KR20240036953A - Pharmaceutical composition for the treatment of liver cancer comprising cannabidiol and an anticancer agent as active ingredients, and use thereof - Google Patents
Pharmaceutical composition for the treatment of liver cancer comprising cannabidiol and an anticancer agent as active ingredients, and use thereof Download PDFInfo
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- KR20240036953A KR20240036953A KR1020220115644A KR20220115644A KR20240036953A KR 20240036953 A KR20240036953 A KR 20240036953A KR 1020220115644 A KR1020220115644 A KR 1020220115644A KR 20220115644 A KR20220115644 A KR 20220115644A KR 20240036953 A KR20240036953 A KR 20240036953A
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- KR
- South Korea
- Prior art keywords
- cannabidiol
- liver cancer
- anticancer agent
- composition
- pharmaceutical composition
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Abstract
본 발명은 칸나비디올(cannabidiol, CBD) 및 항암제를 유효성분으로 포함하는 간암의 예방 또는 치료용 약학 조성물 및 이의 용도에 관한 것이다.
본 발명의 조성물은 칸나비디올과 간암 항암제 중 하나인 카보잔티닙을 병용처리할 경우, 현저히 우수한 간암 억제 효능을 나타내는 것을 확인하였는 바, 상기 조성물을 이용하여 간암 치료 효과를 증진시킬 수 있다.The present invention relates to a pharmaceutical composition for preventing or treating liver cancer containing cannabidiol (CBD) and an anticancer agent as active ingredients, and its use.
It has been confirmed that the composition of the present invention exhibits significantly superior liver cancer inhibition efficacy when combined with cannabidiol and cabozantinib, one of the liver cancer anticancer drugs. Therefore, the liver cancer treatment effect can be improved by using the composition.
Description
본 발명은 칸나비디올(cannabidiol, CBD) 및 항암제를 유효성분으로 포함하는 간암의 예방 또는 치료용 약학 조성물 및 이의 용도에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating liver cancer containing cannabidiol (CBD) and an anticancer agent as active ingredients, and its use.
대마(***, Cannabis sativa L.)는 중앙 아시아를 중심으로 12,000년 전부터 열대와 온대지방에서 널리 재배된 삼과(Cannabaceae) 대마속의 한해살이 식물로 야생삼을 포함하며, 의·약학적 성분으로 알려진 다양한 종류의 칸나비노이드 화합물을 함유하는 칸나비스 케모바스(cannabis chemovars)와 그의 변형체, 변종 var. indica 및 var. kafiristanica를 포함한 칸나비스 사티바 서브스페시스 사티바(Cannabis sativa subspecies sativa), 칸나비스 사티바 서브스페시스 인디카(Cannabis sativa subspecies indica), 칸나비스 사티바 서브스페시스 루데라리스(Cannabis sativa subspecies ruderalis) 및 유전 교배, 자기 교배 또는 그의 교잡 식물을 통칭해서 말한다.Hemp (Cannabis sativa L.) is an annual plant of the Cannabaceae genus, which has been widely cultivated in tropical and temperate regions, mainly in Central Asia, for 12,000 years. It includes wild ginseng and various types known for their medical and pharmaceutical properties. Cannabis chemovars containing cannabinoid compounds and their variants, strains var. indica and var. Cannabis sativa subspecies sativa, including kafiristanica, Cannabis sativa subspecies indica, and Cannabis sativa subspecies ruderalis. and genetic crosses, self-crosses, or hybrid plants thereof.
중국을 비롯한 한국의 전통 의약서에서는 대마 종자의 껍질을 제거한 마자인(麻子仁) 또는 화마인(火麻仁)이 변비, 당뇨, 통증질환, 월경불순, 피부질환 및 이질 등에 사용되어 왔고, 삼잎인 대마초(***草, 마엽(麻葉))는 구충제, 모발보호, 천식, 진통작용, 마취, 이뇨제 등으로 사용한 바 있다. 또한 마근(麻根)은 난산 치료와 어혈 해소에, 마피(麻皮)는 타박상과 열림창동에, 마화(麻化)는 마비증상과 가려움증 등에 사용했으며, 마분(麻賁)은 난산, 변비, 통풍, 진관, 불면 등에 대마의 각 부위에 따라 병증에 맞게 사용한 기록들이 전해진다.In traditional medicine in China and Korea, Mazain (麻子仁) or Hwamain (火麻仁), obtained by removing the skin of hemp seeds, has been used for constipation, diabetes, pain diseases, menstrual irregularities, skin diseases and dysentery, and hemp leaves. Cannabis (***草, hemp leaf) has been used as an anthelmintic, hair protection, asthma, analgesic, anesthetic, and diuretic. In addition, horse root (麻根) was used to treat dystocia and relieve blood stagnation, hemp root (麻皮) was used for bruises and open wounds, horseradish (麻化) was used for paralysis and itching, and horseradish (麻賁) was used to treat dystocia, constipation, etc. There are records of the use of cannabis according to the condition for each part of the plant, such as gout, gingivitis, and insomnia.
대마에는 약 400여 개의 화합물이 있으며, 그 중 대부분이 칸나비노이드(cannabinoids), 테르펜(terpenes), 및 페놀류 화합물(phenolic compounds)이고 이중 의·약학적 중요 천연 성분인 칸나비노이드류는 90여 가지로 대마에서만 발견되는 성분도 다수 있다. 대마의 칸나비노이드류 중 향정신성 성분은 △9-테트라히드로칸나비놀(△9-tetrahydrocannabinol, △9-THC)이고, 칸나비디올(cannabidiol, CBD)은 비향정신성 성분으로 아드레날린 수용체 및 칸나비노이드 수용체를 비롯한 인체 내 다양한 수용체를 통해 생리활성 효과를 나타내는 성분으로 알려져 있다.There are about 400 compounds in cannabis, most of which are cannabinoids, terpenes, and phenolic compounds, of which about 90 cannabinoids are important natural ingredients in medicine and pharmaceuticals. There are many ingredients found only in hemp. Among the cannabinoids of cannabis, the psychoactive ingredient is △9-tetrahydrocannabinol (△9-THC), and cannabidiol (CBD) is a non-psychoactive ingredient that acts on adrenergic receptors and cannabinoid receptors. It is known to be an ingredient that exhibits bioactive effects through various receptors in the human body, including .
한편, 대한민국 통계청의 분석에 따르면 암은 대한민국의 제 1의 사망원인으로 남성이 31.7%, 여성이 22.5%를 차지하며 전체 인구의 31.7%가 암으로 사망한다. 암을 치료하기 위한 방법으로는 수술을 통한 치료, 방사선 치료 그리고 항암제 투여를 통한 치료 등이 있으나 이러한 치료방법들은 부작용이 수반되거나, 암의 진행 정도에 따라 시술이 제한적으로 적용된다. 특히, 대부분의 항암제는 분열이 왕성한 세포의 세포주기를 멈추게 하고 사멸케 하는 메커니즘으로 작동하기 때문에 세포 이외에도 정상적으로 분열하는 세포를 공격해서 탈모, 식욕부진 그리고 백혈구 감소로 인한 면역력 저하 등의 부작용을 동반한다. 따라서, 저농도의 항암제를 사용하면서도 치료 효과로 극대화하기 위한 기술이 필요한 실정이다.Meanwhile, according to an analysis by the National Statistical Office of the Republic of Korea, cancer is the number one cause of death in Korea, accounting for 31.7% in men and 22.5% in women, and 31.7% of the total population dies from cancer. Methods for treating cancer include surgery, radiation therapy, and anticancer drug administration, but these treatment methods involve side effects or are limited in application depending on the progress of the cancer. In particular, most anticancer drugs operate by a mechanism that stops the cell cycle of actively dividing cells and causes them to die, so they attack cells that are normally dividing in addition to cells, resulting in side effects such as hair loss, loss of appetite, and decreased immunity due to a decrease in white blood cells. . Therefore, there is a need for technology to maximize the therapeutic effect while using low concentrations of anticancer drugs.
이러한 배경 하에, 항암제 및 칸나비디올을 병용 처리에 따른 현저히 향상된 항암 효능을 확인하여 본 발명을 완성하였다.Against this background, the present invention was completed by confirming significantly improved anticancer efficacy following combined treatment with an anticancer agent and cannabidiol.
일 양상은 칸나비디올(cannabidiol, CBD) 및 항암제를 유효성분으로 포함하는 간암의 예방 또는 치료용 약학 조성물을 제공한다.One aspect provides a pharmaceutical composition for preventing or treating liver cancer containing cannabidiol (CBD) and an anticancer agent as active ingredients.
다른 양상은 칸나비디올(cannabidiol, CBD)을 포함하는, 간암의 항암 효과 증진용 약학 조성물을 제공한다.Another aspect provides a pharmaceutical composition for enhancing the anticancer effect of liver cancer, comprising cannabidiol (CBD).
일 양상은 칸나비디올(cannabidiol, CBD) 및 항암제를 유효성분으로 포함하는 간암의 예방 또는 치료용 약학 조성물을 제공하는 것이다.One aspect is to provide a pharmaceutical composition for preventing or treating liver cancer containing cannabidiol (CBD) and an anticancer agent as active ingredients.
본 명세서에서의 용어, "칸나비디올(Cannabidiol, CBD)"은 하기 화학식 1(IUPAC name: 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol))로 표시되는 대마를 구성하는 주된 화합물 중 하나로서, 환각 증세를 일으키는 테트라하이드로칸나비놀(tetrahydrocannabinol: THC)과 많이 비교되는 물질이다. 우리나라의 경우 마약류로 지정되어 많은 연구가 이루어지고 있지 않으나, 실제로 향정신성 효과가 거의 없어 외국의 경우 통증이나 기억 장애, 불안 등의 증상 완화를 위한 의료용으로 사용하며, 과도한 유분 생성을 억제하는 것이 알려져 여드름 피부용 화장품 성분과 관련된 연구도 활발히 이루어지고 있다. 또한, 칸나비디올은 신경 활성의 흥분-억제 평형(excitatory-inhibitory equilibrium)에 관여함으로써, 발작을 일으키는 간질 증후군에서 효과적일 수 있음을 시사하는 여러 보고가 있다.As used herein, the term "cannabidiol (CBD)" has the following formula 1 (IUPAC name: 2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2 -en-1-yl]-5-pentylbenzene-1,3-diol) is one of the main compounds that make up cannabis, and is often compared to tetrahydrocannabinol (THC), which causes hallucinogenic symptoms. It is a substance. In Korea, it is designated as a narcotic and not much research is being done, but in fact, it has almost no psychoactive effect, so in foreign countries, it is used for medical purposes to relieve symptoms such as pain, memory impairment, and anxiety, and is known to suppress excessive oil production for acne. Research on skin cosmetic ingredients is also being actively conducted. In addition, there are several reports suggesting that cannabidiol may be effective in epilepsy syndromes that cause seizures by participating in the excitatory-inhibitory equilibrium of neural activity.
[화학식 1] [Formula 1]
상기 칸나비디올은 칸나비디올의 유도체, 이의 입체이성질체, 이의 약학적으로 허용가능한 염, 이의 수화물, 및 이의 용매화물로 구성된 군에서 선택된 하나 이상을 포함하는 것일 수 있다.The cannabidiol may include one or more selected from the group consisting of cannabidiol derivatives, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof.
본 명세서에서의 용어 “약학적으로 허용가능한 염"은, 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약제학적으로 사용될 수 있는 형태의 염을 의미하는데, 통상적으로 금속염, 유기 염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기 염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다. 특히 바람직한 염으로는, 화합물이 그 내에 산성관능기를 가지는 경우, 알칼리 금속염 (예컨대, 나트륨염, 칼륨염 등), 알칼리 토금속염 (예컨대, 칼슘염, 마그네슘염, 바륨염 등) 등과 같은 무기염, 및 암모늄염과 같은 유기 염이 있으며, 화합물이 그 내에 염기성 관능기를 가지는 경우, 염산, 브롬화수소산, 질산, 황산, 인산 등과 같은 무기산과의 염, 아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, p-톨루엔술폰산 등과 같은 유기산과의 염이 있다.The term “pharmaceutically acceptable salt” as used herein refers to a salt that can be used pharmaceutically among salts that are substances in which cations and anions are combined by electrostatic attraction, and are usually metal salts and organic bases. It can be a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, etc. For example, metal salts include alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salts, etc.) salt, magnesium salt, barium salt, etc.), aluminum salt, etc.; salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, and triethanolamine. , cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.; salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; Salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; basic amino acids and The salt may be a salt with arginine, lysine, ornithine, etc., and the salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, etc. A particularly preferable salt is one in which the compound has an acidic functional group. When present, there are inorganic salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, barium salts, etc.), and organic salts such as ammonium salts, and the compound may be contained within them. When having a basic functional group, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc., salts with organic acids such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. There is a salt of .
본 명세서에서의 용어 "암"은 신체 조직의 자율적인 과잉 성장에 의해 비정상적으로 자라난 종양, 또는 종양을 형성하는 병을 의미한다. 상기 암은 고형암일 수 있으며, 구체적으로 간암일 수 있다. 또한, 상기 '간암'은 흔히 흔히 간세포암(hepatocellular carcinoma, HCC)을 의미하며, 간을 이루고 있는 간세포에서 생겨난 악성 종양을 말한다. 간암 중 원발성 간암이 90% 정도를 차지한다. 기저 간질환이 있는 경우 간암이 발생하기 쉬으며, 간암 환자의 75~85%에서 간경변이 있으며, 간경변 환자의 10~30%가 간암이 발생한다고 알려져 있다.The term “cancer” herein refers to a tumor that grows abnormally due to autonomous excessive growth of body tissue, or a disease that forms a tumor. The cancer may be a solid cancer, and specifically may be liver cancer. In addition, the term 'liver cancer' commonly refers to hepatocellular carcinoma (HCC), which refers to a malignant tumor that arises from hepatocytes that make up the liver. Primary liver cancer accounts for about 90% of liver cancer. It is known that liver cancer is more likely to occur if there is underlying liver disease, 75-85% of liver cancer patients have cirrhosis, and 10-30% of liver cirrhosis patients develop liver cancer.
상기 조성물에서 상기 칸나비디올과 항암제는 병용 투여 되는 것일 수 있으며, 구체적으로, 상기 칸나비디올은 항암제와 하나의 제형으로 동시에 투여되거나, 또는 항암제와 별개의 제형으로 동시에 또는 순차적으로 투여되는 것일 수 있다.In the composition, the cannabidiol and the anticancer agent may be administered in combination. Specifically, the cannabidiol may be administered simultaneously with the anticancer agent in one formulation, or may be administered simultaneously or sequentially in a separate formulation from the anticancer agent. there is.
본 명세서에서의 용어 "병용투여"는, 치료요법의 개별성분들을 동시, 순차적으로, 또는 개별적으로 투여하는 방식으로 이룰 수 있다. 2이상의 약물을 동시에 또는 순차적으로 투여하거나, 또는 일정한 또는 정해지지 않은 간격으로 교대로 투여하는 등의 방법으로 병용 치료 효과를 얻는 것으로, 병용치료법은 이에 한정되지 아니하지만, 예를 들어 반응정도, 반응 속도, 질병 진행까지의 기간 또는 생존 기간을 통해 측정된 효능이 병용 치료법의 성분 중 하나 또는 나머지를 통상적인 용량으로 투약하여 얻을 수 있는 효능보다 치료학적으로 우수하면서 상승효과를 제공할 수 있는 것으로 정의될 수 있다.As used herein, the term “combined administration” can be achieved by administering the individual components of the treatment simultaneously, sequentially, or individually. The combination treatment effect is obtained by administering two or more drugs simultaneously or sequentially, or alternately at regular or undetermined intervals. The combination treatment method is not limited to this, but includes, for example, degree of response and speed of response. , which is defined as one in which the efficacy measured through the time to disease progression or survival period is therapeutically superior to and can provide a synergistic effect over the efficacy that can be obtained by administering one or the remaining components of the combination therapy at a conventional dose. You can.
상기 조성물은 상기 칸나비디올 및 항암제를 9:1 내지 1:9의 농도 비율로 포함하는 것일 수 있다. 구체적으로, 칸나비디올 및 항암제의 농도 비율(칸나비디올:항암제)은 9:1 내지 1:9, 9:1 내지 1:7, 9:1 내지 1:5, 9:1 내지 1:4, 9:1 내지 1:3, 9:1 내지 1:2, 9:1 내지 1:1, 7:1 내지 1:9, 7:1 내지 1:7, 7:1 내지 1:5, 7:1 내지 1:4, 7:1 내지 1:3, 7:1 내지 1:2, 7:1 내지 1:1, 5:1 내지 1:9, 5:1 내지 1:7, 5:1 내지 1:5, 5:1 내지 1:4, 5:1 내지 1:3, 5:1 내지 1:2, 5:1 내지 1:1, 4:1 내지 1:9, 4:1 내지 1:7, 4:1 내지 1:5, 4:1 내지 1:4, 4:1 내지 1:3, 4:1 내지 1:2, 4:1 내지 1:1, 3:1 내지 1:9, 3:1 내지 1:7, 3:1 내지 1:5, 3:1 내지 1:4, 3:1 내지 1:3, 3:1 내지 1:2, 3:1 내지 1:1, 2:1 내지 1:9, 2:1 내지 1:7, 2:1 내지 1:5, 2:1 내지 1:4, 2:1 내지 1:3, 2:1 내지 1:2, 2:1 내지 1:1, 1:1 내지 1:9, 1:1 내지 1:7, 1:1 내지 1:5, 1:1 내지 1:4, 1:1 내지 1:3, 또는 1:1 내지 1:2일 수 있다.The composition may contain the cannabidiol and the anticancer agent at a concentration ratio of 9:1 to 1:9. Specifically, the concentration ratio of cannabidiol and anticancer agent (cannabidiol:anticancer agent) is 9:1 to 1:9, 9:1 to 1:7, 9:1 to 1:5, 9:1 to 1:4. , 9:1 to 1:3, 9:1 to 1:2, 9:1 to 1:1, 7:1 to 1:9, 7:1 to 1:7, 7:1 to 1:5, 7 :1 to 1:4, 7:1 to 1:3, 7:1 to 1:2, 7:1 to 1:1, 5:1 to 1:9, 5:1 to 1:7, 5:1 to 1:5, 5:1 to 1:4, 5:1 to 1:3, 5:1 to 1:2, 5:1 to 1:1, 4:1 to 1:9, 4:1 to 1 :7, 4:1 to 1:5, 4:1 to 1:4, 4:1 to 1:3, 4:1 to 1:2, 4:1 to 1:1, 3:1 to 1:9 , 3:1 to 1:7, 3:1 to 1:5, 3:1 to 1:4, 3:1 to 1:3, 3:1 to 1:2, 3:1 to 1:1, 2 :1 to 1:9, 2:1 to 1:7, 2:1 to 1:5, 2:1 to 1:4, 2:1 to 1:3, 2:1 to 1:2, 2:1 to 1:1, 1:1 to 1:9, 1:1 to 1:7, 1:1 to 1:5, 1:1 to 1:4, 1:1 to 1:3, or 1:1 to It could be 1:2.
상기 칸나비디올은 조성물에 1 내지 50 μM의 농도로 포함된 것일 수 있다. 구체적으로, 상기 칸나비디올은 1 내지 50 μM, 1 내지 45 μM, 1 내지 40 μM, 1 내지 35 μM, 1 내지 30 μM, 1 내지 25 μM, 1 내지 20 μM, 1 내지 15 μM, 5 내지 50 μM, 5 내지 45 μM, 5 내지 40 μM, 5 내지 35 μM, 5 내지 30 μM, 5 내지 25 μM, 5 내지 20 μM, 5 내지 15 μM, 10 내지 50 μM, 10 내지 45 μM, 10 내지 40 μM, 10 내지 35 μM, 10 내지 30 μM, 10 내지 25 μM, 10 내지 20 μM, 10 내지 15 μM, 15 내지 50 μM, 15 내지 45 μM, 15 내지 40 μM, 15 내지 35 μM, 15 내지 30 μM, 15 내지 25 μM, 15 내지 20 μM, 20 내지 50 μM, 20 내지 45 μM, 20 내지 40 μM, 20 내지 35 μM, 20 내지 30 μM 또는 20 내지 25 μM의 농도로 포함되는 것일 수 있다.The cannabidiol may be included in the composition at a concentration of 1 to 50 μM. Specifically, the cannabidiol is 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM, 1 to 20 μM, 1 to 15 μM, 5 to 5 μM. 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM, 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM, 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 50 μM, 15 to 45 μM, 15 to 40 μM, 15 to 35 μM, 15 to 15 μM It may be included at a concentration of 30 μM, 15 to 25 μM, 15 to 20 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM, 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM. .
상기 항암제는 조성물에 1 내지 100 μM의 농도로 포함된 것일 수 있다. 구체적으로, 상기 항암제는 1 내지 100 μM, 1 내지 80 μM, 1 내지 60 μM, 1 내지 50 μM, 1 내지 45 μM, 1 내지 40 μM, 1 내지 35 μM, 1 내지 30 μM, 1 내지 25 μM, 1 내지 20 μM, 1 내지 15 μM, 5 내지 100 μM, 5 내지 80 μM, 5 내지 60 μM, 5 내지 50 μM, 5 내지 45 μM, 5 내지 40 μM, 5 내지 35 μM, 5 내지 30 μM, 5 내지 25 μM, 5 내지 20 μM, 5 내지 15 μM, 10 내지 100 μM, 10 내지 80 μM, 10 내지 60 μM, 10 내지 50 μM, 10 내지 45 μM, 10 내지 40 μM, 10 내지 35 μM, 10 내지 30 μM, 10 내지 25 μM, 10 내지 20 μM, 10 내지 15 μM, 15 내지 100 μM, 15 내지 80 μM, 15 내지 60 μM, 15 내지 50 μM, 15 내지 45 μM, 15 내지 40 μM, 15 내지 35 μM, 15 내지 30 μM, 15 내지 25 μM, 15 내지 20 μM, 20 내지 100 μM, 20 내지 80 μM, 20 내지 60 μM, 20 내지 50 μM, 20 내지 45 μM, 20 내지 40 μM, 20 내지 35 μM, 20 내지 30 μM 또는 20 내지 25 μM의 농도로 포함되는 것일 수 있다. 상기 항암제는 간암 항암제로서, 카보잔티닙 (Cabozantinib), 소라페닙(Sorafenib), 렌바티닙(Lenvatinib) 및 레고라페닙(Regorafenib)로 구성된 군에서 선택된 하나 이상을 포함하는 것일 수 있으며, 구체적으로 카보잔티닙 (Cabozantinib)을 포함하는 것일 수 있다.The anticancer agent may be included in the composition at a concentration of 1 to 100 μM. Specifically, the anticancer agent is 1 to 100 μM, 1 to 80 μM, 1 to 60 μM, 1 to 50 μM, 1 to 45 μM, 1 to 40 μM, 1 to 35 μM, 1 to 30 μM, 1 to 25 μM. , 1 to 20 μM, 1 to 15 μM, 5 to 100 μM, 5 to 80 μM, 5 to 60 μM, 5 to 50 μM, 5 to 45 μM, 5 to 40 μM, 5 to 35 μM, 5 to 30 μM , 5 to 25 μM, 5 to 20 μM, 5 to 15 μM, 10 to 100 μM, 10 to 80 μM, 10 to 60 μM, 10 to 50 μM, 10 to 45 μM, 10 to 40 μM, 10 to 35 μM , 10 to 30 μM, 10 to 25 μM, 10 to 20 μM, 10 to 15 μM, 15 to 100 μM, 15 to 80 μM, 15 to 60 μM, 15 to 50 μM, 15 to 45 μM, 15 to 40 μM , 15 to 35 μM, 15 to 30 μM, 15 to 25 μM, 15 to 20 μM, 20 to 100 μM, 20 to 80 μM, 20 to 60 μM, 20 to 50 μM, 20 to 45 μM, 20 to 40 μM , may be included at a concentration of 20 to 35 μM, 20 to 30 μM, or 20 to 25 μM. The anticancer agent is a liver cancer anticancer agent, and may include one or more selected from the group consisting of Cabozantinib, Sorafenib, Lenvatinib, and Regorafenib, and specifically, Cabozantinib. It may include cabozantinib.
본 명세서에서의 용어, "카보잔티닙 (Cabozantinib)"은 하기 화학식 2로 표시되는 화합물로서, 갑상선 수질암, 신세포암 및 간세포암을 치료하는 데 사용되는 항암제로서, 티로신 키나아제 c-Met 및 VEGFR2을 억제하는 것으로 알려져 있다.As used herein, the term "Cabozantinib" is a compound represented by the following formula (2), and is an anticancer agent used to treat medullary thyroid cancer, renal cell carcinoma, and hepatocellular carcinoma, and is an anticancer agent that inhibits tyrosine kinase c-Met and VEGFR2. is known to inhibit.
[화학식 2] [Formula 2]
상기 카보잔티닙은 카보잔티닙의 유도체, 이의 입체이성질체, 이의 약학적으로 허용가능한 염, 이의 수화물, 및 이의 용매화물로 구성된 군에서 선택된 하나 이상을 포함하는 것일 수 있다.The cabozantinib may include one or more selected from the group consisting of cabozantinib derivatives, stereoisomers thereof, pharmaceutically acceptable salts thereof, hydrates thereof, and solvates thereof.
본 명세서에서의 용어 "치료"는, 본 발명의 조성물의 투여에 의해 간암 질환의 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다.The term “treatment” as used herein refers to any action that improves or beneficially changes the symptoms of liver cancer disease by administering the composition of the present invention.
본 명세서에서의 용어 "예방"은, 본 발명의 조성물의 투여에 의해 간암 질환 또는 질환의 발병 가능성이 억제되거나 지연되는 모든 행위를 의미한다.The term “prevention” as used herein refers to any action that suppresses or delays the possibility of developing a liver cancer disease or disease by administering the composition of the present invention.
상기 조성물은 칸나비디올 및 항암제를 병용 투여함으로서, 간암 세포의 증식 억제 및 세포 사멸을 보다 효과적으로 유도하는 것일 수 있다. 구체적으로, 상기 조성물은 간암 세포의 세포사멸(apoptosis) 및 자가포식(autophagy) 중 하나 이상의 효과를 유도 또는 증진하는 것일 수 있다.The composition may inhibit the proliferation of liver cancer cells and induce cell death more effectively by administering cannabidiol and an anticancer agent in combination. Specifically, the composition may induce or enhance one or more effects of apoptosis and autophagy of liver cancer cells.
일 실시예에 따르면, 상기 조성물은 세포사멸(apoptosis) 관련 인자인 PARP, Cleaved caspase9 및 Cleaved caspase8 단백질의 발현 증가를 유도하고, 자가포식(Autophagy) 관련 인자인 LC3-II 단백질의 발현 증가를 유도함을 확인하였는 바, 칸나비디올 및 항암제을 병용 투여할 경우 항암 효과가 현저히 향상되는 것을 알 수 있다.According to one embodiment, the composition induces an increase in the expression of PARP, Cleaved caspase9, and Cleaved caspase8 proteins, which are apoptosis-related factors, and increases the expression of LC3-II protein, an autophagy-related factor. As confirmed, it can be seen that the anticancer effect is significantly improved when cannabidiol and anticancer drugs are administered together.
상기 약학 조성물은 약학적으로 허용 가능한 담체를 포함할 수 있다. 상기 "약학적으로 허용 가능한 담체"란 생물체를 자극하지 않으면서, 주입되는 화합물의 생물학적 활성 및 특성을 저해하지 않는 담체 또는 희석제를 의미할 수 있다. 여기서 "약학적으로 허용되는"의 의미는 유효성분의 활성을 억제하지 않으면서 적용(처방) 대상이 적응 가능한 이상의 독성을 지니지 않는다는 의미이다. 상기 약학적 조성물에 사용 가능한 상기 담체의 종류는 당해 기술 분야에서 통상적으로 사용되고 약학적으로 허용되는 담체라면 어느 것이든 사용할 수 있다. 상기 담체의 비제한적인 예로는, 락토스, 덱스트로스, 말토 덱스트린, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 글리세롤, 에탄올, 전분, 아카시아 고무, 알기네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로스, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 식염수, 멸균수, 링거액, 완충 식염수, 알부민 주사 용액, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 또는 광물유 등을 들 수 있다. 이들은 단독으로 사용되거나 2 종 이상을 혼합하여 사용될 수 있다. 상기 약학적 조성물은 유효성분 이외에 약학적으로 허용되는 담체를 포함하여 당업계에 공지된 통상의 방법으로 투여 경로에 따라 경구용 제형 또는 비경구용 제형으로 제조될 수 있다. 상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제제화하여 사용될 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier. The “pharmaceutically acceptable carrier” may mean a carrier or diluent that does not irritate living organisms and does not inhibit the biological activity and properties of the injected compound. Here, “pharmaceutically acceptable” means that it does not inhibit the activity of the active ingredient and does not have any toxicity beyond what the subject of application (prescription) can adapt to. The type of carrier that can be used in the pharmaceutical composition can be any carrier that is commonly used in the art and is pharmaceutically acceptable. Non-limiting examples of the carrier include lactose, dextrose, maltodextrin, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, glycerol, ethanol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, saline, sterile water, Ringer's solution, buffered saline, albumin injection solution, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or Mineral oil, etc. may be mentioned. These may be used individually or in combination of two or more types. The pharmaceutical composition may be prepared into an oral formulation or a parenteral formulation depending on the route of administration by a conventional method known in the art, including a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods.
상기 약학 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제제화하여 사용될 수 있다. 상기 약학 조성물을 제제화할 경우, 일반적으로 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 또는 계면활성제 등의 희석제 또는 부형제를 추가하여 조제될 수 있다.The pharmaceutical composition can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. When formulating the pharmaceutical composition, it may be prepared by adding diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, or surfactants.
상기 약학 조성물이 경구용 제형으로 제조될 경우, 적합한 담체와 함께 당업계에 공지된 방법에 따라 분말, 과립, 정제, 환제, 당의정제, 캡슐제, 액제, 겔제, 시럽제, 현탁액, 웨이퍼 등의 제형으로 제조될 수 있다. 이때 약학적으로 허용되는 적합한 담체의 예로서는 락토스, 글루코스, 슈크로스, 덱스트로스, 솔비톨, 만니톨, 자일리톨 등의 당류, 옥수수 전분, 감자 전분, 밀 전분 등의 전분류, 셀룰로오스, 메틸셀룰로오스, 에틸셀룰로오스, 나트륨 카르복시메틸셀룰로오스, 하이드록시프로필메틸셀룰로오스 등의 셀룰로오스류, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 마그네슘 스테아레이트, 광물유, 맥아, 젤라틴, 탈크, 폴리올, 식물성유 등을 들 수 있다. 제제화활 경우 필요에 따라 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 및/또는 부형제를 포함하여 제제화할 수 있다.When the pharmaceutical composition is prepared as an oral dosage form, it is prepared in the form of powders, granules, tablets, pills, sugar-coated tablets, capsules, solutions, gels, syrups, suspensions, wafers, etc. according to methods known in the art along with a suitable carrier. It can be manufactured with At this time, examples of suitable pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose, dextrose, sorbitol, mannitol, and xylitol, starches such as corn starch, potato starch, and wheat starch, cellulose, methylcellulose, and ethylcellulose. Cellulose such as sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate, mineral oil, malt, gelatin, talc, polyol, vegetable. Yu, etc. can be mentioned. In the case of formulation, if necessary, diluents and/or excipients such as fillers, extenders, binders, wetting agents, disintegrants, and surfactants may be included in the formulation.
상기 약학 조성물이 비경구용 제형으로 제조될 경우, 적합한 담체와 함께 당업계에 공지된 방법에 따라 주사제, 경피 투여제, 비강 흡입제 및 좌제의 형태로 제제화될 수 있다. 주사제로 제제화활 경우 적합한 담체로서는 멸균수, 에탄올, 글리세롤이나 프로필렌 글리콜 등의 폴리올 또는 이들의 혼합물을 들 수 있으며, 바람직하게는 링거 용액, 트리에탄올 아민이 함유된 PBS(phosphate buffered saline)나 주사용 멸균수, 5% 덱스트로스 같은 등장 용액 등을 사용할 수 있다. 경피 투여제로 제제화할 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태로 제제화될 수 있다. 비강 흡입제의 경우 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 등의 적합한 추진제를 사용하여 에어로졸 스프레이 형태로 제제화될 수 있으며, 좌제로 제제화할 경우 그 기제로는 위텝솔(witepsol), 트윈(tween) 61, 폴리에틸렌글리콜류, 카카오지, 라우린지, 폴리옥시에틸렌 소르비탄 지방산 에스테르류, 폴리옥시에틸렌 스테아레이트류, 소르비탄 지방산 에스테르류 등이 사용될 수 있다.When the pharmaceutical composition is prepared as a parenteral formulation, it can be formulated in the form of injections, transdermal administration, nasal inhalation, and suppositories along with a suitable carrier according to methods known in the art. When formulated as an injection, suitable carriers include sterile water, ethanol, polyols such as glycerol or propylene glycol, or mixtures thereof, preferably Ringer's solution, phosphate buffered saline (PBS) containing triethanol amine, or sterile injectable solution. Isotonic solutions such as water or 5% dextrose can be used. When formulated for transdermal administration, it can be formulated in the form of ointments, creams, lotions, gels, external solutions, paste preparations, linear preparations, and aerol preparations. In the case of nasal inhalation, it can be formulated in the form of an aerosol spray using suitable propellants such as dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, and carbon dioxide. When formulated as a suppository, the base is Wethepsol ( witepsol), Tween 61, polyethylene glycols, cocoa fat, laurel paper, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene stearates, sorbitan fatty acid esters, etc. can be used.
상기 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있는데, 상기 용어 "약학적으로 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 발명 조성물과 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 상기 약학 조성물은 단독으로 투여하거나 공지된 간암 질환에 대한 치료 효과를 나타내는 것으로 알려진 성분과 병용하여 투여될 수 있다. 상기 요소를 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하다.The pharmaceutical composition may be administered in a pharmaceutically effective amount, where the term "pharmaceutically effective amount" means an amount sufficient to treat or prevent a disease with a reasonable benefit/risk ratio applicable to medical treatment or prevention. , the effective dose level is determined by the severity of the disease, the activity of the drug, the patient's age, weight, health, gender, the patient's sensitivity to the drug, the administration time of the composition of the present invention used, the route of administration and excretion rate, the treatment period, and the drug used. It can be determined according to factors including drugs combined or used simultaneously with the inventive composition and other factors well known in the medical field. The pharmaceutical composition may be administered alone or in combination with ingredients known to exhibit therapeutic effects on liver cancer diseases. It is important to consider all of the above factors and administer the amount that will achieve maximum effect with the minimum amount without side effects.
상기 약학 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 0.1ng 내지 약 1,000 mg/kg, 바람직하게는 1 ng 내지 약 100 mg/kg로 투여할 수 있고, 본 발명의 조성물의 투여빈도는 특별히 이에 제한되지 않으나, 1일 1회 투여하거나 또는 용량을 분할하여 수회 투여할 수 있다. 상기 투여량 또는 투여횟수는 어떠한 면으로든 본원의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition can be determined by a person skilled in the art in consideration of the purpose of use, the degree of addiction of the disease, the patient's age, weight, gender, antecedent history, or the type of substance used as an active ingredient. For example, the pharmaceutical composition of the present invention can be administered at about 0.1 ng to about 1,000 mg/kg, preferably 1 ng to about 100 mg/kg per adult, and the frequency of administration of the composition of the present invention is specifically determined by this. Although not limited, it can be administered once a day, or the dose can be divided and administered several times. The above dosage or frequency of administration does not limit the scope of the present application in any way.
다른 양상은 칸나비디올(cannabidiol, CBD)을 포함하는, 간암의 항암 효과 증진용 약학 조성물을 제공하는 것이다. 상기에서 설명한 내용과 동일한 부분은 상기 조성물에도 공히 적용된다.Another aspect is to provide a pharmaceutical composition for enhancing the anticancer effect of liver cancer, including cannabidiol (CBD). The same parts as described above also apply to the composition.
상기 조성물은 항암제 병용 투여용 조성물일 수 있으며, 구체적으로 상기 조성물은 항암제와 병용 투여 되는 것일 수 있다.The composition may be a composition for combined administration with an anticancer agent, and specifically, the composition may be administered in combination with an anticancer agent.
본 명세서에서의 용어, "암 치료 효과 증진"또는 "항암 효과 증진”은 항암제의 활성을 유도 또는 증진시키거나, 암세포의 항암제에 대한 내성을 감소시키거나, 또는 항암제에 대한 감수성/민감성 증가시켜 항암제의 암 치료 효과를 개선 및/또는 향상시키는 것을 의미하는 것일 수 있다.As used herein, the term “enhancement of cancer treatment effect” or “enhancement of anticancer effect” refers to inducing or enhancing the activity of an anticancer agent, reducing the resistance of cancer cells to an anticancer agent, or increasing the sensitivity/sensitivity to an anticancer agent. It may mean improving and/or enhancing the cancer treatment effect of.
또 다른 양상은 상기 간암의 예방 또는 치료용 약학 조성물 또는 간암의 항암 효과 증진용 약학 조성물을 개체에 개체에 투여하는 단계를 포함하는 간암 치료 또는 예방 방법을 제공하는 것이다. 상기에서 설명한 내용과 동일한 부분은 상기 방법에도 공히 적용된다.Another aspect is to provide a method of treating or preventing liver cancer, including the step of administering the pharmaceutical composition for preventing or treating liver cancer or the pharmaceutical composition for enhancing the anti-cancer effect of liver cancer to a subject. The same parts as described above also apply to the above method.
본 명세서에서 사용되는 용어 "개체"는 간암 질환이 발병되거나 발병할 위험이 있는 쥐, 가축, 인간 등을 포함하는 포유동물, 조류, 파충류, 양식어류 등을 제한 없이 포함할 수 있으며, 상기 개체는 인간을 제외하는 것일 수 있다.The term “individual” used herein may include, without limitation, mammals, birds, reptiles, farmed fish, etc., including rats, livestock, humans, etc., that develop or are at risk of developing liver cancer disease, and the entity is This may exclude humans.
상기 약학 조성물은 약학적으로 유효한 양으로 단일 또는 다중 투여될 수 있다. 이때, 조성물은 액제, 산제, 에어로졸, 주사제, 수액제(링겔), 캡슐제, 환제, 정제, 좌제 또는 패치의 형태로 제형화되어 투여할 수 있다. 상기 간암 예방 또는 치료용 약학 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여도 투여될 수 있다.The pharmaceutical composition may be administered singly or multiple times in a pharmaceutically effective amount. At this time, the composition can be formulated and administered in the form of a solution, powder, aerosol, injection, infusion solution (injection), capsule, pill, tablet, suppository, or patch. The administration route of the pharmaceutical composition for preventing or treating liver cancer can be administered through any general route as long as it can reach the target tissue.
상기 약학 조성물은 특별히 이에 제한되지 않으나, 목적하는 바에 따라 복강내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 경피패치투여, 경구 투여, 비내 투여, 폐내 투여, 직장내 투여 등의 경로를 통해 투여 될 수 있다. 다만, 경구 투여 시에는 제형화되지 않은 형태로도 투여할 수 있고, 위산에 의하여 상기 약학 조성물의 유효성분이 변성 또는 분해될 수 있기 때문에 경구용 조성물은 활성 약제를 코팅하거나 위에서의 분해로부터 보호되도록 제형화된 형태 또는 경구용 패치형태로 구강내에 투여할 수도 있다. 또한, 상기 조성물은 활성 물질이 표적세포로 이동할 수 있는 임의의 장치에 의해 투여될 수 있다.The pharmaceutical composition is not particularly limited thereto, but may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, transdermal patch, oral administration, intranasal administration, intrapulmonary administration, intrarectal administration, etc., depending on the purpose. It can be administered via any route. However, during oral administration, it can be administered in an unformulated form, and since the active ingredients of the pharmaceutical composition may be denatured or decomposed by stomach acid, the oral composition is formulated to coat the active agent or protect it from decomposition in the stomach. It can also be administered orally in the form of a tablet or oral patch. Additionally, the composition can be administered by any device that allows the active substance to move to target cells.
본 발명의 조성물은 칸나비디올과 간암 항암제 중 하나인 카보잔티닙을 병용처리할 경우, 현저히 우수한 간암 억제 효능을 나타내는 것을 확인하였는 바, 상기 조성물을 이용하여 간암 치료 효과를 증진시킬 수 있다.It has been confirmed that the composition of the present invention exhibits significantly superior liver cancer inhibition efficacy when combined with cannabidiol and cabozantinib, one of the liver cancer anticancer drugs. Therefore, the liver cancer treatment effect can be improved by using the composition.
도 1은 칸나비디올의 농도별 처리에 따른 HepG2 세포 또는 Hep3B 세포의 생존율을 나타낸 도면이다.
도 2는 칸나비디올 및 화학항암제의 병용 처리에 따른 HepG2 세포의 생존율을 나타낸 도면이다.
도 3은 칸나비디올 및 화학항암제의 병용 처리에 따른 Hep3B 세포의 생존율을 나타낸 도면이다.
도 4는 칸나비디올 및 카보잔티닙의 병용 처리에 따른 HepG2 세포의 PARP, cleaved caspase9, cleaved caspase8 및 LC3B의 발현 수준을 웨스턴 블랏팅으로 분석한 결과를 나타낸 도면이다.Figure 1 is a diagram showing the survival rate of HepG2 cells or Hep3B cells according to treatment with different concentrations of cannabidiol.
Figure 2 is a diagram showing the survival rate of HepG2 cells according to the combined treatment of cannabidiol and chemotherapy.
Figure 3 is a diagram showing the survival rate of Hep3B cells according to the combined treatment of cannabidiol and chemotherapy.
Figure 4 is a diagram showing the results of Western blotting analysis of the expression levels of PARP, cleaved caspase9, cleaved caspase8, and LC3B in HepG2 cells following combined treatment with cannabidiol and cabozantinib.
이하 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.This will be described in more detail through examples below. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples.
또한, 하기 실시예들에서 사용한 칸나비디올 화합물은 서울지방식품의약품안전청의 마약류(대마) 학술연구자 허가 (제1564호, 제1979호 및 제2083호)를 바탕으로 제조하여 사용하였다.In addition, the cannabidiol compounds used in the following examples were manufactured and used based on the narcotic (cannabis) academic researcher permit (Nos. 1564, 1979, and 2083) from the Seoul Regional Food and Drug Safety Administration.
실시예 1: 칸나비디올의 암세포 독성 평가Example 1: Evaluation of cancer cell toxicity of cannabidiol
칸나비디올(cannabidiol, CBD)의 간암세포에 대한 독성을 평가하기 위해, 하기와 같은 실험을 수행하였다.To evaluate the toxicity of cannabidiol (CBD) to liver cancer cells, the following experiment was performed.
구체적으로, HCC (Hepatocellular carcinoma) 세포주인 HepG2 세포 또는 Hep3B 세포를 96-웰 플레이트에 1 Х 104 cells/well 농도로 접종하고, 37 ℃, 10% CO2 인큐베이터에서 24시간 배양한 후, 칸나비디올을 농도별로 처리하고, 48시간 동안 동일 조건에서 배양하였다. 배양 완료 후, WST-8 용액(Quanti-MaxTM, BIOMAX, Korea)을 배지에 1/10씩 첨가하고, 37 ℃에서 1시간 동안 추가 배양한 후 450 nm에서 흡광도를 측정하여 세포 생존률을 확인하였으며, 아무 처리도 하지 않은 대조군에 대한 비율로 나타냈다. 본 실험은 독립적으로 3회 반복하여 수행하였다.Specifically, HepG2 cells or Hep3B cells, which are HCC (Hepatocellular carcinoma) cell lines, were inoculated into a 96-well plate at a concentration of 1 Х 10 4 cells/well, cultured in an incubator at 37°C, 10% CO 2 for 24 hours, and then incubated with cannabi. Diols were treated at different concentrations and cultured under the same conditions for 48 hours. After completion of incubation, 1/10 of WST-8 solution (Quanti-MaxTM, BIOMAX, Korea) was added to the medium, and further cultured at 37°C for 1 hour, and the cell viability was confirmed by measuring absorbance at 450 nm. It is expressed as a ratio to the control group that did not receive any treatment. This experiment was independently repeated three times.
그 결과, HepG2 세포에서 칸나비디올에 대한 IC50 값은 32.52 μM으로 확인되고, Hep3B 세포에서 칸나비디올에 대한 IC50 값은 32.63 μM으로 확인되었는 바(도 1), 상기 농도 이하에서는 칸나비디올이 HepG2 세포 Hep3B 세포에 독성을 나타내지 않음을 알 수 있다. 한편, 이후의 실험에서는 칸나비디올 농도를 20 μM로 설정하여 진행하였다.As a result, the IC 50 value for cannabidiol in HepG2 cells was confirmed to be 32.52 μM, and the IC 50 value for cannabidiol in Hep3B cells was confirmed to be 32.63 μM (Figure 1). Below the above concentration, cannabidiol It can be seen that diol does not show toxicity to HepG2 cells and Hep3B cells. Meanwhile, in subsequent experiments, the cannabidiol concentration was set to 20 μM.
실시예 2: 칸나비디올 및 카보잔티닙 병용 처리의 암세포 사멸 효능 평가Example 2: Evaluation of cancer cell killing efficacy of cannabidiol and cabozantinib combination treatment
간암 치료제로 알려져 있는 카보잔티닙 (Cabozantinib)를 칸나비디올(cannabidiol, CBD)과 병용 처리한 경우의 암세포 사멸 효능을 평가하기 위해, 하기와 같은 실험을 수행하였다.To evaluate the cancer cell killing efficacy of cabozantinib, a known liver cancer treatment, in combination with cannabidiol (CBD), the following experiment was performed.
구체적으로, 간암세포주인 HepG2 세포 또는 Hep3B 세포를 96-웰 플레이트에 1Х104 cells/well 농도로 접종하고, 37 ℃, 10% CO2 인큐베이터에서 24시간 배양한 후, 카보잔티닙을 농도별로 처리하고, 칸나비디올(20 μM)을 처리하거나 미처리한 후, 48시간 동안 동일 조건에서 배양하였다. 배양 완료 후, WST-8 용액(Quanti-MaxTM, BIOMAX, Korea)을 배지에 1/10씩 첨가하고, 37 ℃에서 1시간 동안 추가 배양한 후 450 nm에서 흡광도를 측정하여 세포 생존률을 확인하였으며, 아무 처리도 하지 않은 대조군에 대한 비율로 나타냈다. 본 실험은 독립적으로 3회 반복하여 수행하였다. 또한, 양성 대조군으로서, 카보잔티닙 대신 소라페닙(Sorafenib), 렌바티닙(Lenvatinib) 또는 레고라페닙(Regorafenib)을 각각 처리하였다.Specifically, liver cancer cell lines HepG2 cells or Hep3B cells were inoculated into 96-well plates at a concentration of 1Х10 4 cells/well, cultured in an incubator at 37°C and 10% CO 2 for 24 hours, and then treated with cabozantinib at different concentrations. , were treated or untreated with cannabidiol (20 μM) and then cultured under the same conditions for 48 hours. After completion of incubation, 1/10 of WST-8 solution (Quanti-MaxTM, BIOMAX, Korea) was added to the medium, and further cultured at 37°C for 1 hour, and then the absorbance was measured at 450 nm to confirm cell viability. It is expressed as a ratio to the control group that did not receive any treatment. This experiment was independently repeated three times. Additionally, as a positive control, Sorafenib, Lenvatinib, or Regorafenib were treated instead of cabozantinib, respectively.
그 결과, 카보잔티닙을 단독 처리한 경우보다 칸나비디올 및 카보잔티닙을 병용 처리한 경우 HepG2 세포 또는 Hep3B 세포에 대한 카보잔티닙 독성이 현저히 증가한 것을 확인하였으며, 구체적으로 칸나비디올 병용 처리시 카보잔티닙에 대한 세포독성(IC50)이 칸나비디올 미처리군과 비교하여 70% 이상 낮은 농도에서도 세포독성을 나타내는 것을 확인하였다 (도 2 및 도 3).As a result, it was confirmed that cabozantinib toxicity to HepG2 cells or Hep3B cells was significantly increased when cannabidiol and cabozantinib were treated in combination compared to when cabozantinib was treated alone, specifically when treated with cannabidiol in combination. It was confirmed that cabozantinib exhibited cytotoxicity (IC 50 ) even at a concentration that was more than 70% lower than that of the cannabidiol untreated group (Figures 2 and 3).
또한, 양성 대조군으로서 카보잔티닙 대신 소라페닙, 렌바티닙 또는 레고라페닙을 각각 처리한 경우에도 칸나비디올 병용 처리 효과를 나타냈음을 확인하였다.In addition, it was confirmed that the cannabidiol combination treatment showed an effect even when sorafenib, lenvatinib, or regorafenib was treated instead of cabozantinib as a positive control.
따라서, 상기 결과를 토대로, 카보잔티닙 및 칸나비디올을 병용처리할 경우, 간암에 대한 항암 효과를 현저히 증가시킬 수 있음을 알 수 있다.Therefore, based on the above results, it can be seen that the combined treatment of cabozantinib and cannabidiol can significantly increase the anticancer effect against liver cancer.
실시예 3: 칸나비디올 및 카보잔티닙 병용 처리의 항암효과 작용기전 분석Example 3: Analysis of the anticancer effect mechanism of cannabidiol and cabozantinib combination treatment
카보잔티닙 (Cabozantinib) 및 칸나비디올(cannabidiol, CBD) 병용 처리에 따른 간암세포 사멸 효과에 대한 작용 기전을 분석하기 위해, 하기와 같은 실험을 수행하였다.In order to analyze the mechanism of action of the liver cancer cell killing effect of the combined treatment of cabozantinib and cannabidiol (CBD), the following experiment was performed.
구체적으로, 간암세포주인 HepG2 세포를 6-웰 플레이트에 3Х105 cells/well 농도로 접종하고, 37 ℃, 10% CO2 인큐베이터에서 24시간 배양한 후, 카보잔티닙을 농도별로 처리하고, 칸나비디올(20 μM)을 처리하거나 미처리한 후, 24시간 동안 동일 조건에서 배양하였다. 배양 완료 후, 세포를 채집하여 bradford assay (Bio-Rad, japan)를 사용하여 단백질을 정량화하고, 단백질 (30 ug/well)을 NuPAGE 4-12% Bis-Tris 젤(Invitrogen)에 전기영동으로 분리하고 PVDF로 트랜스퍼하였다. 다음으로, 상기 PVDF 막을 PARP, cleaved caspase9, cleaved caspase8, LC3B 또는 GAPDH에 대한 특이적 1차 항체 (Monoclonal 항체, Cell signaling technology, USA)와 상온에서 1시간동안 반응시킨 후, 항-래빗 2차 항체 (Cell signaling technology) 로 1시간동안 반응시켰다. PVDF에 결합된 항체는 ECL Advance Western Blotting Detection Reagents (GE Healthcare, UK) 및 LAS 4000 이미징 시스템(Fujifilm, Japan)을 사용하여 시각화하였다.Specifically, HepG2 cells, a liver cancer cell line, were inoculated into a 6-well plate at a concentration of 3Х10 5 cells/well, cultured in an incubator at 37°C and 10% CO 2 for 24 hours, then treated with cabozantinib at different concentrations, and cannabi After being treated or not with diol (20 μM), the cells were cultured under the same conditions for 24 hours. After completion of culture, cells were collected, proteins were quantified using bradford assay (Bio-Rad, Japan), and proteins (30 ug/well) were separated by electrophoresis on NuPAGE 4-12% Bis-Tris gel (Invitrogen). and transferred to PVDF. Next, the PVDF membrane was reacted with a specific primary antibody against PARP, cleaved caspase9, cleaved caspase8, LC3B, or GAPDH (Monoclonal antibody, Cell signaling technology, USA) at room temperature for 1 hour, followed by an anti-rabbit secondary antibody. (Cell signaling technology) and reacted for 1 hour. Antibodies bound to PVDF were visualized using ECL Advance Western Blotting Detection Reagents (GE Healthcare, UK) and LAS 4000 imaging system (Fujifilm, Japan).
그 결과, 카보잔티닙 및 칸나비디올을 병용 처리할 경우 카보잔티닙 농도 의존적으로 세포사멸(apoptosis) 관련 인자인 PARP, Cleaved caspase9 및 Cleaved caspase8 단백질의 발현이 증가하는 것을 확인하였으며, 자가포식(Autophagy) 관련 인자인 LC3-II의 발현 또한 증가하는 것을 확인하였다 (도 4).As a result, it was confirmed that when cabozantinib and cannabidiol were treated together, the expression of PARP, Cleaved caspase9, and Cleaved caspase8 proteins, which are factors related to apoptosis, increased in a cabozantinib concentration-dependent manner, and autophagy (Autophagy) ) The expression of LC3-II, a related factor, was also confirmed to increase (Figure 4).
상기 결과를 토대로 카보잔티닙 및 칸나비디올의 병용 처리는 암세포의 세포사멸 또는 자가소화작용을 유도함으로서 암세포 사멸을 유도할 수 있음을 알 수 있다.Based on the above results, it can be seen that the combined treatment of cabozantinib and cannabidiol can induce cancer cell death by inducing apoptosis or autophagy of cancer cells.
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.The description of the present invention described above is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential features of the present invention. will be. Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
Claims (9)
The composition according to claim 1, wherein the composition is administered in combination with an anticancer agent.
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