KR102212792B1 - Combination therapy of anticancer drugs and aripiprazole - Google Patents
Combination therapy of anticancer drugs and aripiprazole Download PDFInfo
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- KR102212792B1 KR102212792B1 KR1020190031002A KR20190031002A KR102212792B1 KR 102212792 B1 KR102212792 B1 KR 102212792B1 KR 1020190031002 A KR1020190031002 A KR 1020190031002A KR 20190031002 A KR20190031002 A KR 20190031002A KR 102212792 B1 KR102212792 B1 KR 102212792B1
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- South Korea
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- cancer
- anticancer
- aripiprazole
- cells
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Abstract
본 발명은 아리피프라졸(aripiprazole)을 유효성분으로 포함하는 항암 보조제에 관한 것으로서, 상기 아리피프라졸은 항암제에 대한 감수성을 증진시키는 효과가 있어, 항암제와 병용 투여한 경우 암세포 또는 다중약물내성 암세포의 세포사멸을 증가시킴으로써, 특히, 항암제 내성 암의 치료에 유용하게 사용할 수 있다. The present invention relates to an anticancer adjuvant comprising aripiprazole as an active ingredient, wherein aripiprazole has an effect of enhancing sensitivity to an anticancer agent, and when administered in combination with an anticancer agent, apoptosis of cancer cells or multidrug resistant cancer cells is increased. By doing so, it can be especially useful for the treatment of anticancer drug-resistant cancer.
Description
본 발명은 아리피프라졸을 유효성분으로 포함하는 항암 보조제; 및 아리피프라졸 및 항암제를 유효성분으로 포함하는 항암용 조성물에 관한 것이다. The present invention is an anticancer adjuvant comprising aripiprazole as an active ingredient; And it relates to a composition for anticancer comprising aripiprazole and an anticancer agent as an active ingredient.
항암제 내성암을 일으키는 기작중에서 가장 대표적인 방법은 암세포의 세포막에 P-gp (P-glycoprotein) 단백질을 과발현(overexpression) 하는 것이다. 즉, 내성암세포는 P-gp를 과발현하여 세포내에 들어온 자신에게 toxic한 항암제를 밖으로 배출 (pumping-out 또는 efflux) 하는 방어기작으로 진화된 세포라고도 볼 수 있다. P-gp를 과발현하는 내성암세포는 기존의 항암제를 투여해도 죽지 않을 뿐만 아니라 항암제 양을 늘려야 하기 때문에 항암제로 인한 인체의 독성이 증가될 수밖에 없다. 따라서, P-gp의 과발현을 억제하거나 배출 능력을 저하시켜서 내성암세포에 항암제를 오랫동안 유지할 수 있는 약물의 병용투여가 요구된다.Among the mechanisms that cause anticancer drug-resistant cancer, the most representative method is to overexpress the P-gp (P-glycoprotein) protein in the cell membrane of cancer cells. In other words, resistant cancer cells can be regarded as cells that have evolved as a defense mechanism that overexpresses P-gp and discharges (pumping-out or efflux) anticancer drugs that are toxic to them that have entered the cell. Resistant cancer cells overexpressing P-gp do not die even if the existing anticancer drugs are administered, and because the amount of the anticancer drugs must be increased, the toxicity of the human body due to the anticancer drugs is inevitably increased. Accordingly, there is a need for concurrent administration of a drug capable of maintaining an anticancer agent for a long time in resistant cancer cells by inhibiting overexpression of P-gp or reducing its excretion ability.
P-gp를 과발현하는 내성암을 타겟할 수 있는 병용투여 약물에 대한 많은 연구가 지난 10-20년간 진행되어 왔다. 1세대 약물인 베라파밀(verapamil)이 개발되었고, 이후 컴퓨터 시뮬레이션등을 통한 비-경쟁적 억제제인 3세대 약물의 개발에 까지 이르는 다양한 시도가 되어 오고 있다. 계속적으로 병용 투여 약물이 개발되고 있지만, 아직까지 P-gp 과발현 또는 활성을 막고 항암제의 효율을 높일 수 있는 임상 프로토콜이 만들어 지지 않은 상태다. 특히, 정상세포내에서도 발현되고 있는 P-gp 때문에 개발된 P-gp 억제제를 투여할 시, 인체내에 정상세포에도 영향을 끼치는 것이 큰 문제로 대두되고 있다. 따라서, 연구자들은 정상세포에는 무해하거나 정상세포의 기능을 유지시키면서 P-gp를 과발현하는 내성암에만 특이적으로 작용하는 약물을 찾는데 노력해 왔다. 이러한 노력으로 식물 추출물 중에서도 P-gp 억제 효과가 뛰어난 물질들이 보고되어 왔다. 예를 들어 curcumin, fumagillin, piperine 등이 그 예라고 할 수 있다.Many studies on coadministration drugs that can target resistant cancers that overexpress P-gp have been conducted over the past 10-20 years. Verapamil, a first-generation drug, was developed, and various attempts have been made since then to the development of a third-generation drug, a non-competitive inhibitor, through computer simulation. Although co-administration drugs are continuously being developed, a clinical protocol has not yet been made to prevent overexpression or activity of P-gp and increase the efficiency of anticancer drugs. In particular, when administering a P-gp inhibitor developed because of P-gp, which is also expressed in normal cells, it is becoming a major problem that it affects normal cells in the human body. Therefore, researchers have tried to find drugs that are harmless to normal cells or that specifically act on resistant cancers that overexpress P-gp while maintaining the function of normal cells. With this effort, among plant extracts, substances having an excellent inhibitory effect on P-gp have been reported. For example, curcumin, fumagillin, piperine, etc. are examples.
본 발명의 목적은 아리피프라졸(aripiprazole)을 유효성분으로 포함하는 항암 보조제를 제공하는 것이다. It is an object of the present invention to provide an anticancer adjuvant comprising aripiprazole as an active ingredient.
본 발명의 또 다른 목적은 아리피프라졸(aripiprazole) 및 항암제를 유효성분으로 포함하는 항암용 조성물을 제공하는 것이다. Another object of the present invention is to provide an anticancer composition comprising aripiprazole and an anticancer agent as an active ingredient.
본 발명의 또 다른 목적은 아리피프라졸(aripiprazole) 및 항암제를 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법을 제공하는 것이다. Another object of the present invention is to provide a method for preventing or treating cancer comprising administering aripiprazole and an anticancer agent to an individual.
상기 목적을 달성하기 위하여, 본 발명은 아리피프라졸(aripiprazole)을 유효성분으로 포함하는 항암 보조제를 제공한다. In order to achieve the above object, the present invention provides an anticancer adjuvant comprising aripiprazole as an active ingredient.
본 발명의 일 실시예에 있어서, 상기 아리피프라졸은 항암제에 대한 감수성을 증진시키는 것일 수 있다. In one embodiment of the present invention, the aripiprazole may be one to enhance sensitivity to anticancer drugs.
본 발명의 일 실시예에 있어서, 상기 항암제는 할라벤(Halaven), 빈크리스틴(Vincristine), 빈블라스틴(Vinblastine), 비노렐빈(Vinorelvine), 파클리탁셀(Paclitaxel), 도세탁셀(Docetaxel), 에토포사이드(Etoposide), 토포테칸(Topotecan), 이리노테칸(Irinotecan), 닥티노마이신(Dactinomycin), 독소루비신(Doxorubicin), 다우노루비신(Daunorubicin), 미토마이신(Mitomycin) 또는 블레오마이신(Bleomycin)인 것일 수 있다. In one embodiment of the present invention, the anticancer agent is halaven, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, etoposide ( Etoposide), Topotecan, Irinotecan, Dactinomycin, Doxorubicin, Daunorubicin, Mitomycin, or Bleomycin.
본 발명의 일 실시예에 있어서, 상기 아리피프라졸은 암세포 또는 다중약물내성 암세포의 세포사멸을 증가시키는 것일 수 있다. In one embodiment of the present invention, the aripiprazole may increase apoptosis of cancer cells or multidrug resistant cancer cells.
본 발명의 일 실시예에 있어서, 상기 아리피프라졸은 암세포 또는 다중약물내성 암세포에서 과발현되는 P-gp (P-glycoprotein)의 활성을 억제하는 것일 수 있다. In one embodiment of the present invention, the aripiprazole may inhibit the activity of P-gp (P-glycoprotein) overexpressed in cancer cells or multidrug resistant cancer cells.
본 발명의 일 실시예에 있어서, 상기 아리피프라졸은 항암제와 병용하여 투여되는 것일 수 있고, 항암제와 동시에(simultaneous), 별도로(separate) 또는 순차적(sequential)으로 투여되는 것일 수 있으나, 이에 제한되는 것은 아니다. In one embodiment of the present invention, the aripiprazole may be administered in combination with an anticancer agent, and may be administered simultaneously with the anticancer agent (simultaneous), separately (separate) or sequentially (sequential), but is not limited thereto. .
본 발명의 일 실시예에 있어서, 상기 아리피프라졸은 0.1 내지 5 μM의 농도로 투여되는 것일 수 있고, 바람직하게는 0.5 내지 2.5 μM의 농도로 투여되는 것일 수 있고, 더욱 바람직하게는 2.5 μM의 농도로 투여되는 것일 수 있다. In one embodiment of the present invention, the aripiprazole may be administered at a concentration of 0.1 to 5 μM, preferably may be administered at a concentration of 0.5 to 2.5 μM, more preferably at a concentration of 2.5 μM. It may be administered.
본 발명의 일 실시예에 있어서, 상기 암은 항암제 내성 암인 것일 수 있고, 구체적으로 유방암, 난소암, 대장암, 간암, 갑상선암, 쓸개암, 담도암, 췌장암, 전립선암, 식도암, 자궁경부암, 결장암, 방광암, 중추신경종양, 구강암 및 뇌종양으로 이루어진 그룹에서 선택되는 것일 수 있다. In one embodiment of the present invention, the cancer may be an anticancer drug-resistant cancer, and specifically, breast cancer, ovarian cancer, colon cancer, liver cancer, thyroid cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, prostate cancer, esophageal cancer, cervical cancer, colon cancer , Bladder cancer, central nervous system tumor, oral cancer, and may be selected from the group consisting of brain tumors.
또한, 본 발명은 아리피프라졸(aripiprazole) 및 항암제를 유효성분으로 포함하는 항암용 조성물을 제공한다. In addition, the present invention provides a composition for anticancer comprising aripiprazole and an anticancer agent as an active ingredient.
또한, 본 발명은 아리피프라졸(aripiprazole) 및 항암제를 개체에 투여하는 단계를 포함하는 암의 예방 또는 치료 방법을 제공한다. In addition, the present invention provides a method for preventing or treating cancer comprising administering aripiprazole and an anticancer agent to an individual.
본 발명에 따른 조성물은 항암제에 대한 감수성을 증진시키는 효과가 있어, 항암제와 병용 투여한 경우 암세포 또는 다중약물내성 암세포의 세포사멸을 증가시킴으로써, 특히, 항암제 내성 암의 치료에 유용하게 사용할 수 있다. The composition according to the present invention has an effect of enhancing sensitivity to an anticancer agent, and when administered in combination with an anticancer agent, by increasing apoptosis of cancer cells or multidrug resistant cancer cells, it can be particularly useful for the treatment of anticancer drug-resistant cancer.
도 1A 및 1B는 KBV20C 세포에 24시간(A) 또는 4시간(B) 동안 5 μM의 아리피프라졸(ARI-5) 또는 10 μM의 베라파밀(VER-10, 양성대조군)을 처리한 후, 로다민 염색법을 수행한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 1C는 KBV20C 세포에 24시간 동안 0.1, 0.5, 2.5, 5 μM의 아리피프라졸(ARI) 또는 10 μM의 베라파밀(VER-10, 양성대조군)을 처리한 후, 로다민 염색법을 수행한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 2A 및 2B는 KBV20C 세포에 24시간 동안 0.5, 2.5 μM의 아리피프라졸(ARI-0.5, ARI-2.5), 10 μM의 베라파밀(VER-10), 50 ng/ml의 할라벤(HAL), 할라벤+아리피브라졸(HAL+ARI-0.5, HAL+ARI-2.5) 또는 할라벤+베라파밀(HAL+VER-10)을 처리한 후, 현미경 하(x4)에서 세포를 관찰한 결과(A) 및 아넥신 V 염색 결과(B)이다 (Con: 대조군, 0.1% DMSO 처리군).
도 2C는 KBV20C 세포에 24시간 동안 아리피프라졸(ARI), 할라벤(HAL) 또는 할라벤+아리피프라졸(HAL+ARI)을 처리한 후, 웨스턴블럿을 통해 C-PARP(cleaved poly ADP ribose polymerase), pERK(phosphorylated-extracellular signal-regulated kinase) 및 pH2AX(phosphorylated-H2A histone family member X)의 발현량을 분석한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 3A는 KBV20C 세포에 24시간 동안 0.5, 2.5 μM의 아리피프라졸(ARI-0.5, ARI-2.5), 50 ng/ml의 할라벤(HAL) 또는 할라벤+아리피프라졸(HAL+ARI-0.5, HAL+ARI-2.5)을 처리한 후, FACS를 통해 세포주기를 분석한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 3B는 KBV20C 세포에 24시간 동안 아리피프라졸(ARI), 할라벤(HAL) 또는 할라벤+아리피프라졸(HAL+ARI)을 처리한 후, 웨스턴블럿을 통해 Cyclin D1, CDK4, p21, pRb, Cyclin E, Cdc2, Cyclin B1 및 CDK2 단백질의 발현량을 분석한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 3C는 KBV20C 세포에 24시간 동안 2.5 μM의 아리피프라졸(ARI-2.5), 10 μM의 베라파밀(VER-10), 5 nM의 빈크리스틴(VIN), 빈크리스틴+아리피프라졸(VIN+ARI-2.5) 또는 빈크리스틴+베라파밀(VIN+VER)을 처리한 후, 현미경 하(x10)에서 세포를 관찰한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 4A는 KBV20C 세포에 24시간 동안 2.5 μM의 아리피프라졸(ARI-2.5) 또는 5 μM의 플루페나진(Fluphenazine; FLU-5)을 처리한 후, 로다민 염색법을 수행한 결과이다 (Con: 대조군, 0.1% DMSO 처리군).
도 4B는 KBV20C 세포에 24시간 동안 0.5, 2.5 μM의 아리피프라졸(ARI-0.5, ARI-2.5), 5 μM의 플루페나진(FLU-5), 50 ng/ml의 할라벤(HAL), 할라벤+아리피브라졸(HAL+ARI-0.5, HAL+ARI-2.5) 또는 할라벤+플루페나진(HAL+FLU-5)을 처리한 후, 현미경 하(x10)에서 세포를 관찰한 결과이다 (Con: 대조군, 0.1% DMSO 처리군). 1A and 1B show that KBV20C cells were treated with 5 μM of aripiprazole (ARI-5) or 10 μM of verapamil (VER-10, positive control) for 24 hours (A) or 4 hours (B), followed by rhodamine staining. It is the result of performing (Con: control, 0.1% DMSO treatment group).
Figure 1C is a result of performing rhodamine staining after treating KBV20C cells with 0.1, 0.5, 2.5, 5 μM of aripiprazole (ARI) or 10 μM of verapamil (VER-10, positive control) for 24 hours (Con : Control, 0.1% DMSO treatment group).
Figures 2A and 2B show that in KBV20C cells for 24 hours 0.5, 2.5 μM of aripiprazole (ARI-0.5, ARI-2.5), 10 μM of verapamil (VER-10), 50 ng/ml of halaben (HAL), and halaben + After treatment with Arifibrasol (HAL+ARI-0.5, HAL+ARI-2.5) or Halaben+verapamil (HAL+VER-10), the results of observing cells under a microscope (x4) (A) and Annexin V staining result (B) (Con: control, 0.1% DMSO treated group).
FIG. 2C shows KBV20C cells treated with aripiprazole (ARI), halaben (HAL) or halaben+aripiprazole (HAL+ARI) for 24 hours, and then C-PARP (cleaved poly ADP ribose polymerase), pERK through Western blot. This is the result of analyzing the expression levels of (phosphorylated-extracellular signal-regulated kinase) and pH2AX (phosphorylated-H2A histone family member X) (Con: control group, 0.1% DMSO-treated group).
Figure 3A is a KBV20C cell for 24 hours 0.5, 2.5 μM of aripiprazole (ARI-0.5, ARI-2.5), 50 ng / ml of halaben (HAL) or halaben + aripiprazole (HAL + ARI-0.5, HAL + ARI -2.5) is the result of cell cycle analysis through FACS (Con: control group, 0.1% DMSO treatment group).
FIG. 3B shows KBV20C cells treated with Aripiprazole (ARI), Halaben (HAL) or Halaben + Aripiprazole (HAL+ARI) for 24 hours, and then Cyclin D1, CDK4, p21, pRb, Cyclin E, This is the result of analyzing the expression levels of Cdc2, Cyclin B1 and CDK2 proteins (Con: control group, 0.1% DMSO treatment group).
Figure 3C is a KBV20C cell for 24 hours 2.5 μM aripiprazole (ARI-2.5), 10 μM verapamil (VER-10), 5 nM vincristine (VIN), vincristine + aripiprazole (VIN + ARI-2.5) or After treatment with vincristine + verapamil (VIN + VER), cells were observed under a microscope (x10) (Con: control group, 0.1% DMSO treated group).
Figure 4A is a result of performing rhodamine staining after treatment with 2.5 μM of aripiprazole (ARI-2.5) or 5 μM of fluphenazine (FLU-5) for 24 hours on KBV20C cells (Con: control, 0.1% DMSO treatment group).
Figure 4B is a KBV20C cell for 24 hours 0.5, 2.5 μM of aripiprazole (ARI-0.5, ARI-2.5), 5 μM of fluphenazine (FLU-5), 50 ng / ml of halaben (HAL), halaben This is the result of observing cells under a microscope (x10) after treatment with +arifibrasol (HAL+ARI-0.5, HAL+ARI-2.5) or halaben+flufenazine (HAL+FLU-5) ( Con: control, 0.1% DMSO treatment group).
본 발명의 용어, "항암제 내성(drug-resistance)"은 항암제 치료 요법에 대하여 극히 낮은 감수성을 나타내어 상기 치료 요법에 의하여 암의 증세가 호전, 완화, 경감 또는 치료증상을 나타내지 않는 증상을 말한다. 항암제 내성은 암이 특정 항암제 치료 요법에 대하여 처음부터 내성을 가질 수 있고, 최초에는 내성을 나타내지 않았으나 긴 시간의 치료로 인하여 암세포의 성질이 변하여 동일한 치료제에 대해 더이상 감수성을 나타내지 않게 되어 나타날 수 있다.The term of the present invention, "drug-resistance" refers to a symptom that exhibits extremely low sensitivity to an anticancer treatment regimen, and thus the symptoms of cancer are not improved, alleviated, alleviated or treated by the treatment regimen. Anticancer drug resistance may appear because cancer may be resistant to a specific anticancer treatment regimen from the beginning, and initially did not show resistance, but due to a long treatment, the properties of cancer cells change and thus no longer show sensitivity to the same treatment.
본 발명의 용어, "항암 보조제"는 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제로서, 그 자체로는 항암활성을 나타내지 않으나 항암제와 함께 사용될 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다. 또한, 농도의존적인 항암활성을 나타내는 제제를 그 자체로는 항암활성을 나타내지 않은 수준으로 항암제와 함께 사용할 경우, 상기 항암제의 항암효과를 개선, 향상 또는 증대시킬 수 있는 제제일 수 있다. The term "anti-cancer adjuvant" of the present invention is an agent capable of improving, enhancing or enhancing the anti-cancer effect of an anti-cancer agent, and does not exhibit anti-cancer activity by itself, but when used together with an anti-cancer agent, it improves or enhances the anti-cancer effect of the anti-cancer agent. Or it may be a formulation that can be increased. In addition, when an agent exhibiting concentration-dependent anticancer activity is used with an anticancer agent at a level that does not exhibit anticancer activity by itself, it may be an agent capable of improving, enhancing or increasing the anticancer effect of the anticancer agent.
항암 보조제의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 항암 보조제는 목적하는 바에 따라 복강 내 투여, 정맥 내 투여, 근육 내 투여, 피하 투여, 피내 투여, 경구 투여, 비 내 투여, 폐 내 투여, 직장 내 투여될 수 있으나, 이에 제한되지는 않는다. 또한, 상기 항암 보조제는 활성 물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.The administration route of the anticancer adjuvant may be administered through any general route as long as it can reach the target tissue. The anticancer adjuvant of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intrapulmonary, or rectal administration as desired, but is not limited thereto. Does not. In addition, the anticancer adjuvant may be administered by any device capable of moving the active substance to target cells.
본 발명에 따른 조성물은 조성물의 제조에 통상적으로 사용하는 적절한 담체, 부형제 또는 희석제를 더 포함할 수 있다.The composition according to the present invention may further comprise a suitable carrier, excipient or diluent commonly used in the preparation of the composition.
본 발명에서 사용가능한 담체, 부형제 또는 희석제로는, 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 또는 광물유 등을 들 수 있다.Carriers, excipients or diluents that can be used in the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.
본 발명에 따른 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The composition according to the present invention can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods. have.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 상기 화합물은 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제한다.In the case of formulation, it is prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants that are usually used. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and these solid preparations include at least one excipient, such as starch, calcium carbonate, and sucrose ( sucrose) or lactose (lactose), gelatin, etc. are mixed to prepare.
또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, liquid solutions, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweetening agents, fragrances, and preservatives may be included. .
본 발명의 조성물은 약제학적으로 유효한 양으로 투여될 수 있는데, 본 발명의 용어 "약제학적으로 유효한 양"이란 의학적 치료 또는 예방에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료 또는 예방하기에 충분한 양을 의미하며, 유효 용량 수준은 질환의 중증도, 약물의 활성, 환자의 연령, 체중, 건강, 성별, 환자의 약물에 대한 민감도, 사용된 본 발명 조성물의 투여 시간, 투여 경로 및 배출 비율 치료기간, 사용된 본 발명의 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. The composition of the present invention may be administered in a pharmaceutically effective amount, and the term "pharmaceutically effective amount" of the present invention means an amount sufficient to treat or prevent a disease at a reasonable benefit/risk ratio applicable to medical treatment or prevention. The effective dose level is the severity of the disease, the activity of the drug, the patient's age, weight, health, sex, the patient's sensitivity to the drug, the time of administration of the composition of the present invention used, the route of administration and the rate of excretion of the treatment period, It can be determined according to factors including drugs used in combination or coincidental with the composition of the present invention and other factors well known in the medical field.
본 발명의 조성물의 투여량은 사용목적, 질환의 중독도, 환자의 연령, 체중, 성별, 기왕력, 또는 유효성분으로서 사용되는 물질의 종류 등을 고려하여 당업자가 결정할 수 있다. 예를 들어, 본 발명의 약학 조성물은 성인 1인당 약 0.1 ng 내지 약 100 mg/kg, 바람직하게는 1 ng 내지 약 10 mg/kg로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.The dosage of the composition of the present invention can be determined by those skilled in the art in consideration of the purpose of use, the degree of addiction to the disease, the patient's age, weight, sex, history, or the type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention may be administered in an amount of about 0.1 ng to about 100 mg/kg, preferably 1 ng to about 10 mg/kg per adult, and the frequency of administration of the composition of the present invention is specifically Although not limited, it may be administered once a day or divided into several doses. The above dosage does not in any way limit the scope of the present invention.
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 through examples. These examples are for explaining the present invention more specifically, and the scope of the present invention is not limited to these examples.
실시예 1. 실험방법Example 1. Experimental method
1.1. 사용된 내성세포주 1.1. Resistant cell line used
본 발명에서는 사람구강편평상피암세포주(Human oral squamous carcinoma cell line)인 KB 세포 및 이의 다중약물내성 세포주(multidrugresistant subline)인 KBV20C 세포 (Dr. Yong Kee Kim, College of Pharmacy, Sookmyung Women’s University) 가 사용되었다. KBV20C 세포는 KB 세포에 항암제를 오랫동안 처리하여 P-gp(P-glycoprotein)의 과발현을 통해 항암제에 대한 내성을 가지게 된 세포주이다. 상기 세포는 10% FBS(fetal bovine serum), 100 U/ml penicillin 및 100 μg/ml streptomycin이 포함된 RPMI 1640 배지(WelGENE, Daegu, South Korea)에서 배양되었다. In the present invention, KB cells, a human oral squamous carcinoma cell line, and KBV20C cells (Dr. Yong Kee Kim, College of Pharmacy, Sookmyung Women's University), a multidrugresistant subline thereof, were used. . KBV20C cells are a cell line that has become resistant to anticancer agents through overexpression of P-gp (P-glycoprotein) by treating KB cells with anticancer agents for a long time. The cells were cultured in RPMI 1640 medium (WelGENE, Daegu, South Korea) containing 10% FBS (fetal bovine serum), 100 U/ml penicillin and 100 μg/ml streptomycin.
1.2. 로다민 염색법(Rhodamine123 staining)1.2. Rhodamine123 staining
KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 4시간 또는 24시간 동안 0.1% DMSO (Con, 대조군), 0.1, 0.5, 2.5, 5 μM의 아리피프라졸(aripiprazole, ARI) 또는 10 μM의 베라파밀(verapamil, VER, 양성대조군)을 처리하였다. 이후, 세포는 37℃ 에서 약 1시간 동안 2 μg/ml의 로다민123이 처리되었고, 배지를 제거한 후, PBS로 세척하였다. 염색된 세포는 Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA)를 사용하여 분석하였다. KBV20C cells were dispensed in a 60-mm dish with 30-40% confluence, and 0.1% DMSO (Con, control), 0.1, 0.5, 2.5, 5 μM of aripiprazole, for 4 or 24 hours. ARI) or 10 μM of verapamil (VER, positive control). Thereafter, the cells were treated with 2 μg/ml of rhodamine 123 for about 1 hour at 37° C., the medium was removed, and then washed with PBS. Stained cells were analyzed using a Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA).
1.3. 아넥신 V 염색법(annexin V staining)1.3. Annexin V staining
KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 0.5, 2.5 μM의 아리피프라졸(aripiprazole, ARI), 10 μM의 베라파밀(verapamil, VER, 양성대조군), 50 ng/ml의 할라벤(Halaven, HAL) 단독 또는 이의 조합을 처리하였다. 이후, 세포는 트립신으로 떼어내고 원심분리하여 펠릿을 얻은 후, PBS로 세척하였다. 세포는 5 μl의 아넥신 V-FITC 및 5 μl의 PI를 추가한 100 μl의 바인딩 버퍼(binding buffer)를 첨가하여 상온에서 15분 동안 반응시켰다. 염색된 세포는 Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA)를 사용하여 세포사멸 정도를 분석하였다.KBV20C cells were dispensed in a 60-mm dish with 30-40% confluence, and 0.1% DMSO (Con, control), 0.5, 2.5 μM aripiprazole, for 24 hours. ARI), 10 μM of verapamil (VER, positive control), 50 ng/ml of Halaven (HAL) alone or a combination thereof were treated. Thereafter, the cells were detached with trypsin, centrifuged to obtain a pellet, and washed with PBS. Cells were reacted at room temperature for 15 minutes by adding 100 μl of binding buffer to which 5 μl of Annexin V-FITC and 5 μl of PI were added. The stained cells were analyzed for apoptosis using a Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA).
1.4. 웨스턴블럿1.4. Western Blot
KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 아리피프라졸(aripiprazole, ARI), 50 ng/ml의 할라벤(Halaven, HAL) 단독 또는 이의 조합을 처리하였다. 이후, 세포는 차가운 PBS로 2번 세척되었고, 스크래퍼로 떼어냈다. 전체 단백질 분리를 위해, 세포는 PRO-PREP™ protein extract solution (iNtRON, Seongnam, South Korea)에 부유시킨 후 30분 동안 얼음 위에 두었다. 이후, 4℃, 15,000 × g 로 5분 동안 원심분리하였다. 단백질의 양은 protein assay kit (Bio-Rad, Hercules, CA, USA)을 사용하여 제조사의 지시에 따라 측정되었다. 이후, SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis)를 수행한 후, 멤브레인으로 블럿팅시키고, 각 단백질에 대한 특이적인 항체를 사용하여 단백질의 발현량을 분석하였다. KBV20C cells were dispensed with 30-40% confluence in a 60-mm dish, and 0.1% DMSO (Con, control), aripiprazole, ARI), 50 ng/ml of Halaven (HAL) alone or a combination thereof. Thereafter, the cells were washed twice with cold PBS and removed with a scraper. For total protein isolation, cells were suspended in PRO-PREP™ protein extract solution (iNtRON, Seongnam, South Korea) and placed on ice for 30 minutes. Then, it was centrifuged at 4° C. and 15,000× g for 5 minutes. The amount of protein was measured according to the manufacturer's instructions using a protein assay kit (Bio-Rad, Hercules, CA, USA). Thereafter, SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) was performed, followed by blotting with a membrane, and protein expression levels were analyzed using antibodies specific for each protein.
1.5. 세포주기 분석1.5. Cell cycle analysis
KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 0.5, 2.5 μM의 아리피프라졸(aripiprazole, ARI), 50 ng/ml의 할라벤(Halaven, HAL) 단독 또는 이의 조합을 처리하였다. 이후, 세포는 트립신으로 떼어내고 원심분리하여 펠릿을 얻었고, PBS로 세척한 후, 4℃에서 1시간 동안 75% 에탄올을 첨가하여 부유시켰다. 이후, PBS로 세척하였고, 차가운 PI(propidium iodide) 용액(PBS에 100 μg/ml RNase A 및 50 μg/ml PI)에서 30분 동안 재부유시켰다. 염색된 세포는 Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA)를 사용하여 세포주기를 분석하였다. KBV20C cells were dispensed in a 60-mm dish with 30-40% confluence, and 0.1% DMSO (Con, control), 0.5, 2.5 μM aripiprazole, for 24 hours. ARI), 50 ng/ml of Halaven (HAL) alone or a combination thereof. Thereafter, the cells were detached with trypsin and centrifuged to obtain a pellet, washed with PBS, and then suspended by adding 75% ethanol at 4° C. for 1 hour. Then, it was washed with PBS and resuspended for 30 minutes in a cold PI (propidium iodide) solution (100 μg/ml RNase A and 50 μg/ml PI in PBS). Stained cells were analyzed for cell cycle using a Guava EasyCyte Plus Flow Cytometer (Merck Millipore, Billerica, MA, USA).
실시예 2. 아리피프라졸(aripiprazole)의 P-gp (P-glycoprotein) 활성억제 효과Example 2. Effect of aripiprazole on inhibiting P-gp (P-glycoprotein) activity
본 발명자들은 약물이 P-gp (P-glycoprotein) 활성을 억제하는지 평가하기 위하여 로다민 염색법(Rhodamine123 staining)을 수행하였다. 로다민은 P-gp의 기질로서 P-gp의 활성이 억제되면 로다민이 세포에 축적되므로, 로다민의 양을 통해 P-gp의 활성억제에 대한 정량분석이 가능한 방법이다. The present inventors performed rhodamine staining (Rhodamine123 staining) to evaluate whether the drug inhibits P-gp (P-glycoprotein) activity. Rhodamine is a substrate of P-gp, and when the activity of P-gp is inhibited, rhodamine accumulates in cells, so it is possible to quantitatively analyze the inhibition of P-gp activity through the amount of rhodamine.
그 결과, 4시간 또는 24시간 동안 아리피프라졸(5 μM)을 내성세포주인 KBV20C 세포에 처리한 경우 양성대조군인 10 μM의 베라파밀에 비해 낮은 농도에서도 P-gp의 활성을 현저히 억제하였음을 확인하였다 (도 1A 및 1B). 또한, 24시간 동안 주어진 농도에 따라 아리피프라졸을 처리한 경우 0.1 μM 농도에서 부터 음성대조군에 비해 높은 P-gp의 활성억제 효과가 나타나기 시작했고, 2.5 μM이상의 농도에서는 양성대조군인 베라파밀보다 P-gp의 활성억제 효과가 훨씬 높다는 것을 확인하였다 (도 1C).As a result, it was confirmed that when aripiprazole (5 μM) was treated on the resistant cell line KBV20C cells for 4 hours or 24 hours, the activity of P-gp was remarkably suppressed even at a lower concentration compared to the positive control, 10 μM verapamil (Fig. 1A and 1B). In addition, when aripiprazole was treated at a given concentration for 24 hours, the inhibitory effect of P-gp began to appear higher than that of the negative control at a concentration of 0.1 μM, and at a concentration of 2.5 μM or more, the P-gp was higher than that of the positive control, verapamil. It was confirmed that the inhibitory effect was much higher (Fig. 1C).
상기 결과로부터 낮은 농도의 아리피프라졸(2.5 내지 5 μM)은 내성세포주에서 베라파밀보다 P-gp의 활성억제 효과가 현저함을 확인하였다. From the above results, it was confirmed that aripiprazole at a low concentration (2.5 to 5 μM) had a remarkable inhibitory effect on the activity of P-gp than verapamil in resistant cell lines.
실시예 3. 아리피프라졸(aripiprazole) 및 항암제(할라벤, Halaven)에 의한 내성세포주의 세포사멸(apoptosis) 증가 효과Example 3. Effect of increasing apoptosis in resistant cell lines by aripiprazole and anticancer agents (Halaven)
본 발명자들은 아리피프라졸 및 항암제를 내성세포주인 KBV20C 세포에 병용 처리한 후 세포사멸(apoptosis) 효과를 확인하기 위하여, early 및 late apoptosis의 증가를 측정할 수 있는 아넥신 V 염색(annexin V staining)을 수행하였다. The present inventors performed annexin V staining, which can measure the increase in early and late apoptosis, in order to confirm the apoptosis effect after co-treatment of aripiprazole and an anticancer agent on KBV20C cells, a resistant cell line. I did.
그 결과, 내성세포주인 KBV20C 세포에 아리피프라졸 및 할라벤을 병용 처리한 경우에는 각각 단독으로 처리한 경우보다 세포증식이 감소하고, 세포사멸이 증가되는 효과가 있음을 현미경 하(x4 배율)에서 확인하였다 (도 2A). 또한, 아넥신 V 염색결과에서는 0.5 μM의 아리피프라졸 및 할라벤을 병용 처리한 경우 할라벤을 단독 처리한 경우보다 세포사멸 효과가 증가되었고, 특히, 2.5 μM의 아리피프라졸을 항암제인 할라벤과 병용 처리한 경우에는 10 μM의 베라파밀을 할라벤과 병용 처리한 경우보다 높은 정도의 세포사멸 효과를 나타내었음을 확인하였다 (도 2B). As a result, it was confirmed under a microscope (x4 magnification) that when the resistant cell line KBV20C cells were treated with aripiprazole and halaben in combination, cell proliferation was decreased and apoptosis was increased compared to the case of treatment alone. (Figure 2A). In addition, in the results of Annexin V staining, when 0.5 μM of aripiprazole and halaben were treated in combination, the apoptosis effect was increased compared to the case of halabene alone. In particular, 2.5 μM of aripiprazole was treated in combination with the anticancer drug halabene. In the case, it was confirmed that 10 μM of verapamil was exhibited a higher degree of apoptotic effect than the case of co-treatment with halaben (FIG. 2B).
또한, 본 발명자들은 아리피프라졸 및 항암제를 내성세포주인 KBV20C 세포에 병용 처리한 후 세포사멸(apoptosis)의 효과와 어떠한 cellular signaling pathway와의 관련이 있는지를 확인하기 위하여, C-PARP(cleaved poly ADP ribose polymerase), pERK(phosphorylated-extracellular signal-regulated kinase), pH2AX(phosphorylated-H2A histone family member X) 및 β-actin에 대한 항체를 사용하여 웨스턴블럿을 수행하였다. In addition, the inventors of the present invention in order to confirm the relationship between the cellular signaling pathway and the effect of apoptosis after treating aripiprazole and an anticancer drug in combination with KBV20C cells, a resistant cell line, C-PARP (cleaved poly ADP ribose polymerase). , pERK (phosphorylated-extracellular signal-regulated kinase), pH2AX (phosphorylated-H2A histone family member X) and β-actin were used to perform Western blot.
그 결과, 내성세포주인 KBV20C 세포에 아리피프라졸 및 할라벤을 병용 처리한 경우에는 각각 단독으로 처리한 경우보다 세포사멸의 중요 단백질인 C-PARP 및 DNA 손상 마커인 pH2AX의 발현량이 현저히 증가되었고, 세포성장 signaling pathway의 주요인자인 pERK의 발현량은 현저히 감소되었음을 확인하였다 (도 2C). As a result, when the resistant cell line KBV20C cells were treated with aripiprazole and halaben in combination, the expression levels of C-PARP, an important protein for apoptosis, and pH2AX, a DNA damage marker, were significantly increased compared to the case of treatment alone, respectively. It was confirmed that the expression level of pERK, which is a major factor of the signaling pathway, was significantly reduced (Fig. 2C).
이로써, 본 발명자들은 아리피프라졸 및 항암제를 병용 처리한 경우 낮은 농도에서도 내성세포주의 세포사멸을 증가시키는 효과가 있고, 그 기작으로서 pERK 경로의 감소와 더불어 DNA 손상 및 세포사멸 인자의 발현량을 현저히 증가시키는 효과가 있음을 확인하였다. Accordingly, the present inventors have an effect of increasing apoptosis of resistant cell lines even at low concentrations when aripiprazole and an anticancer agent are co-treated, and as a mechanism, the pERK pathway is reduced and the expression of DNA damage and apoptosis factors is significantly increased. It was confirmed that there is an effect.
실시예 4. 아리피프라졸(aripiprazole) 및 항암제(할라벤, Halaven)에 의한 내성세포주의 세포주기 분석 결과Example 4. Cell cycle analysis results of resistant cell lines by aripiprazole and anticancer agents (Halaven)
본 발명자들은 아리피프라졸 및 항암제를 내성세포주인 KBV20C 세포에 병용 처리한 후 세포주기에 영향을 주는지 확인하기 위하여 세포주기 분석을 수행하였다. 그 결과, 내성세포주인 KBV20C 세포에 아리피프라졸 및 할라벤을 병용 처리한 경우에는 각각 단독으로 처리한 경우보다 G2 phase가 현저히 증가되었다 (도 3A). 특히, 0.5 μM의 아리피프라졸을 할라벤과 병용 처리한 경우에는 G2 phase가 50% 로 나타났고, 2.5 μM의 아리피프라졸을 할라벤과 병용 처리한 경우에는 G2 phase가 92% 로서 G2 arrest가 확연하게 나타났다. The present inventors performed cell cycle analysis in order to confirm whether aripiprazole and an anticancer agent were treated in combination with the resistant cell line, KBV20C cells, and then affected the cell cycle. As a result, when the resistant cell line KBV20C cells were treated in combination with aripiprazole and halaben, the G2 phase was significantly increased compared to the case of treatment alone (Fig. 3A). In particular, when 0.5 μM of aripiprazole was co-treated with halabene, the G2 phase was 50%, and when 2.5 μM of aripiprazole was co-treated with halabene, the G2 phase was 92%, indicating marked G2 arrest.
또한, 본 발명자들은 세포주기 관련 인자인 Cyclin D1, CDK4, p21, pRb, Cyclin E, Cdc2, Cyclin B1 및 CDK2 단백질의 발현량을 확인하기 위하여 웨스턴블럿을 수행하였다. 그 결과, CDK2, CDK4, Cyclin E 및 p21의 발현량에서는 유의한 차이가 나타나지 않았고, Cyclin D1 및 Cyclin B1에서 약간의 증가를 보였으나 미미한 정도였다 (도 3B). 그런데, 내성세포주인 KBV20C 세포에 아리피프라졸 및 할라벤을 병용 처리한 경우에는 각각 단독으로 처리한 경우보다 pRB의 발현량이 확연히 증가되었고, Cdc2의 발현량은 현저히 감소되는 효과가 있었고 (도 3B), 이는 상기 세포주기 분석에서 G2 arrest와 일치된 결과인 것으로 확인되었다. In addition, the present inventors performed Western blot to confirm the expression levels of the cell cycle-related factors Cyclin D1, CDK4, p21, pRb, Cyclin E, Cdc2, Cyclin B1 and CDK2 proteins. As a result, there was no significant difference in the expression levels of CDK2, CDK4, Cyclin E, and p21, and there was a slight increase in Cyclin D1 and Cyclin B1, but it was insignificant (Fig. 3B). However, when aripiprazole and halaben were treated in combination with the resistant cell line KBV20C cells, the expression level of pRB was significantly increased and the expression level of Cdc2 was significantly decreased (Fig. 3B). In the cell cycle analysis, it was confirmed that the result was consistent with G2 arrest.
이로써, 본 발명자들은 아리피프라졸 및 항암제를 병용 처리한 경우 G2 arrest를 통해 내성세포주의 세포사멸을 증가시킬 수 있음을 확인하였다. Accordingly, the present inventors have confirmed that when aripiprazole and an anticancer agent are treated in combination, apoptosis of resistant cell lines can be increased through G2 arrest.
실시예 5. 아리피프라졸(aripiprazole) 및 항암제(빈크리스틴, Vincristine)에 의한 효과Example 5. Effects of aripiprazole and anticancer drugs (vincristine)
본 발명자들은 아리피프라졸이 할라벤 뿐만 아니라 다른 항암제와의 병용 처리에도 세포증식 또는 세포사멸에 대한 효과가 있는지 분석하기 위한 실험을 수행하였다. 간단히, KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 2.5 μM의 아리피프라졸(aripiprazole, ARI), 10 μM의 베라파밀, 5 nM의 빈크리스틴(Vincristine, VIN) 단독 또는 이의 조합을 처리하였다. 이후, 현미경 하에서 세포증식 또는 세포사멸 효과를 분석하였다. The present inventors conducted an experiment to analyze whether aripiprazole has an effect on cell proliferation or apoptosis in combination treatment with not only halaben but also other anticancer agents. Briefly, KBV20C cells were dispensed with 30-40% confluence in a 60-mm dish, 0.1% DMSO (Con, control), 2.5 μM aripiprazole, for 24 hours. ARI), 10 μM of verapamil, 5 nM of Vincristine (VIN) alone or a combination thereof were treated. Thereafter, the effect of cell proliferation or apoptosis was analyzed under a microscope.
그 결과, 항암제인 빈크리스틴을 단독으로 처리하거나 아리피프라졸 또는 베라파밀을 단독으로 처리한 경우에는 대조군과 차이가 없었으나, 베라파밀 또는 아리피프라졸을 빈크리스틴과 병용 처리한 경우에는 세포사멸이 현저히 증가됨을 확인할 수 있었고, 특히, 아리피프라졸의 경우에는 베라파밀보다 더 낮은 농도에서 더 현저히 세포사멸을 증가시키는 효과가 있었다 (도 3C). As a result, when the anticancer agent vincristine was treated alone or aripiprazole or verapamil was treated alone, there was no difference from the control group, but when verapamil or aripiprazole was co-treated with vincristine, apoptosis was significantly increased. , In particular, in the case of aripiprazole, there was an effect of significantly increasing apoptosis at a lower concentration than verapamil (FIG. 3C ).
이로써, 본 발명자들은 아리피프라졸 및 다양한 항암제를 병용 처리한 경우 낮은 농도에서 내성세포주의 세포사멸을 증가시키는 효과가 있음을 확인하였다. Accordingly, the present inventors have confirmed that the combination treatment of aripiprazole and various anticancer agents has an effect of increasing apoptosis of resistant cell lines at a low concentration.
실시예 6. 아리피프라졸(aripiprazole)과 플루페나진(Fluphenazine)의 효과 비교Example 6. Comparison of the effects of aripiprazole and fluphenazine
본 발명자들이 3년전에 논문으로 보고한 플루페나진과의 상대적인 비교를 통해 아리피프라졸이 어느정도 우수한 효과를 가지는 지를 분석하였다. 즉, 아리피프라졸과 플루페나진의 효과를 비교하기 위하여 로다민(Rhodamine123) 염색법을 통해 P-gp 활성억제 정도를 측정하였다. 간단히, KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 2.5 μM의 아리피프라졸(aripiprazole, ARI) 또는 5 μM의 플루페나진(Fluphenazine, FLU)을 처리하였다. 이후, 로다민으로 염색한 후, FACS로 분석되었다. 그 결과, 아리피프라졸은 2.5 μM의 낮은 농도에서도 높은 농도의 플루페나진보다 P-gp 활성억제 효과가 뛰어났음을 확인하였다 (도 4A). Through a relative comparison with fluphenazine, which the present inventors reported in the
또한, 본 발명자들은 아리피프라졸과 플루페나진의 세포증식 또는 세포사멸 효과를 분석하였다. 간단히, KBV20C 세포는 60-mm 디쉬에 30-40% confluence로 분주하고, 24시간 동안 0.1% DMSO (Con, 대조군), 0.5 μM, 2.5 μM의 아리피프라졸(aripiprazole, ARI), 5 μM의 플루페나진(Fluphenazine, FLU), 50 ng/ml의 할라벤(Halaven, HAL) 단독 또는 이의 조합을 처리하였다. 이후, 현미경 하에서 세포증식 또는 세포사멸 효과를 분석하였다. 그 결과, 2.5 μM의 아리피프라졸 및 할라벤을 병용 처리한 경우에는 5 μM의 플루페나진 및 할라벤을 병용 처리한 경우보다 현저하게 세포사멸이 증가되었음을 확인하였다 (도 4B). In addition, the present inventors analyzed the cell proliferation or apoptosis effect of aripiprazole and fluphenazine. Briefly, KBV20C cells were dispensed with 30-40% confluence in a 60-mm dish, and 0.1% DMSO (Con, control), 0.5 μM, 2.5 μM aripiprazole, for 24 hours. ARI), 5 μM of Fluphenazine (FLU), 50 ng/ml of Halaven (HAL) alone or a combination thereof were treated. Thereafter, the effect of cell proliferation or apoptosis was analyzed under a microscope. As a result, it was confirmed that when 2.5 μM of aripiprazole and halaben were treated in combination, apoptosis was significantly increased compared to the case where 5 μM of fluphenazine and halaben were treated in combination (FIG.
이로써, 본 발명자들은 아리피프라졸이 플루페나진보다 P-gp 억제활성 효과가 더 현저하고, 아리피프라졸을 항암제와 병용 처리한 경우 기존 플루페나진보다 낮은 농도에서도 현저하게 내성세포주의 세포사멸을 유도할 수 있음을 확인하였다. Accordingly, the present inventors have found that aripiprazole has a more remarkable P-gp inhibitory effect than fluphenazine, and when aripiprazole is treated in combination with an anticancer agent, it can significantly induce apoptosis of resistant cell lines even at a lower concentration than the existing fluphenazine. Was confirmed.
Claims (15)
상기 항암 보조제는 내성암에서, p-gp가 과발현된 암에 이용되며,
상기 p-gp가 과발현된 암은 p-gp의 과발현으로 항암제에 대한 감수성이 감소된 암이며,
상기 항암 보조제는 암세포에서 항암제에 대한 감수성을 증가시키는 것을 특징으로 하는 항암 보조제.Aripiprazole; And as an anticancer adjuvant comprising Halaven or Vincristine as an active ingredient,
The anticancer adjuvant is used in resistant cancers, cancers in which p-gp is overexpressed,
The cancer in which p-gp is overexpressed is a cancer in which susceptibility to anticancer drugs is reduced by overexpression of p-gp,
The anticancer adjuvant, characterized in that to increase the sensitivity to the anticancer agent in cancer cells.
상기 항암 보조제는 암세포 또는 다중약물내성 암세포의 세포사멸을 증가시키는 것을 특징으로 하는 항암 보조제.The method of claim 1,
The anticancer adjuvant, characterized in that to increase the apoptosis of cancer cells or multi-drug resistant cancer cells.
상기 아리피프라졸은 할라벤 또는 빈크리스틴과 동시에(simultaneous), 별도로(separate) 또는 순차적(sequential)으로 투여되는 것을 특징으로 하는 항암 보조제.The method of claim 1,
The anticancer adjuvant, characterized in that the aripiprazole is administered simultaneously with halaben or vincristine (simultaneous), separately (separate) or sequentially (sequential).
상기 아리피프라졸은 0.5 내지 2.5 μM의 농도로 투여되는 것을 특징으로 하는 항암 보조제. The method of claim 1,
The anticancer adjuvant, characterized in that the aripiprazole is administered at a concentration of 0.5 to 2.5 μM.
상기 암은 유방암, 난소암, 대장암, 간암, 갑상선암, 쓸개암, 담도암, 췌장암, 전립선암, 식도암, 자궁경부암, 결장암, 방광암, 중추신경종양, 구강암 및 뇌종양으로 이루어진 그룹에서 선택되는 것을 특징으로 하는 항암 보조제. The method of claim 1,
The cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, liver cancer, thyroid cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, prostate cancer, esophageal cancer, cervical cancer, colon cancer, bladder cancer, central nervous system tumor, oral cancer, and brain tumor. Anticancer adjuvant.
상기 항암용 조성물은 항암제 내성암에서, p-gp가 과발현된 암에 이용되며,
상기 p-gp가 과발현된 암은 p-gp의 과발현으로 항암제에 대한 감수성이 감소된 암이며,
상기 항암용 조성물은 암세포에서 항암제에 대한 감수성을 증가시키는 것을 특징으로하는 항암용 조성물.Aripiprazole; And as an anticancer composition comprising halaven or vincristine as an active ingredient,
The anticancer composition is used for cancers in which p-gp is overexpressed in anticancer drug-resistant cancer,
The cancer in which p-gp is overexpressed is a cancer in which susceptibility to anticancer drugs is reduced by overexpression of p-gp,
The anticancer composition is an anticancer composition, characterized in that to increase the sensitivity to anticancer agents in cancer cells.
상기 아리피프라졸은 0.5 내지 2.5 μM의 농도로 투여되는 것을 특징으로 하는 조성물. The method of claim 11,
The composition, characterized in that the aripiprazole is administered at a concentration of 0.5 to 2.5 μM.
상기 암은 유방암, 난소암, 대장암, 간암, 갑상선암, 쓸개암, 담도암, 췌장암, 전립선암, 식도암, 자궁경부암, 결장암, 방광암, 중추신경종양, 구강암 및 뇌종양으로 이루어진 그룹에서 선택되는 것을 특징으로 하는 조성물.
The method of claim 11,
The cancer is selected from the group consisting of breast cancer, ovarian cancer, colon cancer, liver cancer, thyroid cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, prostate cancer, esophageal cancer, cervical cancer, colon cancer, bladder cancer, central nervous system tumor, oral cancer, and brain tumor. Composition made by.
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