KR101803000B1 - Pharmaceutical compositions for preventing or treating lung cancer comprising apigenin, curcumin, and honokiol as active ingredients - Google Patents
Pharmaceutical compositions for preventing or treating lung cancer comprising apigenin, curcumin, and honokiol as active ingredients Download PDFInfo
- Publication number
- KR101803000B1 KR101803000B1 KR1020160111383A KR20160111383A KR101803000B1 KR 101803000 B1 KR101803000 B1 KR 101803000B1 KR 1020160111383 A KR1020160111383 A KR 1020160111383A KR 20160111383 A KR20160111383 A KR 20160111383A KR 101803000 B1 KR101803000 B1 KR 101803000B1
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- KR
- South Korea
- Prior art keywords
- apigenin
- curcumin
- lung cancer
- honokiol
- present
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Abstract
Description
본 발명은 아피제닌 또는 커큐민; 및 호노키올 혼합물의 폐암 치료 효과에 관한 것이다.The present invention relates to a pharmaceutical composition comprising apigenin or curcumin; And the effect of treating the lung cancer with the honeycomb mixture.
암(cancer)이란 다양한 원인에 의해 세포의 분열과 사멸 간의 균형이 파괴됨으로써 계속적인 분열과 증식에 의해 발생하는 비정상적인 세포의 집단을 의미하며, 악성종양이라고도 한다. 일반적으로 암은 장기, 백혈구, 뼈, 림프절 등을 포함한 100 가지 이상의 신체의 여러 부분에서 발병하며, 주변 조직으로 침윤하는 현상 및 다른 기관으로 이동하는 전이를 통해 심각한 증상으로 발전하여 최종적으로 사망에 이르게 된다. 그 중, 폐에서 기원하는 악성 종양인 폐암은 그 조직형태에 따라 크게 소세포성 폐암(small cell lung cancer)과 비소세포성 폐암(non-small cell lung cancer)으로 구분된다. 상기 소세포폐암은 발병 조직의 위치에 의해 폐암의 일부로 구분되기는 하나, 다른 폐암과는 임상 경과, 치료법 및 예후 면에서 확연히 구분되는 특징이 있어 상기와 같이 구분하고 있다. 또한, 비소세포폐암은 조직형에 따라 선암, 편평상피세포암 및 대세포암으로 구분된다.Cancer is a group of abnormal cells caused by continuous division and proliferation by destroying the balance between cell division and death due to various causes, and it is also called malignant tumor. In general, cancer develops in more than 100 parts of the body, including organs, leukocytes, bones, lymph nodes, etc., and develops into serious symptoms through the invasion of surrounding tissues and metastasis to other organs, eventually leading to death do. Among them, lung cancer, which is a malignant tumor originating from the lung, is divided into small cell lung cancer and non-small cell lung cancer according to its tissue type. Although the small cell lung cancer is classified as a part of lung cancer by the location of the onset tissue, it is distinguished from the other lung cancer in terms of clinical course, treatment method and prognosis. In addition, non-small cell lung cancer is classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma according to histology.
구체적으로, 소세포폐암은 대체적으로 종괴가 크며 회백색을 띠고 기관지벽을 따라 증식하는 것으로 알려져 있는데, 대부분 진단 당시 수술적 절제가 어려울 정도로 진행되어 있는 경우가 많고, 악성도가 강하여 급속히 성장하며, 림프관이나 혈액 순환을 통하여 전신으로 용이하게 전이되는 반면, 화학요법이나 방사선요법에 의하여 현저한 치료효과를 나타내는 것으로 알려져 있다. 상기 소세포폐암이 전이되는 주요 장기로는 뇌, 간, 뼈, 폐, 부신, 신장 등이 보고되었는데, 주로 기도(기관지나 세기관지)에서 처음 발병하는 것으로 알려져 있다In particular, small-cell lung cancer is a large mass, grayish white, and is known to proliferate along the bronchial wall. In many cases, surgical resection is difficult at the time of diagnosis, and malignancy is rapidly growing. It is known that chemotherapy or radiotherapy has a remarkable therapeutic effect while it is easily transferred to whole body through blood circulation. The major organs in which the small cell lung cancer has metastasized are brain, liver, bone, lung, adrenal, kidney, etc. It is known that it first develops mainly in the airway (bronchus or bronchus)
반면, 비소세포폐암은 상술한 바와 같이 선암(adenocarcinoma), 편평상피세포암(squamous cell acrcinoma) 및 대세포암(large-cell carcinoma)으로 구분된다. 먼저, 선암은 폐말초 부위에서 주로 발생하고, 여성 또는 비흡연자에게서도 잘 발생하며, 크기가 작아도 전이가 되어 있는 경우가 많고, 최근 그의 발생 빈도가 증가하는 추세에 있다. 다음으로, 편평상피세포암은 주로 폐 중심부에서 발견되고, 주로 기관지 내강으로 자라 기관지를 막는 증상을 나타내며, 남성에게 흔하고, 흡연과 밀접하게 관련된 것으로 알려져 있다. 끝으로, 대세포암은 폐표면 근처(폐 말초)에서 주로 발생하고, 절반가량은 큰 기관지에서 발생하며, 전체 폐암의 4 내지 10% 정도를 차지하고, 세포 크기가 대체적으로 크며, 그 중 일부는 빠르게 증식 및 전이되는 경향이 있어 다른 비소세포폐암에 비해 예후가 나쁘다.On the other hand, as described above, non-small cell lung cancer is classified into adenocarcinoma, squamous cell acinoma and large-cell carcinoma. First, adenocarcinomas occur mainly in the lungs, and they occur frequently in women or non-smokers. In many cases, the adenocarcinoma is metastasized even if the size is small, and the incidence of the adenocarcinoma is increasing recently. Next, squamous cell carcinoma is found mainly in the central lung, and it is known to grow up to the lumen of the bronchial tree, blocking the airway, is common to men, and is closely related to smoking. Finally, large cell carcinomas arise mainly in the vicinity of the lung surface (the distal end of the lung), about half in large bronchi, accounting for 4 to 10% of all lung cancers, and generally large cell size, Proliferation and metastasis tend to be worse than other non-small cell lung cancer.
이와 같은 폐암이 조기에 진단될 경우에는, 약물치료 및 방사선 치료등을 통해 회복될 수 있으나, 일정 수준으로 병증이 악화된 경우에는 수술을 통해 병변을 제거하고, 약물치료 및 방사선 치료 등을 통한 치료를 수행하게 되는데, 아직까지는 폐암의 치료에 사용될 수 있도록 공인된 약물은 몇 가지로 제한되어 있어 환자에게 적합한 치료를 수행하기 어렵고, 그 부작용 또한 큰 문제로 대두되고 있으며, 대부분 1차 종양이 관찰된 시점에서는 이미 암의 전이가 발견되어, 수술 이후의 치료 성공률이 저조한 실정이다.When such lung cancer is diagnosed early, it can be recovered through medication or radiation therapy. However, if the disease progresses to a certain level, the lesion is removed through surgery, and treatment with medication or radiation therapy . However, the number of drugs approved for the treatment of lung cancer has been limited to a few, so it is difficult to perform appropriate treatment for the patients, and the side effects are also becoming a major problem. Most primary tumors are observed At the time of diagnosis, cancer metastasis has already been found and the success rate of treatment after surgery is low.
이에 따라, 암 치료를 위한 새로운 접근방법으로 독성이 비교적 낮은 천연물로부터 부작용이 적고 암 종의 전이를 억제하거나 감소시키는 효능이 뛰어난 발암 억제제 및 암 치료제를 개발하기 위한 노력이 계속되고 있으나, 이들 천연물 유래 치료제는 치료효과가 우수하지 못하다는 근본적인 단점이 해소되지 않고 있다(한국 특허공개번호 10-2012-0109139).Accordingly, as a new approach for cancer treatment, efforts have been made to develop cancer-suppressing agents and cancer treatment agents that have a low side effect from natural substances having relatively low toxicity and are excellent in efficacy of inhibiting or reducing cancer metastasis. However, The fundamental disadvantage that the therapeutic effect is not excellent is not solved (Korean Patent Publication No. 10-2012-0109139).
이러한 배경 하에서, 본 발명자들은 보다 안전하면서도 효과적으로 폐암을 치료할 수 있는 제제를 개발하기 위하여 예의 연구 노력한 결과, 아피제닌 또는 커큐민; 및 호노키올 혼합물이 폐암 세포 주의 사멸을 일으키고, 암 세포의 증식을 억제할 수 있음을 확인하여, 폐암 치료용 조성물로 유용하게 사용될 수 있음을 발견하고, 본 발명을 완성하였다.Under these circumstances, the inventors of the present invention have made extensive efforts to develop a formulation that can treat lung cancer more safely and effectively, and as a result, apigenin or curcumin; The present inventors have found that the compound of the present invention can be useful as a composition for treating lung cancer by confirming that a mixture of a compound of the present invention and a hornokiol can cause the death of lung cancer cells and inhibit cancer cell proliferation.
본 발명은 상기와 같은 문제점을 해결하기 위해 안출된 것으로서, 본 발명자들은 아피제닌, 커큐민, 호노키올의 단독 또는 혼합 투여에 의한 폐암 세포 주의 해당 작용 속도 감소, ANT2 발현 억제, HK2 발현 억제, PD-L1 발현 억제 및 ATP 생산을 감소 효과를 확인하고, 이에, 기초하여 본 발명을 완성하게 되었다.Disclosure of the Invention The present invention has been conceived to solve the above-mentioned problems. The present inventors have found that the reduction of the action rate of lung cancer cell by the administration of apigenin, curcumin or honokiol alone or in combination, inhibition of ANT2 expression, inhibition of HK2 expression, L1 expression and ATP production, and thus the present invention has been completed on the basis thereof.
이에, 본 발명의 목적은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition comprising apigenin or curcumin; And a pharmaceutical composition for the prophylaxis or treatment of lung cancer which comprises as an active ingredient honkiol.
또한, 본 발명의 다른 목적은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another object of the present invention is to provide a pharmaceutical composition comprising apigenin or curcumin; And a health functional food composition for preventing or ameliorating lung cancer comprising honkiol as an active ingredient.
그러나 본 발명이 이루고자 하는 기술적 과제는 이상에서 언급한 과제에 제한되지 않으며, 언급되지 않은 또 다른 과제들은 아래의 기재로부터 당업자에게 명확하게 이해될 수 있을 것이다.However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can be clearly understood by those skilled in the art from the following description.
상기와 같은 본 발명의 목적을 달성하기 위하여, 본 발명은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the object of the present invention, the present invention provides a pharmaceutical composition comprising apigenin or curcumin; And a pharmaceutical composition for the prophylaxis or treatment of lung cancer which comprises as an active ingredient honkiol.
본 발명의 다른 목적은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another object of the present invention is to provide a pharmaceutical composition comprising apigenin or curcumin; And a health functional food composition for preventing or ameliorating lung cancer comprising honkiol as an active ingredient.
본 발명의 일 구현예로서, 상기 조성물은 아피제닌 및 호노키올 혼합물을 유효성분으로 포함할 수 있다.In one embodiment of the present invention, the composition may comprise an apigenin and a honeycomb mixture as an active ingredient.
본 발명의 다른 구현예로서, 상기 조성물은 커큐민 및 호노키올 혼합물을 유효성분으로 포함할 수 있다.In another embodiment of the present invention, the composition may comprise a curcumin and a honeycomb mixture as an active ingredient.
본 발명의 또 다른 구현예로서, 상기 조성물은 ANT2 (Adenine nucleotide translocator 2) 유전자의 발현을 감소시킬 수 있다.In another embodiment of the present invention, the composition may reduce the expression of the ANT2 (Adenine nucleotide translocator 2) gene.
본 발명의 다른 구현예로서, 상기 조성물은 HK2 (hexokinase 2) 또는 PD-L1 (Programmed death-ligand 1) 단백질의 발현을 감소시킬 수 있다.In another embodiment of the present invention, the composition may reduce the expression of HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein.
나아가, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 폐암의 예방 또는 치료 방법을 제공한다.Furthermore, the present invention provides a method of preventing or treating lung cancer comprising administering the pharmaceutical composition to a subject.
뿐만 아니라, 본 발명은 상기 약학적 조성물의 폐암의 예방 또는 치료 용도를 제공한다.In addition, the present invention provides the use of the pharmaceutical composition for preventing or treating lung cancer.
본 발명은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 따른 조성물은 아피제닌, 커큐민 또는 호노키올을 단독으로 처리할 경우 보다 혼합 또는 병용 처리 할 경우에 서로 상승적으로 암 세포의 사멸을 유도하는 바, 본 발명의 아피제닌 또는 커큐민; 및 호노키올 혼합물을 유효성분으로 포함하는 폐암의 예방 또는 치료용 약학적 조성물은 항암 효과를 상승시켜 암 세포의 사멸을 유도함으로써 매우 우수한 암 치료 증대 효과를 나타낸다. 따라서 본 발명에 따른 조성물은 폐암의 예방, 개선 또는 치료에 유용하게 사용될 수 있다.The present invention relates to a pharmaceutical composition comprising apigenin or curcumin; And a pharmaceutical composition for preventing or treating lung cancer comprising as an active ingredient. The composition according to the present invention synergistically induces apoptosis of cancer cells when treated with apigenin, curcumin or honokiol alone or in combination with each other, as compared with apigenin or curcumin of the present invention. And a pharmaceutical composition for the prevention or treatment of lung cancer, which comprises a mixture of a hornokiol as an active ingredient, exhibits an excellent cancer therapeutic effect by inducing the killing of cancer cells by raising the anticancer effect. Therefore, the composition according to the present invention can be usefully used for preventing, ameliorating or treating lung cancer.
도 1은 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주 사멸 효과를 확인한 결과이다.
도 2는 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주의 ANT2 발현 억제 효과를 확인한 결과이다.
도 3은 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주의 ATP 생산 감소 효과를 확인한 결과이다.
도 4는 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주의 HK2 발현 억제 효과를 확인한 결과이다.
도 5는 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주의 해당작용 속도 (glycolysis rate) 감소 효과를 확인한 결과이다.
도 6a는 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주 A549에서의 PD-L1 발현 억제 효과를 확인한 결과이다.
도 6b는 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주 H2228에서의 PD-L1 발현 억제 효과를 확인한 결과이다.FIG. 1 shows the results of confirming lung cancer cell killing effect in the case of treatment with honokiol, apigenin and curcumin alone or in combination.
FIG. 2 shows the results of confirming the inhibitory effect of ANC2 on the expression of lung cancer cells in the treatment of monocytoin, apigenin and curcumin alone or in combination.
FIG. 3 shows the results of confirming the effect of reducing the ATP production of lung cancer cells by treating alone or in combination with honokiol, apigenin and curcumin.
FIG. 4 shows the results of confirming the inhibitory effect of HK2 on the expression of lung cancer cells in the treatment with honokiol, apigenin and curcumin alone or in combination.
FIG. 5 is a graph showing the effect of reducing the glycolysis rate of lung cancer cells in the treatment with honokiol, apigenin and curcumin alone or in combination.
FIG. 6A shows the results of confirming the inhibitory effect of PD-L1 on lung cancer cell line A549 in the treatment with honokiol, apigenin and curcumin alone or in combination.
FIG. 6B shows the results of confirming the effect of suppressing the expression of PD-L1 in lung cancer cell line H2228 upon treatment with honokiol, apigenin, curcumin alone or in combination.
본 발명에 따른 조성물은 아피제닌 또는 커큐민; 및 호노키올 혼합물을 유효성분으로 포함하며, 폐암 세포 주의 해당 작용 속도 감소, ANT2 발현 억제, HK2 발현 억제, PD-L1 발현 억제 및 ATP 생산을 감소시켜, 폐암의 예방, 개선 또는 치료 효과를 확인한바, 이에 기초하여 본 발명을 완성하였다.The composition according to the present invention may comprise apigenin or curcumin; And Hunochiol as an active ingredient and confirmed the prevention, amelioration or therapeutic effect of lung cancer by reducing the action rate of lung cancer cell line, inhibiting ANT2 expression, inhibiting HK2 expression, inhibiting PD-L1 expression and ATP production , Thereby completing the present invention.
이하, 본 발명에 대해 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 폐암의 예방 또는 치료용 조성물을 제공한다. 상기 조성물은 약학적 및 건강기능식품 조성물을 포함한다.The present invention relates to a pharmaceutical composition comprising apigenin or curcumin; And a composition for the prophylaxis or treatment of lung cancer, which comprises as an active ingredient honkiol. Such compositions include pharmaceutical and health functional food compositions.
본 발명에서 사용되는 용어, "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 폐암 관련 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.As used herein, the term "prophylactic " means any action that inhibits or delays the onset of a lung cancer-related disease by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"란 본 발명에 따른 약학적 조성물의 투여에 의해 폐암에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" as used in the present invention means all the actions for improving or alleviating symptoms of lung cancer by administration of the pharmaceutical composition according to the present invention.
본 발명의 조성물에 의한 예방, 치료 대상 질병인 "암(cancer)"은 생체 조직 안에서 세포가 무제한으로 증식하여 악성 종양을 일으키는 질환이며, 보다 구체적으로 폐암일 수 있으나, 이에 제한되는 것은 아니다."Cancer", a disease to be prevented and treated by the composition of the present invention, is a disease in which a cell grows indefinitely in a living tissue to cause a malignant tumor. More specifically, the cancer is not limited thereto.
본 발명에서 사용되는 "호노키올(honokiol)"은 폴리페놀계 화합물로, 목련종(Magnolia species)으로부터 분리, 정제 또는 추출될 수 있고, 보다 구체적으로 후박나무에서 분리, 정제 또는 추출될 수 있으나 이에 제한되는 것은 아니며, 화학적으로 합성된 화합물 또는 상업적으로 판매되는 것 모두를 사용할 수 있다. 또한, 호노키올 유도체 또는 유사체일 수 있으나 이에 제한되는 것은 아니다.As used herein, "honokiol" is a polyphenolic compound, which can be isolated, purified or extracted from Magnolia species and, more specifically, can be isolated, purified or extracted from barberry But are not limited to, chemically synthesized compounds or both commercially available ones. It may also be, but is not limited to, a monochiol derivative or analog.
본 발명에서 사용되는 "아피제닌 (apigenin, 5,7,4'-trihydroxyflavone)"은 플라보노이드 계열의 화합물로서, 아까시나무 추출물에서 발견될 뿐 아니라 오렌지, 사과, 체리, 포도 등의 과일과 양파, 파슬리, 샐러리, 보리, 토마토 등의 야채나 차, 와인 등의 음료에 풍부하게 존재하여, 이로부터 분리, 정제 또는 추출될 수 있으나, 이에 제한되는 것은 아니며, 화학적으로 합성된 화합물 또는 상업적으로 판매되는 것 모두를 사용할 수 있다. 또한, 아피제닌 유도체 또는 유사체일 수 있으나 이에 제한되는 것은 아니다.As used herein, the term "apigenin (5,7,4'-trihydroxyflavone)" is a flavonoid-based compound that is found not only in the acacia tree extract but also in fruits such as oranges, apples, cherries, grapes, , Celery, barley, tomato, etc., vegetables, tea, wine, etc., and may be isolated, purified or extracted therefrom, but the present invention is not limited thereto, and chemically synthesized compounds or commercially available products You can use all of them. Also, it may be an apigenin derivative or an analogue, but is not limited thereto.
본 발명에서 사용되는 "커큐민(curcumin)"은 알칼로이드계 화합물로, 강황 또는 울금에서 분리, 정제 또는 추출될 수 있으나, 이에 제한되는 것은 아니며, 화학적으로 합성된 화합물 또는 상업적으로 판매되는 것 모두를 사용할 수 있다. 또한, 커큐민 유도체 또는 유사체 일 수 있으나, 이에 제한되는 것은 아니다.As used herein, "curcumin" is an alkaloid compound, which may be isolated, purified or extracted from turmeric or corn, but not limited thereto, and may be any chemically synthesized compound or commercially available . It may also be a curcumin derivative or analog, but is not limited thereto.
또한, 본 발명에 따른 조성물은 아피제닌 및 호노키올 혼합물을 유효성분으로 포함하는 폐암의 예방, 개선 또는 치료용 조성물일 수 있으나, 이에 제한되는 것은 아니다.In addition, the composition according to the present invention may be a composition for preventing, improving or treating lung cancer comprising an apigenin and a honeycomb mixture as an active ingredient, but is not limited thereto.
또한, 본 발명에 따른 조성물은 커큐민 및 호노키올 혼합물을 유효성분으로 포함하는 폐암의 예방, 개선 또는 치료용 조성물일 수 있으나, 이에 제한되는 것은 아니다.In addition, the composition according to the present invention may be a composition for prevention, improvement or treatment of lung cancer comprising curcumin and a honeycomb mixture as an active ingredient, but is not limited thereto.
또한, 본 발명에 따른 조성물은 ANT2 (Adenine nucleotide translocator 2) 유전자의 발현을 감소시키는 것을 특징으로 한다.In addition, the composition according to the present invention is characterized by decreasing the expression of the ANT2 (Adenine nucleotide translocator 2) gene.
본 발명의 "ANT2(Adenine nucleotide translocator 2)"는 암 세포의 생존, 증식 및 전이에 있어서 중요한 기능을 가지고 있는 유전자이다. 아데닌 뉴클레오타이드 트랜스로카아제/트랜스로캐이터(ANT) 2 단백질은 미토콘드리아 내막에서 가장 많은 단백질이며, 여섯 개의 막관통 나선으로 형성되어 있다. ANT는 미토콘드리아 ATP에서 세포질 ADP로의 변화를 촉매 함으로써 세포 에너지 대사에서 중요한 역할을 하며, 이로써 미토콘드리아 산화적 인산화에 영향을 미친다. 모든 포유동물들은 ANT1 내지 ANT3의 아이소폼(isoform)을 가지고 있으며, 상기 아이소폼 패밀리인, ANT2는 인트라미토콘드리아 ADP로의 변환에서 해당과정에 의해 생산되는 세포질 ATP의 흡수를 증가시키는 것으로 보이며, 그 결과 마토콘드리아 막 전위를 유지할 수 있으며, ANT2의 결실(knockdown)은 암 세포에서 막전위차를 감소시킨다.The "ANT2 (Adenine nucleotide translocator 2)" of the present invention is a gene having important functions in survival, proliferation and metastasis of cancer cells. The adenine nucleotide transreactase / transurocatheter (ANT) 2 protein is the most abundant protein in the mitochondrial inner membrane and is formed by six membrane perforations. ANT plays an important role in cellular energy metabolism by catalyzing changes from mitochondrial ATP to cytoplasmic ADP, thereby affecting mitochondrial oxidative phosphorylation. All mammals have an isoform of ANT1 to ANT3 and the isoform family ANT2 appears to increase the uptake of cellular ATP produced by the process in the conversion to intramitochondrial ADP, It can maintain the Condylar membrane potential, and knockdown of ANT2 reduces membrane potential difference in cancer cells.
또한, 본 발명에 따른 조성물은 HK2 (hexokinase 2) 또는 PD-L1 (Programmed death-ligand 1) 단백질의 발현을 감소시키는 것을 특징으로 한다.In addition, the composition according to the present invention is characterized by decreasing the expression of HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein.
본 발명의 "HK2 (hexokinase 2)"는 6개의 탄소가 존재하는 6탄당을 인산화 시켜 6탄당 인산으로 전환시키는 효소로서, HK2는 정상세포에서는 발현양이 적으나 대부분의 암세포에서는 발현양이 매우 높으며, 포도당을 인산화하는 기능과 더불어 미토톤드리아의 VDAC 단백질과 결합하고 세포사멸기전 (Apoptosis)을 저해하여 암세포의 생존력을 강화시키는 기능을 가지고 있다. 따라서 HK2를 표적으로 하는 암 치료에 효과적으로 사용될 수 있다.The expression "HK2 (hexokinase 2)" of the present invention is an enzyme which converts 6-carbon sugar having 6 carbon atoms to 6-phosphoric acid by phosphorylation. HK2 is a small amount of expression in normal cells but is highly expressed in most cancer cells In addition to phosphorylation of glucose, it binds with VDAC protein of mitotonidia and inhibits apoptosis, thereby enhancing the viability of cancer cells. Therefore, it can be effectively used for cancer treatment targeting HK2.
또한, 본 발명의 "PD-L1(Programmed death-ligand 1)" 단백질은 암 세포의 표면에 존재하는 단백질로서, 암 세포의 사멸 효과를 가지고 있는 T세포가, 암 세포의 표면에 있는 단백질인 PD-L1과 결합하면, T세포는 암 세포를 공격하지 못하여, 암 세포 사멸 효과를 잃게 된다. 면역항암제는 항체가 PD-L1 단백질의 결합을 막아 T세포가 스스로 암세포를 공격하게 만든다. 상기 항암제는 인체 면역시스템을 강화하는 것이어서 기존 항암제에서 생기는 부작용이나 내성이 없다. 따라서 암 세포의 면역 회피 전략의 하나로서 PD-L1의 발현 조절을 통해, 면역검문(immune checkpoint) 기능의 변화를 통하여 종양 특이 T림프구 세포의 기능을 억제할 수 있다.Also, the "PD-L1 (Programmed death-ligand 1)" protein of the present invention is a protein present on the surface of cancer cells, and the T cell having the killing effect of cancer cells is a protein When combined with -L1, T cells do not attack cancer cells and lose the cancer cell killing effect. Immune anticancer drugs block the binding of the PD-L1 protein by the antibody, causing T cells to attack cancer cells themselves. The anticancer agent enhances the human immune system and has no side effects or resistance to conventional anticancer agents. Therefore, it is possible to suppress the function of tumor-specific T lymphocyte cells by changing the immune checkpoint function through modulation of PD-L1 expression as one of immunity avoidance strategies of cancer cells.
본 발명의 일 실시예에서는 폐암 세포 주에 호노키올, 아피제닌, 커큐민을 단독 또는 혼합 처리하여 암 세포의 사멸 효과를 확인(실시예 1 참조)하였으며, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시 폐암 세포 주의 ANT2 발현 억제 효과(실시예 2 참조), ATP 생산 감소 효과(실시예 3 참조), HK2 발현 억제 효과(실시예 4 참조), 해당작용 속도 감소 효과(실시예 5 참조) 및 PD-L1 발현 억제효과(실시예 6 참조)를 확인하였다.In one embodiment of the present invention, the killing effect of cancer cells was confirmed by treating monoclonal or monocyte-treated cells with lung cancer cells alone (see Example 1), and monokinin, apigenin, curcumin alone or in combination (See Example 2), ATP production reduction effect (see Example 3), HK2 expression inhibition effect (see Example 4), corresponding action rate reduction effect (see Example 5), and PD-L1 expression inhibitory effect (see Example 6).
따라서 본 발명의 아피제닌 또는 커큐민; 및 호노키올을 유효성분으로 포함하는 약학적 조성물은 폐암 세포 주의 해당 작용 속도 감소, ANT2 발현 억제, HK2 발현 억제, PD-L1 발현 억제 및 ATP 생산을 감소시키는바, 폐암의 예방, 개선 또는 치료용 조성물의 유효성분으로도 이용될 수 있다.Thus, apigenin or curcumin of the present invention; And a prodrug of the present invention are useful as a preventive, ameliorating, or therapeutic agent for lung cancer, which is effective for reducing the action rate of lung cancer cells, inhibiting ANT2 expression, inhibiting HK2 expression, inhibiting PD- And may also be used as an active ingredient of the composition.
본 발명에 따른 약학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있다. 이때, 약제학적으로 허용되는 담체는 제제 시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성셀룰로스, 폴리비닐피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일등을 포함하나, 이에 한정되는 것은 아니다. 또한, 상기성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, a pharmaceutically acceptable carrier. Herein, pharmaceutically acceptable carriers are those conventionally used at the time of formulation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose But are not limited to, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Further, in addition to the above components, a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like may be further included.
본 발명의 약제학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may vary depending on the condition and weight of the patient, The mode of administration, the route of administration, and the time, but may be appropriately selected by those skilled in the art.
본 발명의 약제학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 얄려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래 의 치료제와는 순차적 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. In the present invention, the term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, sequentially or concurrently with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
구체적으로 본 발명의 약제학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율 및 배설속도, 질병종류, 병용되는 약물에 따라 달라질 수 있으며, 일반적으로는 체중 1kg 당 0.001 내지 150mg, 바람직하게는 0.01 내지 100mg을 매일 또는 격일 투여하거나, 1일 1내지 3회로 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감 될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the age, sex, condition, body weight, absorbency, inactivation rate and excretion rate of the active ingredient in the body, type of disease, 0.001 to 150 mg, preferably 0.01 to 100 mg, per 1 kg of body weight may be administered daily or every other day, or one to three divided doses per day. However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
또한, 본 발명의 조성물은 폐암 관련 질환의 예방 또는 개선을 목적으로 건강기능식품에 첨가될 수 있다. 본 발명의 폐암 예방 또는 개선 효과를 갖는 화합물을 식품 첨가물로 사용할 경우, 상기 화합물을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상적인 방법에 따라 적절하게 사용할 수 있다. 유효성분의 혼합양은 사용 목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조 시 본 발명의 화합물은 원료에 대하여 15 중량% 이하, 바람직하게는 10 중량% 이하의 양으로 첨가된다. 그러나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.In addition, the composition of the present invention may be added to a health functional food for the purpose of preventing or ameliorating lung cancer-related diseases. When the compound having the lung cancer prevention or ameliorating effect of the present invention is used as a food additive, the compound can be added as it is, or can be used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment). Generally, the compound of the present invention is added in an amount of not more than 15% by weight, preferably not more than 10% by weight based on the raw material in the production of food or beverage. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range.
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 육류, 소시지, 빵, 쵸코렛, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include dairy products such as meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include health functional foods in a conventional sense.
본 발명의 건강음료 조성물은 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물은 포도당 및 과당과 같은 모노사카라이드, 말토오스 및 수크로오스와 같은 디사카라이드, 덱스트린 및 시클로덱스트린과 같은 폴리사카라이드, 및 자일리톨, 소르비톨 및 에리트리톨 등의 당알콜이다. 감미제로서는 타우마틴, 스테비아 추출물과 같은 천연 감미제나, 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100㎖당 일반적으로 약 0.01-0.20g, 바람직하게는 약 0.04-0.10g 이다.The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. The above-mentioned natural carbohydrates are monosaccharides such as glucose and fructose, polysaccharides such as disaccharides such as maltose and sucrose, dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like. The ratio of the natural carbohydrate is generally about 0.01-0.20 g, preferably about 0.04-0.10 g, per 100 ml of the composition of the present invention.
상기 외에 본 발명의 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 조성물은 천연 과일쥬스, 과일쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 조성물 100 중량부 당 0.01-0.20 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acids and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, A carbonating agent used in a carbonated beverage, and the like. In addition, the composition of the present invention may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. The proportion of such additives is not critical, but is generally selected in the range of 0.01-0.20 parts by weight per 100 parts by weight of the composition of the present invention.
본 발명의 다른 양태로서, 본 발명은 상기 약학적 조성물을 개체에 투여하는 단계를 포함하는 폐암의 치료 방법을 제공한다. 본 발명에서 "개체"란 질병의 치료를 필요로 하는 대상을 의미하고, 보다 구체적으로는, 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.In another aspect of the present invention, the present invention provides a method for treating lung cancer comprising administering the pharmaceutical composition to a subject. The term " individual "as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a mammal such as a human or non-human primate, mouse, dog, cat, horse and cattle .
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
[[ 실시예Example ]]
실시예 1. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주 사멸 효과Example 1. Effect of Honkiol, Apigenin, Curcumin alone or Mixed on Lung Cancer Cells
호노키올, 아피제닌, 커큐민의 폐암 세포 주 사멸 효과를 확인하기 위해, 인간 폐암 세포 주 A549(adenocarcinomic human alveolar basal epithelial cells)를 대상으로 호노키올, 아피제닌, 커큐민(Sigma-Aldrich)을 단독 또는 혼합하여 처리하였다. 인간 폐암 세포 주에 호노키올, 아피제닌, 커큐민을 처리한 농도는 투여 농도 곡선(dose-concentration curve)을 통해서, 단독 투여 시 세포 사멸이 20% 유도되는 농도(IC20: inhibitory concentration 20)인 10 μM로 정하여 단독 또는 혼합하여 처리하였다. 처리 24시간 후, 폐암 세포 주의 사멸 효과는 CCK8 assay(Cell Counting Kit-8, Dojindo Molecular Technologies, Inc)를 이용하여 분석하였다.In order to confirm the effect of Hunokiol, apigenin and curcumin on the lung cancer cell death, human lung cancer cell line A549 (adenocarcinomic human alveolar basal epithelial cells) was administered alone or mixed with honokiol, apigenin, and curcumin (Sigma-Aldrich) Lt; / RTI > Concentrations of hornokiol, apigenin and curcumin in human lung cancer cells were determined by the dose-concentration curve using the IC 20 (inhibitory concentration 20) mu M, alone or in combination. After 24 hours of treatment, lung cancer cell killing effect was analyzed using CCK8 assay (Cell Counting Kit-8, Dojindo Molecular Technologies, Inc).
그 결과, 도 1에 나타낸 바와 같이, 호노키올, 아피제닌 또는 커큐민의 단독 처리에 비해 혼합 처리 시 세포사멸 효과가 현저하게 증가하였다. 구체적으로, 호노키올 단독 처리에 의한 세포 사멸이 19%, 아피제닌 단독 처리에 의한 세포 사멸이 22%, 커큐민 단독 처리에 의한 세포 사멸이 20%인 결과와 비교하여, 호노키올 + 아피제닌 혼합물에 의한 세포 사멸이 79%, 호노키올 + 커큐민 혼합물에 의한 세포 사멸이 83%를 나타내었다. 상기 혼합물에 의한 세포 사멸 효과는 단순한 상가효과(additive effect)가 아닌 상승효과(synergistic effect)임을 확인할 수 있다. 상기로부터, 폐암 환자 치료 시, 호노키올, 아피제닌, 커큐민의 단독 투여에 비해 호노키올 + 아피제닌, 또는 호노키올 + 커큐민의 혼합 투여가 폐암 치료 효능을 증대시킬 수 있을 것으로 기대된다.As a result, as shown in Fig. 1, the cell killing effect was remarkably increased in the mixed treatment, compared with the monoclonal treatment with honokiol, apigenin or curcumin. Specifically, compared to the results of cell death by 19% of Honokeol alone, 22% of apigenin-only treatment, and 20% of apoptosis by curcumin alone treatment, Cell death was 79% and cell death by hornokiol + curcumin mixture was 83%. It can be confirmed that the cell killing effect by the mixture is not a simple additive effect but a synergistic effect. From the above, it is expected that the combined administration of honokiol + apigenin or honokiol + curcumin in the treatment of patients with lung cancer, compared with monotherapy of honokiol, apigenin and curcumin, may enhance lung cancer therapeutic efficacy.
실시예 2. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주의 ANT2 발현 억제 효과Example 2 Inhibitory Effect of Honkiol, Apigenin and Curcumin on the ANT2 Expression of Lung Cancer Cells
호노키올, 아피제닌, 커큐민의 ANT2 발현 억제 효과를 확인하기 위해, 인간 폐암 세포 주 A549를 대상으로 호노키올, 아피제닌, 커큐민을 단독 또는 혼합하여 처리하였다. 그 후, 폐암 세포 주의 ANT2 mRNA 발현이 억제되는 것을 확인하고자 qRT-PCR 분석을 수행하였다. 보다 구체적으로, 인간 폐암 세포 주 A549에 10 μM의 호노키올, 아피제닌, 커큐민을 단독 또는 혼합 처리한 후, 24시간 뒤, RNAs를 추출하고(TRIzol® RNA Isolation Reagents, Thermo Sientific), 역전사 반응(RT: reverse transcription)을 통해 cDNA를 합성한(PrimeScript 1st strand cDNA Synthesis Kit, Takara) 후, SYBR(SYBR Premix Ex Taq, Takara)을 이용하여 실시간 중합효소 반응 (real-time polymerase chain reaction : qPCR)을 실시하였다. 분석 대상인 ANT2 (adenine nucleotide translocase 2)는 암 세포의 생존, 증식 및 전이에 매우 중요한 역할을 한다고 잘 알려진 유전자이다.In order to confirm the effect of inhibiting the ANT2 expression of honokiol, apigenin and curcumin, human lung cancer cell line A549 was treated with honokiol, apigenin and curcumin alone or in combination. After that, qRT-PCR analysis was performed to confirm that the expression of ANT2 mRNA in lung cancer cells was inhibited. More specifically, RNAs were extracted (TRIzol® RNA Isolation Reagents, Thermo Sientific), the reverse transcription reaction was performed 24 hours after the human lung cancer cell line A549 was treated with 10 μM of Honkiol, Apigenin and Curcumin alone or mixed Real-time polymerase chain reaction (qPCR) was performed using SYBR (SYBR Premix Ex Taq, Takara) after cDNA synthesis (PrimeScript 1st strand cDNA Synthesis Kit, Takara) Respectively. ANT2 (adenine nucleotide translocase 2) is a well known gene that plays an important role in the survival, proliferation and metastasis of cancer cells.
qRT-PCR 실험 결과의 분석은 하기의 공식을 이용하였다.Analysis of the results of qRT-PCR experiments was performed using the following formula.
[fold change = 2 - ΔΔCt, where ΔΔCt = (Ct of gene of interest, treated - Ct of HK gene, treated) - (Ct of gene of interest, control - Ct of HK gene, control), Ct was the threshold cycle number and HK was the house-keeping gene.](fold change = 2 - ΔΔCt, where ΔΔCt = (Ct of gene of interest, treated - Ct of HK gene, treated) number and HK was the house-keeping gene.]
또한, qPCR에 사용된 프라이머의 염기서열은 하기 표 1에 나타내었다.The base sequences of the primers used in qPCR are shown in Table 1 below.
그 결과, 도 2에 나타낸 바와 같이, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리에 의해 ANT2 발현이 감소된 것을 확인하였으며, 호노키올, 아피제닌, 커큐민 단독 처리에 비해 호노키올 + 아피제닌, 또는 호노키올 + 커큐민 처리시, ANT2의 발현 억제 효과가 상대적으로 높은 것을 확인하였다.As a result, as shown in Fig. 2, ANT2 expression was decreased by the treatment of monocytoin, apigenin, and curcumin alone or mixed, and compared with monokine treatment with honokiol, apigenin and curcumin, Or the effect of inhibiting the expression of ANT2 was relatively high in the honokiol + curcumin treatment.
상기로부터, 호노키올 + 아피제닌, 또는 호노키올 + 커큐민 혼합 투여에 의하여, ANT2 작은 간섭 RNA인 shRNA(short hairpin RNA) 또는 siRNA(short interfering RNA)에 의한 암 치료 효과와 유사한 치료 효과를 기대할 수 있을 것으로 판단된다. 뿐만 아니라, 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리에 의한 ANT2 감소 효과는 작은 간섭 RNA를 이용하여 ANT2를 감소시켜, 암 치료를 시행할 때 갖게 되는 문제점인 siRNA 또는 shRNA의 체내로의 운반(delivery system)에 관한 문제를 해결 할 수 있을 것으로 기대된다.From the above, a therapeutic effect similar to that of cancer treatment by shRNA (short hairpin RNA) or siRNA (short interfering RNA), which is an ANT2 small interference RNA, can be expected by the combination of honokiol + apigenin or honokiol + curcumin . In addition, antinociceptive effects of honokiol, apigenin, curcumin, or curcumin alone or with mixed treatment reduce the ANT2 using small interfering RNAs, resulting in the delivery of siRNA or shRNA into the body delivery system) that can be used to solve these problems.
실시예 3. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주의 ATP 생산 감소 효과Example 3 Reduction of ATP Production in Lung Cancer Cells by Honokeol, Apigenin, Curcumin alone or Mixed Treatment
상기 실시예 2의 결과, 인간 폐암 세포 주에 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리하였을 때, ANT2 발현이 효과적으로 억제되는 것을 확인하였다. 따라서 ANT2의 기능이 암 세포의 ATP 생산에 결정적인 역할을 하는 것에 기인하여, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리가 암 세포의 ATP 생산을 감소시킬 것이라 예상하였다.As a result of the above Example 2, it was confirmed that ANT2 expression was effectively inhibited when human lung cancer cells were treated with monocytoin, apigenin, curcumin alone or in combination. Therefore, antineoplastic activity of ANT2 is thought to play a crucial role in the ATP production of cancer cells, suggesting that treatment of monoclonal, apigenin, curcumin alone or in combination would reduce ATP production in cancer cells.
이에, ANT2 발현 억제로 인한 폐암 세포 주의 ATP 생산 감소 효과를 확인하고자, 인간 폐암 세포 주 A549에 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리한 후, CellTiter-Glo™ Luminescent Cell Viability assay kits (Promega)를 이용하여 분석하였다.In order to confirm the effect of inhibiting ANT2 expression, ATP production of lung cancer cells was evaluated by using CellTiter-Glo ™ Luminescent Cell Viability assay kits (Promega ).
그 결과, 도 3에 나타낸 바와 같이, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시, 인간 폐암 세포 주의 ATP 생산을 효과적으로 감소시킨 결과를 확인하였으며, 특히 호노키올 + 아피제닌, 호노키올 + 커큐민의 혼합 투여 시, 단독 투여에 비해 ATP 생산 감소 효과가 상대적으로 증대되었다.As a result, as shown in FIG. 3, it was confirmed that ATP production of human lung cancer cell line was effectively reduced when monoclonal, apigenin and curcumin were treated alone or in combination. In particular, , The effect of reducing ATP production relative to single administration was relatively increased.
상기로부터, 생존의 필수 에너지원인 ATP의 감소는 암 세포의 성장을 억제시키고, 궁극적으로 암 세포의 사멸을 유도하므로, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 투여가 ANT2 발현 억제로 인한 ATP 생산 감소를 유도했을 것이라 판단되며, 이로써 암 세포에서 ATP 생산 억제 효과를 통해, 향상된 암 치료 효과를 기대할 수 있다.From the above, it can be concluded that the reduction of ATP, which is an essential energy of survival, inhibits the growth of cancer cells and ultimately induces the death of cancer cells, so that the administration of monoclonal, apigenin, curcumin alone or in combination causes ATP production , And thus, it is expected that an improved cancer treatment effect can be expected by inhibiting ATP production in cancer cells.
실시예 4. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주의 HK2 발현 억제 효과Example 4 Inhibitory Effect of Honkiol, Apigenin and Curcumin on the Expression of HK2 Expression in Lung Cancer Cells
호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리로 인한 ANT2 발현 억제가 해당작용에 관여하는 효소인 hexokinase 2(HK2)의 발현을 조절하는지 확인하고자, 인간 폐암 세포 주 A549를 대상으로 호노키올, 아피제닌, 커큐민을 단독 또는 혼합하여 처리한 후, qRT-PCR을 이용하여 분석하였다.To determine whether the inhibition of ANT2 expression by either alone or in combination with honokiol, apigenin, and curcumin modulates the expression of hexokinase 2 (HK2), the enzyme involved in the action, human lung cancer cell line A549 Jenine, and curcumin, either singly or in combination, and then analyzed using qRT-PCR.
qRT-PCR 실험 결과의 분석은 하기의 공식을 이용하였다.Analysis of the results of qRT-PCR experiments was performed using the following formula.
[fold change = 2 - ΔΔCt, where ΔΔCt = (Ct of gene of interest, treated - Ct of HK gene, treated) - (Ct of gene of interest, control - Ct of HK gene, control), Ct was the threshold cycle number and HK was the house-keeping gene.](fold change = 2 - ΔΔCt, where ΔΔCt = (Ct of gene of interest, treated - Ct of HK gene, treated) number and HK was the house-keeping gene.]
또한, qPCR에 사용된 프라이머의 염기서열은 하기 표 2에 나타내었다.The base sequences of the primers used in qPCR are shown in Table 2 below.
그 결과, 도 4에 나타낸 바와 같이, 호노키올, 아피제닌, 커큐민을 단독 또는 혼합 처리하였을 때, HK2의 발현이 효과적으로 감소되는 것을 확인하였으며, 호노키올, 아피제닌, 커큐민 단독 처리에 비해 호노키올 + 아피제닌, 또는 호노키올 + 커큐민을 혼합 처리하였을 때, HK2의 발현 억제 효과가 상대적으로 높게 나타났다.As a result, as shown in FIG. 4, it was confirmed that the expression of HK2 was effectively reduced when monoclonal or monocyte treated with honokiol, apigenin, or curcumin was effectively treated, and compared with monoclonal, apigenin, The effect of inhibiting the expression of HK2 was relatively high when mixed with apigenin or honokiol + curcumin.
상기 HK2 효소는 정상세포에서 그 발현양이 적으나 대부분의 암 세포에서는 HK2의 발현양이 매우 높다. 또한, 상기 HK2 효소는 포도당을 인산화 할 뿐만 아니라, 미토톤드리아의 VDAC 단백질과 결합하여 세포사멸기전(Apoptosis)을 저해하며, 그 결과, 암 세포의 생존력을 강화시키는 기능을 한다. 따라서 호노키올 + 아피제닌 혼합물, 또는 호노키올 + 커큐민 혼합물의 처리로 인한 HK2 발현을 현저하게 억제시킴으로써, HK2를 표적으로 하는 암 치료에 있어서, 그 치료 효과를 증대시킬 것으로 기대된다.Although the expression of HK2 enzyme is low in normal cells, the expression level of HK2 is very high in most cancer cells. In addition, the HK2 enzyme not only phosphorylates glucose but also binds to VDAC protein of mitoton dria to inhibit apoptosis, thereby enhancing the viability of cancer cells. Therefore, it is expected that the treatment effect of HK2-targeted cancer will be enhanced by remarkably inhibiting HK2 expression due to the treatment of a mixture of Honkiol + Apigenin or Honkiol + Curcumin.
실시예 5. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주의 해당작용 속도 (glycolysis rate) 감소 효과Example 5 Reduction of the glycolysis rate of lung cancer cells by treatment with honokiol, apigenin, curcumin alone or in combination
상기 실시예 4의 결과에서, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리로 인한 HK2 발현 억제 효과를 확인하였다. 이에, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리가 폐암 세포 주의 해당작용 속도를 감소시키는지 확인하고자, 인간 폐암 세포 주 A549를 대상으로 호노키올, 아피제닌, 커큐민을 단독 또는 혼합하여 처리한 후, Lactate Assay Kit (Biovision)을 이용하여 분석하였다.In the results of Example 4, the effect of inhibiting HK2 expression by the treatment of monoclonal, apigenin and curcumin alone or mixed was confirmed. In order to confirm whether the treatment of Hunochiol, apigenin and curcumine alone or in combination reduces the rate of action of lung cancer cells, human lung cancer cell line A549 was treated with either alone or in combination with honokiol, apigenin and curcumin And then analyzed using the Lactate Assay Kit (Biovision).
그 결과, 도 5에 나타낸 바와 같이, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리로 인하여, 인간 폐암 세포 주의 해당작용 감소 효과를 확인 하였으며, 특히 호노키올, 아피제닌, 커큐민의 단독 투여보다, 호노키올 + 아피제닌 또는 호노키올 + 커큐민의 혼합 투여 시, 해당작용 감소 효과가 증대된 것을 확인하였다.As a result, as shown in Fig. 5, the effect of reducing the action of human lung cancer cell line was confirmed by the treatment of monoclonal, apigenin and curcumin alone or in combination. In particular, as compared with the administration of monocytoin, apigenin, It was confirmed that the effect of reducing the action was increased when the combination of honokiol + apigenin or honokiol + curcumin was administered.
한편, 암 세포의 포도당 대사에 있어, 미토콘드리아의 산화적 인산화 경로에 결함이 존재하기 때문에, 주로 해당 과정만으로 ATP를 생산할 것이라는 가정 하에, 해당 과정을 통한 ATP 생산성은 산화적 인산화보다 비효율적이므로, 암 세포는 충분한 ATP를 생산하기 위하여 해당 과정을 매우 높은 수준으로 수행하여야 한다. 따라서 암 대사 관련 효소의 억제를 통한 대사억제는 암 치료의 표적으로서 그 가치가 매우 높게 평가되고 있는 바, 호노키올 + 아피제닌, 또는 호노키올 + 커큐민의 혼합 처리로 인한 해당작용 감소효과는 효과적인 폐암 치료로 연결될 수 있을 것으로 기대된다.On the other hand, in the glucose metabolism of cancer cells, the ATP productivity through the process is more ineffective than the oxidative phosphorylation, assuming that the oxidative phosphorylation pathway of mitochondria is defective and that ATP will be produced mainly by the process alone, Should perform the process at a very high level to produce sufficient ATP. Therefore, metabolic inhibition through inhibition of cancer-related enzymes is highly valued as a target of cancer therapy, and the effect of reducing the action of the combination of honokiol + apigenin or honokiol + It is expected to be linked to treatment.
실시예 6. 호노키올, 아피제닌, 커큐민 단독 또는 혼합 처리 시 폐암 세포 주의 PD-L1 발현 억제 효과Example 6 Inhibitory Effect of Honkiol, Apigenin, Curcumin alone or Mixed Treatment on PD-L1 Expression in Lung Cancer Cells
호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리로 인한 인간 폐암 세포주의 PD-L1의 발현 억제 효과를 확인하고자, 인간 폐암 세포 주 A549 및 H2228을 대상으로 호노키올, 아피제닌, 커큐민을 단독 또는 혼합하여 처리한 후, PD-L1의 단백질 수준에서의 발현 정도를 Western-blot을 이용하여 분석하였다(PD-L1 antibody ; cell-signaling, Actin antibody : santa cruze).In order to examine the effect of inhibiting the expression of PD-L1 in human lung cancer cell lines due to the treatment of monoclonal, apoptotic, and curcumin alone or in combination, the human lung cancer cell lines A549 and H2228 were treated with monoclonal, apigenin, (PD-L1 antibody; cell-signaling, Actin antibody: santa cruze). The expression level of PD-L1 at the protein level was analyzed by Western blot.
도 6a에 나타낸 바와 같이, 상기 실시예 1 내지 실시예 5에서 사용된 폐암 세포 주 A549에서는 PD-L1의 발현이 매우 낮기(PD-L1low) 때문에, 호노키올, 아피제닌, 커큐민에 의한 PD-L1의 발현 감소 여부를 확인하기 어렵다고 판단하여, PD-L1의 발현이 비교적 높은 폐암 세포 주 H2228(PD-L1high)을 사용하였다.As shown in FIG. 6A, PD-L1 expression was very low (PD-L1 low ) in lung cancer cell line A549 used in Examples 1 to 5, L1 expression in the lung was difficult to confirm, and the lung cancer cell line H2228 (PD-L1 high ), in which the expression of PD-L1 was relatively high , was used.
그 결과, 도 6b에 나타낸 바와 같이, 호노키올, 아피제닌, 커큐민의 단독 또는 혼합 처리 시, 효과적으로 PD-L1의 발현이 억제됨을 관찰하였다. 특히 호노키올, 아피제닌 또는 커큐민의 단독 처리 시에는 PD-L1의 발현 감소가 매우 약하게 관찰 되는 반면, 호노키올 + 아피제닌 또는 호노키올 + 커큐민의 혼합 처리 시에는 PD-L1의 발현이 매우 강하게 억제되는 것을 관찰하였다.As a result, as shown in Fig. 6 (b), it was observed that the expression of PD-L1 was effectively inhibited when honokiol, apigenin, curcumin alone or in combination. In particular, the decrease in the expression of PD-L1 was observed very weakly when monocytes treated with monocytoin, apigenin or curcumin, while the expression of PD-L1 was very strongly inhibited in the mixed treatment of monocytoin + apigenin or honokiol + curcumin .
암 세포의 사멸 효과를 가지고 있는 T세포가, 암 세포의 표면에 있는 단백질인 PD-L1과 결합하면, T세포는 암 세포를 공격하지 못하여, 암 세포 사멸 효과를 잃게 된다. 면역항암제는 항체가 PD-L1 단백질의 결합을 막아 T세포가 스스로 암세포를 공격하게 만든다. 이러한 항암제는 인체 면역시스템을 강화하는 것이어서 기존 항암제에서 생기는 부작용이나 내성이 없다. 따라서 암 세포의 면역 회피 전략의 하나로서 PD-L1의 발현 조절을 통해, 면역검문(immune checkpoint) 기능의 변화를 통하여 종양 특이 T림프구 세포의 기능을 억제할 수 있다. 즉, 종양세포에서 이러한 억제 면역검문을 활성화시킴으로써 종양특이 T-림프구 세포의 공격을 회피한다. 최근 PD-L1에 대한 단클론항체를 이용하여 그 기능을 억제함으로써 종양특이 T-림프구 세포 활성 및 효과를 증강시킴으로써 항종양 효과를 얻을 수 있다고 알려져 있으며, PD-L1을 표적으로 하는 치료법은 다양한 암세포에서 지금까지 없었던 매우 효과적인 임상 효능을 나타내고 있다.When a T cell that has a killing effect on a cancer cell binds to a protein PD-L1 on the surface of the cancer cell, the T cell can not attack the cancer cell, and the cancer cell killing effect is lost. Immune anticancer drugs block the binding of the PD-L1 protein by the antibody, causing T cells to attack cancer cells themselves. These anticancer drugs strengthen the body's immune system and have no side effects or resistance to conventional anticancer drugs. Therefore, it is possible to suppress the function of tumor-specific T lymphocyte cells by changing the immune checkpoint function through modulation of PD-L1 expression as one of immunity avoidance strategies of cancer cells. In other words, the inhibition of tumor-specific T-lymphocyte cells is avoided by activating such inhibitory immune detection in tumor cells. Recently, it has been known that an anti-tumor effect can be obtained by enhancing the tumor-specific T-lymphocyte cell activity and effect by inhibiting its function by using a monoclonal antibody against PD-L1, and the therapeutic method targeting PD- Has demonstrated a very effective clinical efficacy not previously available.
상기로부터, 호노키올 + 아피제닌 또는 호노키올 + 커큐민의 혼합 투여에 의한 ANT2 또는 HK2 발현 억제는 직접적인 세포 사멸을 유도할 뿐만 아니라, PD-L1 억제를 통해 폐암 세포의 면역 회피 기전을 극복할 수 있으므로, 궁극적으로 암 치료 효능을 증대시킬 수 있을 것으로 기대된다.From the above, inhibition of ANT2 or HK2 expression by mixed administration of honokiol + apigenin or honokiol + curcumin not only induces direct cell death, but also overcomes the immunological evasion mechanism of lung cancer cells through PD-L1 inhibition , And is expected to ultimately increase cancer treatment efficacy.
전술한 본 발명의 설명은 예시를 위한 것이며, 본 발명이 속하는 기술분야의 통상의 지식을 가진 자는 본 발명의 기술적 사상이나 필수적인 특징을 변경하지 않고서 다른 구체적인 형태로 쉽게 변형이 가능하다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예들은 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.
Claims (10)
Apigenin or curcumin; And a pharmaceutical composition for preventing or treating lung cancer.
상기 조성물은 아피제닌 및 호노키올을 유효성분으로 포함하는, 폐암의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
Wherein the composition comprises apigenin and honokiol as an active ingredient.
상기 조성물은 커큐민 및 호노키올을 유효성분으로 포함하는, 폐암의 예방 또는 치료용 약학적 조성물.
The method according to claim 1,
Wherein the composition comprises curcumin and honokiol as an active ingredient.
상기 조성물은 ANT2 (Adenine nucleotide translocator 2) 유전자의 발현을 감소시키는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
Wherein the composition reduces the expression of the ANT2 (Adenine nucleotide translocator 2) gene.
상기 조성물은 HK2 (hexokinase 2) 또는 PD-L1 (Programmed death-ligand 1) 단백질의 발현을 감소시키는 것을 특징으로 하는, 약학적 조성물.
The method according to claim 1,
Wherein the composition reduces the expression of HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein.
Apigenin or curcumin; And a health functional food composition for preventing or ameliorating lung cancer.
상기 조성물은 아피제닌 및 호노키올을 유효성분으로 포함하는, 폐암의 예방 또는 개선용 건강기능식품 조성물.
The method according to claim 6,
Wherein the composition comprises apigenin and honokiol as an active ingredient.
상기 조성물은 커큐민 및 호노키올을 유효성분으로 포함하는, 폐암의 예방 또는 개선용 건강기능식품 조성물.
The method according to claim 6,
Wherein said composition comprises curcumin and honokiol as an active ingredient.
상기 조성물은 ANT2 (Adenine nucleotide translocator 2) 유전자의 발현을 감소시키는 것을 특징으로 하는, 건강기능식품 조성물.
The method according to claim 6,
Wherein the composition reduces the expression of the ANT2 (Adenine nucleotide translocator 2) gene.
상기 조성물은 HK2 (hexokinase 2) 또는 PD-L1 (Programmed death-ligand 1) 단백질의 발현을 감소시키는 것을 특징으로 하는, 건강기능식품 조성물.The method according to claim 6,
Wherein the composition reduces the expression of HK2 (hexokinase 2) or PD-L1 (Programmed death-ligand 1) protein.
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