으로 하는 암 예방 또는 치료용 약학적 조성물:
조합 1) 타목시펜 및 다이클로페낙의 조합;
조합 3) 타목시펜 및 아세클로페낙의 조합;
조합 7) 소라페닙 및 다이클로페낙의 조합;
조합 8) 소라페닙 및 프루비프로펜의 조합;
조합 9) 소라페닙 및 덱시부프로펜의 조합; 및
조합 10) 소라페닙 및 나프록센의 조합.The method of claim 3,
Wherein said pharmaceutical composition is selected from the group consisting of the following combinations:
Combination 1) a combination of tamoxifen and diclofenac;
Combination 3) a combination of tamoxifen and aceclofenac;
Combination 7) a combination of sorafenib and diclofenac;
Combination 8) a combination of sorapenib and prubiprofen;
Combination 9) a combination of sorafenib and dexibuprofen; And
Combination 10) Combination of sorafenib and naproxen.
상기 암은 유방암, 간암, 대장암 및 폐암으로 이루어진 군으로부터 선택된 1종 이상인 것인 암 예방 또는 치료용 약학적 조성물.The method according to claim 1,
Wherein the cancer is at least one selected from the group consisting of breast cancer, liver cancer, colon cancer and lung cancer.
상기 암은 유방암 및 간암으로 이루어진 군으로부터 선택된 1종 이상인 것인 암 예방 또는 치료용 약학적 조성물.6. The method of claim 5,
Wherein the cancer is at least one selected from the group consisting of breast cancer and liver cancer.
다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);
를 포함하는 암 예방 또는 개선용 건강기능식품 조성물.An anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel; And
A ratio of one species selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) Nonsteroidal Antiinflammatory Drugs (NSAIDs);
Or a pharmaceutically acceptable salt thereof.
다이클로페낙(diclofenac; DCF), 나프록센(naproxen), 아세클로페낙(aceclofenac; ace), 프루비프로펜(flurbiprofen; flur) 및 덱시부프로펜(dexibuprofen; dexi)으로 이루어진 군으로부터 선택되는 1종의 비스테로이드성 항염증제(Nonsteroidal Antiinflammatory Drugs; NSAIDs);
를 포함하는 암 예방 또는 개선용 건강식품 조성물.An anticancer agent selected from the group consisting of tamoxifen (TAM), sorafenib (sora), 5-fluorouracil (5-FU) and paclitaxel; And
A ratio of one species selected from the group consisting of diclofenac (DCF), naproxen, aceclofenac (ace), flurbiprofen (flur) and dexibuprofen (dexi) Nonsteroidal Antiinflammatory Drugs (NSAIDs);
Or a pharmaceutically acceptable salt thereof.
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| KR101598122B1 (en) | 2015-04-10 | 2016-02-26 | 인하대학교 산학협력단 | Composition for preventing or treating pancreatic cancer comprising sorafenib and melatonin |
| WO2016073835A1 (en) * | 2014-11-06 | 2016-05-12 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Compositions and methods of diazeniumdiolate-based prodrugs for treating cancer |
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| US20170128417A1 (en) * | 2014-07-01 | 2017-05-11 | Vicus Therapeutics, Llc | Combination drug therapies for cancer and methods of making and using them |
| WO2016073835A1 (en) * | 2014-11-06 | 2016-05-12 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Compositions and methods of diazeniumdiolate-based prodrugs for treating cancer |
| KR101598122B1 (en) | 2015-04-10 | 2016-02-26 | 인하대학교 산학협력단 | Composition for preventing or treating pancreatic cancer comprising sorafenib and melatonin |
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