KR20200134528A - Composition for preventing and treating a cancer comprising melatonin - Google Patents
Composition for preventing and treating a cancer comprising melatonin Download PDFInfo
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- KR20200134528A KR20200134528A KR1020190060083A KR20190060083A KR20200134528A KR 20200134528 A KR20200134528 A KR 20200134528A KR 1020190060083 A KR1020190060083 A KR 1020190060083A KR 20190060083 A KR20190060083 A KR 20190060083A KR 20200134528 A KR20200134528 A KR 20200134528A
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- multiple myeloma
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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Abstract
Description
본 발명은 멜라토닌의 항암 활성에 관한 것으로, 구체적으로 멜라토닌의 소포체 스트레스(ER-stress) 유발로 인한 암세포 사멸 효과에 관한 것이다.The present invention relates to the anticancer activity of melatonin, and specifically relates to the effect of killing cancer cells by inducing ER-stress of melatonin.
인간의 몸을 구성하고 있는 가장 작은 단위를 세포(cell)이라 부르는데 정상적인 세포는 세포 내 조절기능에 의해 분열하며 성장하고 죽어 없어지기도 하며 세포수의 균형을 유지한다. 어떤 원인으로 세포가 손상을 받은 경우, 치료를 받아 정상 세포로 역할을 하거나 회복이 안 된 경우 스스로 사멸하게 된다. 그러나 여러 가지 이유로 인해 세포의 유전자에 변화가 일어나면 비정상적으로 세포가 변하여 불완전하게 성숙하고, 세포주기가 조절되지 않아 세포분열을 계속하는데 이를 암(cancer)이라 정의한다.The smallest unit that makes up the human body is called a cell. Normal cells divide, grow, die, and disappear by intracellular regulatory functions, and maintain the balance of the number of cells. If a cell is damaged for some reason, it acts as a normal cell after receiving treatment, or if it cannot recover, it dies by itself. However, when a change in the gene of a cell occurs due to various reasons, the cell abnormally changes and matures incompletely, and the cell cycle is not regulated to continue cell division, which is defined as cancer.
현재, 암의 치료를 위해서는 수술 요법, 방사선 치료 요법 및 화학요법 등이 사용되고 있다. 이중에서, 화학요법은 항암제를 이용하여 암을 치료하는 방법을 말한다. 오늘날에는 약 60여종의 다양한 항암제가 사용되고 있으며, 최근 암 발생 및 암 세포의 특성에 관한 지식이 많이 알려짐에 따라, 새로운 항암제 개발에 관한 연구가 활발하게 진행되고 있다. 항암 화학치료에 있어 많은 환자들은 항암제의 부작용에 의하여 고통을 받고 있으며, 특히 항암제의 독성으로 인하여 제한적인 투여가 이루어지고 있다. 임상에서 사용되고 있는 항암물질은 암세포뿐만 아니라 정상세포에도 영향을 미치며 투여회수가 반복되면서 치료에 실패하는 등 부작용 및 항암제 내성과 같은 문제점을 가지고 있다. 암 자체의 다양성 및 발병기전의 다양화로 인해 야기되는 기존항암제의 부작용을 극복할 수 있는 새로운 형태의 항암제 치료물질 연구가 진행되고 있다.Currently, surgical therapy, radiation therapy, and chemotherapy are used for the treatment of cancer. Among them, chemotherapy refers to a method of treating cancer using an anticancer agent. Today, about 60 kinds of various anticancer agents are being used, and as knowledge about cancer incidence and characteristics of cancer cells is widely known, research on the development of new anticancer agents is actively progressing. In chemotherapy, many patients suffer from the side effects of anticancer drugs, and in particular, limited administration is performed due to the toxicity of anticancer drugs. Anticancer substances used in clinical practice affect not only cancer cells but also normal cells, and have problems such as side effects and resistance to anticancer drugs such as failure of treatment with repeated administrations. Research on new types of anticancer therapeutic substances that can overcome the side effects of existing anticancer drugs caused by the diversity of cancer itself and the diversification of pathogenesis are underway.
한편, 소포체(endoplasmic reticulum)는 리보좀이 붙어있는 조면 소포체 (rough ER, RER)와 활면 소포체(smooth ER, SER)가 존재한다. 조면 소포체는 단백질 합성이 주된 기능이며 세포 내 단백질의 약 1/3이 조면 소포체에서 합성이 된다. 활면 소포체는 대부분의 세포에서 발견되며, 다양한 지질과 스테로이드 호르몬을 합성하고 칼슘 저장소로 세포 내 칼슘 농도를 조절하는데 중요한 역할을 하게 된다. 여러 가지 생리적 또는 병리적인 상태에 의해 소포체 내에 칼슘 항상성, 당단백질의 당화과정(glycosylation) 또는 이황화 결합(disulfide bond) 형성 등이 제대로 이루어지지 않았을 때 단백질 접힘 (folding)이 제대로 일어나지 않게 되고, 이 때 소포체가 처리할 수 있는 능력 이상의 unfolded 단백질이 축적되거나 칼슘이 고갈되어 소포체의 기능 손상이 발생하는데 이러한 상태를 소포체 스트레스라고 한다(Zhao & Ackerman, 2006; 김미경과 박근규, 2008). On the other hand, endoplasmic reticulum includes rough ER (RER) and smooth ER (SER) to which ribosomes are attached. The main function of the rough endoplasmic reticulum is protein synthesis, and about a third of the intracellular proteins are synthesized in the rough endoplasmic reticulum. The smooth endoplasmic reticulum is found in most cells, synthesizes various lipids and steroid hormones, and plays an important role in regulating intracellular calcium concentration as a calcium reservoir. When calcium homeostasis, glycosylation or disulfide bond formation in the endoplasmic reticulum is not properly formed due to various physiological or pathological conditions, protein folding does not occur properly. Unfolded proteins that exceed the ability of the endoplasmic reticulum to process are accumulated or calcium is depleted, resulting in functional impairment of the endoplasmic reticulum. This condition is called endoplasmic reticulum stress (Zhao & Ackerman, 2006; Mikyung Kim and Geunkyu Park, 2008).
소포체 스트레스(ER stress)는 여러 신호전달을 통해서 세포사멸 (apoptosis)과 다량의 활성산소(reactive oxygen species, ROS) 형성을 증가시켜 세포의 손상을 초래한다. 소포체 스트레스가 발생하면 세포는 생존하기 위한 방어기전을 가지는 데 이를 소포체 스트레스 반응(ER stress response)라고 한다. 소포체 스트레스가 극복이 되지 못할 정도로 심각하여 소포체가 제 기능을 회복할 수 없을 때(ATF4 및 CHOP 발현)는 세포사멸(apoptosis) 경로가 활성화되어 손상된 세포를 제거한다. The endoplasmic reticulum stress (ER stress) increases apoptosis and the formation of large amounts of reactive oxygen species (ROS) through various signal transductions, resulting in damage to cells. When endoplasmic reticulum stress occurs, cells have a defense mechanism to survive, which is called ER stress response. When the endoplasmic reticulum stress is so severe that it cannot be overcome and the endoplasmic reticulum cannot recover its function (expressing ATF4 and CHOP), the apoptosis pathway is activated to remove the damaged cells.
활성 산소(reactive oxygen species, ROS)는 호흡을 하는 동안 미토콘드리아에서 생성되며, 특정 효소의 작용에 의해서 생성된다고 알려져 있다(Kamata and Hirata, Cell Signal, 1999). 낮은 수치의 ROS는 세포내의 신호를 조절하며, 정상 세포의 성장에 있어서 중요한 역할을 한다고 알려져 있다(Burdon, Free Radic. Biol. Med,1995). Reactive oxygen species (ROS) is produced in the mitochondria during respiration and is known to be produced by the action of specific enzymes (Kamata and Hirata, Cell Signal, 1999). It is known that low levels of ROS regulate intracellular signals and play an important role in the growth of normal cells (Burdon, Free Radic. Biol. Med, 1995).
ROS 산물이 암세포에서 증가된다는 보고가 있으며(Cancer Res., 1991); Burdon, 1995), 종양이 진행되는 동안 증가되는 ROS는 뉴클리어팩터 카파B(nuclear factor kappa-light-chain-enhancer of activated B cells, NF-κB)와 활성 단백질 1(activator protein 1, AP-1) 전사인자의 발현을 유도시킨다고 알려져 있다(Gupta et al., Carcinogenesis, 1999). 산화적 스트레스 역시 DNA의 손상을 일으켜 게놈(Genome)의 불안정을 유도하고, 이는 암이 진행되는데 영향을 끼친다고 알려졌다(Jackson and Loeb, Mutat. Res., 2001). 따라서, ROS는 암의 발병과, 진행 그리고 유지와 관련된 여러 역할을 한다고 추정된다. It has been reported that ROS products are increased in cancer cells (Cancer Res., 1991); Burdon, 1995), ROS increased during tumor progression is nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). ) It is known to induce the expression of transcription factors (Gupta et al., Carcinogenesis, 1999). Oxidative stress also causes DNA damage, leading to instability of the genome, which is known to affect cancer progression (Jackson and Loeb, Mutat. Res., 2001). Therefore, it is estimated that ROS plays several roles in the onset, progression, and maintenance of cancer.
근래의 연구에 따르면, ROS는 상피세포 성장인자(epidermal growth factor, EGF)와 혈소판유래성장인자(platelet-derived growth factor, PDGF)와 같은 성장인자에 자극받은 세포에서 발생된다고 보고되었다(Bae et al., J. Biol. Chem.,1997, 2000). 스트레스를 받지 않는 조건에서 ROS는 세포의 성장을 촉진시키는 역할을 수행하나, 세포가 스트레스를 받는 조건에서는 세포사멸을 활성화시키고, 조절한다고 알려져 있다. ROS의 수치는 세포가 다양한 스트레스 물질(예를 들어, 항암제)에 노출되었을 때 증가된다(Jabs, Biochem. Pharmacol., 1999). 또한, 세포사멸 신호 조절 키나이제 1(Apoptosis signal-regulating kinase 1, ASK1), 씨-준-아미노말단 키나아제(c-Jun N-terminal kinase, JNK), p38과 같은 세포사멸 관련 유전자를 자극하여 세포사멸을 유도한다고 알려졌다(Benhar et al., Mol. Cell. Biol., 2001). 그 외에도 p53을 통한 세포사멸을 유도하는데 중요한 역할을 하는 것으로 알려져 있다(Polyak et al., Nature, 1997).According to recent studies, ROS has been reported to occur in cells stimulated by growth factors such as epithelial growth factor (EGF) and platelet-derived growth factor (PDGF) (Bae et al. ., J. Biol. Chem., 1997, 2000). ROS plays a role in promoting cell growth under stress-free conditions, but is known to activate and regulate apoptosis under stress-free conditions. The level of ROS increases when cells are exposed to various stressors (eg, anticancer agents) (Jabs, Biochem. Pharmacol., 1999). In addition, by stimulating apoptosis-related genes such as apoptosis signal-regulating kinase 1 (ASK1), c-Jun N-terminal kinase (JNK), and p38 It is known to induce death (Benhar et al., Mol. Cell. Biol., 2001). In addition, it is known to play an important role in inducing apoptosis through p53 (Polyak et al., Nature, 1997).
세포사멸(apoptosis)을 회피하는 것은 악성 세포의 전형적인 특징이며, 세포사멸에 대한 세포의 저항성은 중요한 임상적 문제가 된다 (Jia et al., 2012; Lopez-Beltran et al., 2007). Avoiding apoptosis is a typical feature of malignant cells, and the resistance of cells to apoptosis is an important clinical problem (Jia et al., 2012; Lopez-Beltran et al., 2007).
한편, 다발성 골수종은 백혈병, 림프종과 함께 대표적인 혈액종양으로 B림프구의 성숙형태인 형질세포가 증식하는 혈액암이다. 평균 65세 이상의 고령에서 발병하며, 비교적 동양인에서는 낮은 발병률을 보이며, 1980년대 우리나라 발병률은 연간 100명이내로 매우 낮았다. 그러나 급속한 산업화에 따른 공해, 환경호르몬에 노출증가, 고령화로 인해 다발성 골수종 환자는 지속적으로 증가하고 있다. 지난 20년간 다른 암종의 발생률은 5배의 증가에 머물렀으나, 다발성 골수종의 경우, 약 30배 이상의 발생 증가를 보이고 있다. On the other hand, multiple myeloma is a typical hematologic tumor along with leukemia and lymphoma, and is a blood cancer in which plasma cells, which are mature forms of B lymphocytes, proliferate. It occurs in the elderly over 65 years of age on average, and the incidence rate is relatively low in Asians, and the incidence rate in Korea in the 1980s was very low, within 100 per year. However, the number of patients with multiple myeloma continues to increase due to pollution caused by rapid industrialization, increased exposure to environmental hormones, and aging. In the past 20 years, the incidence of other carcinomas has remained at a 5-fold increase, but in the case of multiple myeloma, the incidence of multiple myeloma has increased by about 30 times or more.
이러한 다발성 골수종의 치료는 멜팔란과 프레드니존을 이용한 표준화학요법 (MP요법), 65세 이하의 환자에 적용되는 고용량 화학요법 및 조혈모세포 이식요법, 기존치료에 반응하지 않는 불응암이나 재발된 골수종에 대한 표적치료가 있다. 그러나 현재 사용되는 약물들에 내성암 및 불응암이 발생하여 다발성 골수종으로 인한 사망률은 매우 높다. 특히 최근 2차 약제로 FDA 승인을 얻은 표적치료제인 벨케이드(bortezomib)가 치료불응암 및 재발암에 효과가 높은 것으로 보고되었으나, 전체반응율은 35%, 완전관해율은 10%로 미미한 실정이며, 이미 이 약물의 내성암이 보고되고 있다. 따라서, 이러한 다발성 골수종의 치료불응이나 재발암을 효과적으로 치료하여 다발성 골수종환자의 생존율을 획기적으로 증가시킬 수 있는 치료요법의 개발이 필요하다. The treatment of multiple myeloma is standard chemotherapy with melphalan and prednisone (MP therapy), high-dose chemotherapy and hematopoietic stem cell transplantation applied to patients under the age of 65, refractory cancer that does not respond to conventional treatment or relapsed myeloma. There are targeted treatments. However, due to the development of resistant and refractory cancers to currently used drugs, the mortality rate from multiple myeloma is very high. In particular, it has been reported that bortezomib, a target therapy approved by the FDA as a second drug, is highly effective in treatment refractory and recurrent cancer, but the overall response rate is 35% and the complete response rate is insignificant at 10%. Drug-resistant cancer has been reported. Therefore, there is a need for the development of a treatment regimen that can dramatically increase the survival rate of patients with multiple myeloma by effectively treating refractory or recurrent cancer of multiple myeloma.
한편, 멜라토닌(MELATONIN)은 1958년 소의 송과선(pineal gland)에서 최초로 분리된 이래(Lerner et al., J.Am. Soc. 80, 2587, 1958), 박테리아, 조류를 포함한 모든 동·식물에서 발견되는 물질이다(Herdeland & Poeggeler, J. Peneal Res. 34, 233-241, 2003). 동물에서는 뇌의 송과선에서 생합성되어 혈액에 배출되며, 24시간 주기리듬(circadian rhythm), 계절적 리듬(seasonal rhythm) 및 광주기(photoperiodism) 조절에 관여하는 호르몬으로 역할을 한다(Reiter, Experientia 49, 654-664, 1993). 그 외 면역증강(Carrillo-Vocp et al., Endocrine 27, 189-200, 2005), 항염증 반응(Jung et al., J. Pineal Res. 48, 239-250, 2010),및 미토콘드리아의 항상성을 유지하는데 관여한다(Paradies et al., J. Pineal Res. 48, 297-310, 2010). 특히 멜라토닌은 트립토판 유도체로 적은 분자량(232 g/mol)으로서 특이하게 친수/친유성 특성(amphiphilic molecule)을 가지고 있어(shida et al., J.Pineal Res. 16, 198-201, 1994; Ceraulo et al., J. Pineal Res.26, 108-112, 1999), 세포막을 자유롭게 왕래하며, 세포의 모든 기관에 존재하는 것으로 알려져 있다.(Herdeland, Biofactors 35, 183-192, 2009). 또한, 멜라토닌은 노화, 항산화, 및 항염증 등 다양한 신체 기능을 조절하는 것으로 알려져 있다. Meanwhile, since MELATONIN was first isolated from the pineal gland of cattle in 1958 (Lerner et al., J. Am. Soc. 80, 2587, 1958), it was found in all animals and plants including bacteria and algae. (Herdeland & Poeggeler, J. Peneal Res. 34, 233-241, 2003). In animals, it is biosynthesized in the pineal gland of the brain and excreted into the blood, and plays a role as a hormone involved in the regulation of circadian rhythm, seasonal rhythm, and photoperiodism for 24 hours (Reiter, Experientia 49, 654). -664, 1993). Other immunity enhancement (Carrillo-Vocp et al., Endocrine 27, 189-200, 2005), anti-inflammatory response (Jung et al., J. Pineal Res. 48, 239-250, 2010), and mitochondrial homeostasis It is involved in maintenance (Paradies et al., J. Pineal Res. 48, 297-310, 2010). In particular, melatonin is a tryptophan derivative with a small molecular weight (232 g/mol) and has a unique hydrophilic/lipophilic molecule (shida et al., J. Pineal Res. 16, 198-201, 1994; Ceraulo et al. al., J. Pineal Res. 26, 108-112, 1999), freely traverses the cell membrane, and is known to exist in all organs of cells (Herdeland, Biofactors 35, 183-192, 2009). In addition, melatonin is known to regulate various body functions, such as aging, antioxidant, and anti-inflammatory.
현재 항암제의 부작용에서 가장 큰 문제 중 하나는 불면증과 이로 인한 우울증 유발이며 이로 인해 항암제의 효과를 더욱 저하시킨다. 암환자의 30%가 불면증을 앓고 있으며, 전이가 강한 유방암과 폐암에서는 40%가 수면장애를 앓고 있고, 암환자의 50%가 불면증을 앓는 등 일반적 증상이다. 이에 다른 수면제 등을 복용하기도 하며, 독성이 강한 항암제와 더불어 이러한 부작용을 완화시키기 위한 보조치료제를 함께 복용하고 있는 실정이다. Currently, one of the biggest problems in side effects of anticancer drugs is insomnia and the resulting depression, which further reduces the effectiveness of anticancer drugs. 30% of cancer patients suffer from insomnia, 40% of breast cancer and lung cancer with strong metastasis suffer from sleep disturbance, and 50% of cancer patients suffer from insomnia. Accordingly, other sleeping pills are sometimes taken, and an adjuvant therapy to alleviate these side effects is being taken along with a highly toxic anticancer drug.
멜라토닌은 이러한 보조치료제로 임상에서 사용되고 있으며, 이러한 점을 이용하여 멜라토닌을 항암제로 개발하기 위해 많은 연구들이 진행되었으며, 유방암에서 가장 많은 연구가 진행되었으나 다발성 골수종 등을 포함하는 혈액암에서는 연구된 바 없다. Melatonin is used clinically as such an adjuvant therapy, and using this point, many studies have been conducted to develop melatonin as an anticancer agent, and although the most studies have been conducted in breast cancer, it has not been studied in blood cancer including multiple myeloma. .
이에 본 발명자들은 소포체 스트레스를 조절하여 암을 예방하고 치료할 수 있는 부작용이 적은 암 치료제를 찾고자 예의 연구 노력하여 멜라토닌이 암세포에서 소포체 스트레스를 유발하여 효과적으로 세포사멸 시킬 수 있음을 확인하고 본 발명을 완성하였다.Accordingly, the present inventors have made intensive research efforts to find a cancer treatment that can prevent and treat cancer by controlling endoplasmic reticulum stress and have fewer side effects, confirming that melatonin can induce endoplasmic reticulum stress in cancer cells and effectively apoptosis, and completed the present invention. .
본 발명의 목적은 멜라토닌(MELATONIN)을 유효성분으로 포함하는 다발성 골수종(multiple myeloma)의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of multiple myeloma containing melatonin (MELATONIN) as an active ingredient.
또한 본 발명의 목적은, 멜라토닌을 유효성분으로 포함하는 다발성 골수종의 항암보조제를 제공하는 것이다. It is also an object of the present invention to provide an anticancer adjuvant for multiple myeloma containing melatonin as an active ingredient.
또한 본 발명의 목적은, 멜라토닌을 유효성분으로 포함하는 다발성 골수종의 예방 또는 개선용 식품 조성물을 제공하는 것이다. It is also an object of the present invention to provide a food composition for preventing or improving multiple myeloma, comprising melatonin as an active ingredient.
상기 목적의 달성을 위해, 본 발명은 멜라토닌을 유효성분으로 포함하는 다발성 골수종의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating multiple myeloma comprising melatonin as an active ingredient.
또한, 본 발명은 멜라토닌을 유효성분으로 포함하는 다발성 골수종 항암보조제를 제공한다.In addition, the present invention provides a multiple myeloma anticancer adjuvant comprising melatonin as an active ingredient.
아울러, 본 발명은 멜라토닌을 함유하는 다발성 골수종의 예방 또는 개선용 식품 조성물을 제공한다.In addition, the present invention provides a food composition for preventing or improving multiple myeloma containing melatonin.
본 발명에 따르면, 멜라토닌을 유효성분으로 이용 시, in vitro 상에서 다발성 골수종 세포 독성 효과를 가지며, PARP 절단 증가 및 p-eIF2α 발현을 증가시킴으로써 다발성 골수종 세포 사멸을 유발하는 효과가 있다. 또한, 다발성 골수종 세포에서 활성산소(ROS) 생성을 증가시키는 효과가 있다. According to the present invention, when melatonin is used as an active ingredient, it has multiple myeloma cytotoxic effects in vitro, and increases PARP cleavage and p-eIF2α expression, thereby inducing multiple myeloma cell death. In addition, there is an effect of increasing the production of reactive oxygen species (ROS) in multiple myeloma cells.
따라서 다발성골수종을 예방, 치료 또는 개선할 수 있는 효과를 가지므로, 다발성 골수종을 예방, 치료 또는 개선하기 위한 의약품, 건강기능식품 등 다양한 방면에서 유용하게 사용될 수 있다. Therefore, since it has the effect of preventing, treating, or improving multiple myeloma, it can be usefully used in various fields such as medicines and health functional foods for preventing, treating or improving multiple myeloma.
도 1은 멜라토닌 처리에 의한 정상대장세포 CCD-18Co와 정상신장세포 MDBK, 그리고 다발성 골수종 세포주 U937과 THP-1 들의 세포 생존율을 확인한 도이다.
도 2는 멜라토닌 처리에 의한 다발성 골수종 세포주 THP-1 에서의 세포사멸 관련 단백질들의 발현 정도를 확인한 도이다.
도 3은 멜라토닌 처리에 의한 다발성 골수종 세포주 U937과 THP-1 에서의 활성산소의 발현을 정도를 확인한 도이다. 1 is a diagram showing the cell viability of normal colon cells CCD-18Co and normal kidney cells MDBK, and multiple myeloma cell lines U937 and THP-1 by melatonin treatment.
FIG. 2 is a diagram illustrating the level of expression of proteins related to apoptosis in the multiple myeloma cell line THP-1 by melatonin treatment.
3 is a diagram showing the degree of expression of reactive oxygen species in multiple myeloma cell lines U937 and THP-1 by melatonin treatment.
이하, 본 발명의 구현예로 본 발명을 상세히 설명하기로 한다. 다만, 하기 구현예는 본 발명에 대한 예시로 제시되는 것으로, 이에 의해 본 발명이 제한되지는 않으며 본 발명은 후술하는 특허청구범위의 기재 및 그로부터 해석되는 균등 범주 내에서 다양한 변형 및 응용이 가능하다.Hereinafter, the present invention will be described in detail as an embodiment of the present invention. However, the following embodiments are presented as examples of the present invention, whereby the present invention is not limited, and the present invention can be variously modified and applied within the scope of equality interpreted from the description of the claims to be described later. .
본 발명은 멜라토닌을 유효성분으로 포함하는 다발성 골수종의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention provides a pharmaceutical composition for the prevention or treatment of multiple myeloma comprising melatonin as an active ingredient.
또한, 본 발명은 멜라토닌을 유효성분으로 포함하는 다발성 골수종 항암보조제를 제공한다.In addition, the present invention provides a multiple myeloma anticancer adjuvant comprising melatonin as an active ingredient.
일 구현예에서, 상기 암은 대장암, 유방암, 다발성골수종, 자궁암, 자궁경부암, 난소암, 전립선암, 뇌종양, 두경부암종, 흑색종, 골수종, 백혈병, 림프종, 위암, 폐암, 췌장암, 비소세포성폐암, 간암, 식도암, 소장암, 항문부근암, 나팔관암종, 자궁내막암종, 질암종, 음문암종, 호지킨병, 방광암, 신장암, 수뇨관암, 신장세포암종, 신장골반암종, 골암, 피부암, 두부암, 경부암, 피부흑색종, 안구내흑색종, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 중추신경계(central nervous system; CNS) 종양, 1차 CNS 림프종, 척수종양, 뇌간신경교종 및 뇌하수체선종으로 구성된 군으로부터 선택되는 어느 하나일 수 있으며, 다발성골수종인 것이 더욱 바람직하다. In one embodiment, the cancer is colon cancer, breast cancer, multiple myeloma, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, brain tumor, head and neck carcinoma, melanoma, myeloma, leukemia, lymphoma, gastric cancer, lung cancer, pancreatic cancer, non-small cell cancer. Lung cancer, liver cancer, esophageal cancer, small intestine cancer, anal muscle cancer, fallopian tube carcinoma, endometrial carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, bladder cancer, kidney cancer, ureter cancer, renal cell carcinoma, renal pelvic carcinoma, bone cancer, skin cancer, Head cancer, cervical cancer, skin melanoma, intraocular melanoma, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, central nervous system (CNS) tumor, primary CNS lymphoma, It may be any one selected from the group consisting of spinal cord tumors, brainstem glioma, and pituitary adenoma, more preferably multiple myeloma.
일 구현예에서, 암의 예방 또는 치료는 암세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸에 의해 달성될 수 있다.In one embodiment, the prevention or treatment of cancer may be achieved by apoptosis due to stress of the endoplasmic reticulum (ER) of cancer cells.
본 발명에서 사용되는 용어, "세포사멸"은 아폽토시스 또는 세포자멸사라고도 하며, 일종의 계획된 세포 죽음(programmed cell death; PCD)으로서, 우리 몸 안에 입력되어 있는 생체 프로그램에 의해 비정상 세포, 손상된 세포, 노화된 세포가 스스로 자살해 사멸함으로써 전체적인 신체 건강을 유지하도록 하는 메커니즘이다.As used herein, the term "cell death" is also referred to as apoptosis or apoptosis, and is a kind of programmed cell death (PCD), which is abnormal cells, damaged cells, and aged by a biological program input into our body. It is a mechanism by which cells commit suicide and die, thereby maintaining overall physical health.
본 발명에서, 용어 "예방"이란 본 발명에 따른 약학적 조성물의 투여에 의해 암의 발생, 확산 및 재발을 억제 또는 지연시키는 모든 행위를 의미하고, "치료"란 상기 약학적 조성물의 투여에 의해 암의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경하는 모든 행위를 의미한다.In the present invention, the term "prevention" refers to all actions of inhibiting or delaying the occurrence, spread, and recurrence of cancer by administration of the pharmaceutical composition according to the present invention, and "treatment" refers to the administration of the pharmaceutical composition. It refers to any action that improves or beneficially alters the symptoms of an individual suspected of or developed cancer.
본 발명에서 사용되는 용어 "치료"란 본 발명의 멜라토닌을 포함하는 조성물의 투여로 암세포의 사멸 또는 암의 증세를 호전시키거나 이롭게 변경하는 모든 행위를 의미한다. 본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자라면, 대한의학협회 등에서 제시된 자료를 참조하여 본원의 조성물이 효과가 있는 질환의 정확한 기준을 알고, 개선, 향상 및 치료된 정도를 판단할 수 있을 것이다.The term "treatment" as used in the present invention refers to any action that improves or beneficially alters the death of cancer cells or symptoms of cancer by administration of the composition containing melatonin of the present invention. Those of ordinary skill in the technical field to which the present invention pertains can know the exact criteria of the disease in which the composition of the present application is effective, and determine the degree of improvement, improvement and treatment by referring to data presented by the Korean Medical Association. will be.
본 발명에서 유효성분과 결합하여 사용된 "치료학적으로 유효한 양"이란 용어는 대상 질환을 예방 또는 치료하는데 유효한 멜라토닌의 약학적으로 허용 가능한 염의 양을 의미하며, 본 발명의 조성물의 치료적으로 유효한 양은 여러 요소, 예를 들면 투여방법, 목적부위, 환자의 상태 등에 따라 달라질 수 있다.The term "therapeutically effective amount" used in combination with an active ingredient in the present invention refers to the amount of a pharmaceutically acceptable salt of melatonin that is effective in preventing or treating a target disease, and the therapeutically effective amount of the composition of the present invention is It may vary depending on various factors, such as the method of administration, the target site, and the patient's condition.
따라서, 인체에 사용 시 투여량은 안전성 및 효율성을 함께 고려하여 적정량으로 결정되어야 한다. 동물실험을 통해 결정한 유효량으로부터 인간에 사용되는 양을 추정하는 것도 가능하다. 유효한 양의 결정시 고려할 이러한 사항은, 예를 들면 Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed.(2001), Pergamon Press; 및 E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed.(1990), Mack Publishing Co.에 기술되어있다.Therefore, when used in the human body, the dosage should be determined as an appropriate amount in consideration of safety and efficiency. It is also possible to estimate the amount used in humans from the effective amount determined through animal experiments. These considerations when determining the effective amount are described, for example, in Hardman and Limbird, eds., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. (2001), Pergamon Press; And E.W. Martin ed., Remington's Pharmaceutical Sciences, 18th ed. (1990), Mack Publishing Co.
본 발명의 약학조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에서 사용되는 용어, "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효용량 수준은 환자의 건강상태, 암의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 배합 또는 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여, 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, the term "pharmaceutically effective amount" refers to an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment and not cause side effects, and the effective dose level is the patient's Health status, type of cancer, severity, drug activity, sensitivity to drugs, method of administration, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used in combination or concurrently, and other factors well known in the medical field Can be determined according to. The composition of the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. In consideration of all the above factors, it is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects, which can be easily determined by a person skilled in the art.
본 발명의 약학조성물은 생물학적 제제에 통상적으로 사용되는 담체, 희석제, 부형제 또는 둘 이상의 이들의 조합을 포함할 수 있다. 본 발명에서 사용되는 용어, "약학적으로 허용 가능한"이란 상기 조성물에 노출되는 세포나 인간에게 독성이 없는 특성을 나타내는 것을 의미한다. 상기 담체는 조성물을 생체 내 전달에 적합한 것이면 특별히 제한되지 않으며, 예를 들면, Merck Index, 13th ed., Merck & Co. Inc. 에 기재된 화합물, 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로스 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분이상을 혼합하여 이용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한, 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등 과 같은 주이용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 더 나아가 당 분야의 적정한 방법으로 또는 Remington's Pharmaceutical Science(Mack Publishing Company, Easton PA, 18th, 1990)에 개시되어 있는 방법을 이용하여 각 질환에 따라 또는 성분에 따라 바람직하게 제제화할 수 있다.The pharmaceutical composition of the present invention may contain a carrier, a diluent, an excipient, or a combination of two or more commonly used in biological preparations. The term "pharmaceutically acceptable" as used in the present invention means exhibiting properties that are not toxic to cells or humans exposed to the composition. The carrier is not particularly limited as long as it is suitable for in vivo delivery of the composition, and, for example, Merck Index, 13th ed., Merck & Co. Inc. Compounds described in, saline, sterilized water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components can be mixed and used, and other antioxidants, buffers, bacteriostatic agents, etc. Conventional additives can be added. In addition, a diluent, a dispersant, a surfactant, a binder, and a lubricant may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., a pill, capsule, granule, or tablet. Further, it may be preferably formulated according to each disease or component by an appropriate method in the art or by using a method disclosed in Remington's Pharmaceutical Science (Mack Publishing Company, Easton PA, 18th, 1990).
본 발명의 약학 조성물은 약학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본 발명에 따른 약학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 중량부 내지 90 중량부 포함되는 것이 바람직하나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additives include starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate, Lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powder cellulose, hydroxypropyl cellulose, opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, stearic acid Calcium, sucrose, dextrose, sorbitol, talc, and the like can be used. The pharmaceutically acceptable additive according to the present invention is preferably contained in an amount of 0.1 parts by weight to 90 parts by weight based on the composition, but is not limited thereto.
본 발명의 약학적 조성물은 유효성분으로서 멜라토닌 이외에 공지된 항암제를 추가로 포함할 수 있고, 이들 질환의 치료를 위해 공지된 다른 치료와 병용될 수 있다. 다른 치료에는 화학요법, 방사선치료, 호르몬 치료, 골수 이식, 줄기-세포 대체치료, 다른 생물학적 치료, 면역치료 등이 포함되지만, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may further contain known anticancer agents in addition to melatonin as an active ingredient, and may be used in combination with other known treatments for the treatment of these diseases. Other treatments include, but are not limited to, chemotherapy, radiation therapy, hormone therapy, bone marrow transplantation, stem-cell replacement therapy, other biological therapy, immunotherapy, and the like.
본 발명의 약학적 조성물에 포함될 수 있는 항암제의 예시에는 DNA 알킬화제(DNA alkylating agents)로 메클로에타민(mechloethamine), 클로람부칠(chlorambucil), 페닐알라닌(phenylalanine), 무스타드(mustard), 사이클로포스파미드(cyclophosphamide), 이포스파미드(ifosfamide), 카르무스틴(carmustine: BCNU), 로무스틴(lomustine: CCNU), 스트렙토조토신(streptozotocin), 부술판(busulfan), 티오테파(thiotepa), 시스플라틴(cisplatin) 및 카보플라틴(carboplatin); 항암 항생제(anti-cancer antibiotics)로 닥티노마이신(dactinomycin: actinomycin D), 독소루비신(doxorubicin: adriamycin), 다우노루비신(daunorubicin), 이다루비신(idarubicin), 미토크산트론(mitoxantrone), 플리카마이신(plicamycin), 마이토마이신 C(mitomycin C) 및 블레오마이신(bleomycin); 및 식물 알카로이드(plant alkaloids)로 빈크리스틴(vincristine), 빈블라스틴(vinblastine), 파클리탁셀(paclitaxel), 도세탁셀(docetaxel), 에토포시드(etoposide), 테니포시드(teniposide), 토포테칸(topotecan) 및 이리도테칸(iridotecan) 등이 포함되지만, 이에 한정되는 것은 아니다.Examples of anticancer agents that can be included in the pharmaceutical composition of the present invention include mechloethamine, chlorambucil, phenylalanine, mustard, and cyclophospha as DNA alkylating agents. Cyclophosphamide, ifosfamide, carmustine (BCNU), lomustine (CCNU), streptozotocin, busulfan, thiotepa, cisplatin ( cisplatin) and carboplatin; As anti-cancer antibiotics, dactinomycin (actinomycin D), doxorubicin (adriamycin), daunorubicin, idarubicin, mitoxantrone, plicama Plicamycin, mitomycin C and bleomycin; And plant alkaloids as vincristine, vinblastine, paclitaxel, docetaxel, etoposide, teniposide, topotecan And iridotecan, but are not limited thereto.
일 측면에서, 본 발명은 멜라토닌을 이를 필요로 하는 개체에게 혼합하여 투여하거나 각각의 추출물을 동시에 투여하는 단계를 포함하는, 암을 예방 또는 치료하는 방법에 관한 것이다.In one aspect, the present invention relates to a method for preventing or treating cancer, comprising the step of administering melatonin mixed to an individual in need thereof or administering each extract simultaneously.
본 발명에서 사용되는 용어, "개체"란, 상기 암이 발병하였거나 발병할 수 있는 인간을 포함한 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함한 모든 동물을 의미하고, 본 발명의 약학적 조성물을 개체에게 투여함으로써 상기 질환들을 효과적으로 예방 또는 치료할 수 있다.As used herein, the term "individual" refers to monkeys, cattle, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, mice, rabbits, including humans who have or may develop the cancer It means all animals including guinea pigs, and the above diseases can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to an individual.
본 발명의 약학적 조성물은 기존의 치료제와 병행하여 투여될 수 있다.The pharmaceutical composition of the present invention can be administered in combination with an existing therapeutic agent.
본 발명에서 사용되는 용어, "투여"란, 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 목적하는 방법에 따라 비 경구 투여(예를 들어 정맥 내, 피하, 복강 내 또는 국소에 주사 제형으로 적용)하거나 경구 투여할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설률 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 조성물의 경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데, 통상적으로 사용되는 단순 희석제인 물, 액체 파라핀 이외에 다양한 부형제, 예컨대 습윤제, 감미제, 방향제, 보존제 등이 함께 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함된다. 본 발명의 약학적 조성물은 활성물질이 표적 세포로 이동할 수 있는 임의의 장치에 의해 투여될 수도 있다. 바람직한 투여방식 및 제제는 정맥주사제, 피하 주사제, 피내주사제, 근육 주사제, 점적 주사제 등이다. 주사제는 생리식염액, 링겔액 등의 수성용제, 식물유, 고급 지방산 에스테르(예, 올레인산에칠 등), 알코올 류(예, 에탄올, 벤질알코올, 프로필렌글리콜, 글리세린 등) 등의 비수성 용제 등을 이용하여 제조할 수 있고, 변질 방지를 위한 안정화제(예, 아스코르빈산, 아황산수소나트륨, 피로아황산나트륨, BHA, 토코페롤, EDTA 등), 유화제, pH 조절을 위한 완충제, 미생물발육을 저지하기 위한 보존제 (예, 질산페닐수은, 치메로살, 염화벤잘코늄, 페놀, 크레솔, 벤질알코올 등) 등의 약학적 담체를 포함할 수 있다.As used herein, the term "administration" means providing a predetermined substance to a patient by any suitable method, and parenteral administration (for example, intravenous, subcutaneous, intraperitoneal or topical administration) according to the desired method. It can be applied as an injection formulation) or can be administered orally, and the dosage range varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease. Liquid formulations for oral administration of the composition of the present invention include suspensions, liquid solutions, emulsions, syrups, etc., and various excipients, such as wetting agents, sweetening agents, fragrances, preservatives, in addition to water and liquid paraffin, which are commonly used simple diluents. Etc. may be included together. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, suppositories, and the like. The pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to target cells. Preferred modes of administration and formulations are intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drop injections and the like. Injectables include aqueous solvents such as physiological saline and ring gel solutions, vegetable oils, higher fatty acid esters (e.g., oleic acid ethyl, etc.), alcohols (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.). It can be prepared by using, and stabilizers for preventing deterioration (e.g., ascorbic acid, sodium hydrogen sulfite, sodium pyrosulfite, BHA, tocopherol, EDTA, etc.), emulsifiers, buffers for pH control, and for inhibiting microbial growth Preservatives (eg, phenyl mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.) may contain pharmaceutical carriers.
일 측면에서, 본 발명은 멜라토닌을 유효성분으로 포함하는 항암보조제에 관한 것이다.In one aspect, the present invention relates to an anticancer adjuvant comprising melatonin as an active ingredient.
본 발명의 멜라토닌은 화학적 항암 약물(항암제) 등과 함께 투여함으로써, 암세포의 사멸 효과를 통해 종래의 항암제의 암 치료 효과를 증가시킬 수 있다. 병용 투여는 상기 항암제와 동시에 또는 순차적으로 이루어질 수 있다.By administering the melatonin of the present invention together with a chemical anticancer drug (anticancer agent) or the like, it is possible to increase the cancer treatment effect of a conventional anticancer agent through the killing effect of cancer cells. The combined administration may be performed simultaneously or sequentially with the anticancer agent.
일 측면에서, 본 발명은 멜라토닌을 함유하는 암의 예방 또는 개선용 식품 조성물에 관한 것이다.In one aspect, the present invention relates to a food composition for preventing or improving cancer containing melatonin.
본 발명의 조성물을 식품 조성물로 사용하는 경우, 상기 멜라토닌을 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용할 수 있고, 통상의 방법에 따라 적절하게 사용할 수 있다. 상기 조성물은 유효성분 이외에 식품학적으로 허용 가능한 식품보조첨가제를 포함할 수 있으며, 유효성분의 혼합량은 사용목적(예방, 건강 또는 치료적 처치)에 따라 적합하게 결정될 수 있다.When the composition of the present invention is used as a food composition, the melatonin may be added as it is or may be used together with other foods or food ingredients, and may be appropriately used according to a conventional method. In addition to the active ingredient, the composition may contain food additives acceptable for food, and the mixing amount of the active ingredient may be appropriately determined according to the purpose of use (prevention, health, or therapeutic treatment).
본 발명에서 사용되는 용어 "식품보조첨가제"란 식품에 보조적으로 첨가될 수 있는 구성요소를 의미하며, 각 제형의 건강기능식품을 제조하는데 첨가되는 것으로서 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알콜, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다.The term "food supplementary additive" used in the present invention refers to a component that can be added auxiliary to food, and is added to the manufacture of health functional foods of each formulation, and can be appropriately selected and used by those skilled in the art. Examples of food additives include various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavors, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloid thickeners. , pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, etc. are included, but the types of food additives of the present invention are not limited by the above examples.
본 발명의 식품 조성물에는 건강기능식품이 포함될 수 있다. 본 발명에서 사용되는 용어 "건강기능식품"이란 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 정제, 캅셀, 분말, 과립, 액상 및 환 등의 형태로 제조 및 가공한 식품을 말한다. 여기서 '기능성'이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 건강기능식품은 통상의 기술 분야에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 통상의 기술 분야에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 건강기능식품의 제형 또한 건강기능식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나, 본 발명의 건강기능식품은 항암제의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The food composition of the present invention may contain a health functional food. The term "health functional food" used in the present invention refers to food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and pills using raw materials or ingredients having useful functions for the human body. Here, the term'functionality' means obtaining useful effects for health purposes such as controlling nutrients or physiological effects on the structure and function of the human body. The health functional food of the present invention can be prepared by a method commonly used in the general technical field, and at the time of manufacture, it can be prepared by adding raw materials and ingredients commonly added in the general technical field. In addition, the formulation of the health functional food may be prepared without limitation as long as it is a formulation recognized as a health functional food. The food composition of the present invention can be prepared in various forms of formulation, and unlike general drugs, it has the advantage of not having side effects that may occur when taking a drug for a long period of time using food as a raw material, and is excellent in portability. Health functional foods can be consumed as an adjuvant to enhance the effectiveness of anticancer drugs.
또한, 본 발명의 조성물이 사용될 수 있는 건강식품의 종류에는 제한이 없다. 아울러 본 발명의 멜라토닌을 활성성분으로 포함하는 조성물은 당업자의 선택에 따라 건강기능식품에 함유될 수 있는 적절한 기타 보조 성분과 공지의 첨가제를 혼합하여 제조할 수 있다. 첨가할 수 있는 식품의 예로는 육류, 소세지, 빵, 쵸코렛, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림 류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등이 있으며, 본 발명에 따른 추출물을 주성분으로 하여 제조한 즙, 차, 젤리 및 주스 등에 첨가하여 제조할 수 있다.In addition, there is no limitation on the kind of health food in which the composition of the present invention can be used. In addition, the composition containing melatonin of the present invention as an active ingredient may be prepared by mixing appropriate other auxiliary ingredients and known additives that may be contained in health functional foods according to the choice of a person skilled in the art. Examples of foods that can be added include meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and There are vitamin complexes and the like, and can be prepared by adding the extract according to the present invention as a main component, such as juice, tea, jelly, and juice.
본 발명의 멜라토닌은 천연 식물을 원료로 하므로 약학적 조성물 또는 식품 조성물로 사용할 경우에도 일반적인 합성 화합물에 비하여 부작용이 덜할 수 있으므로, 안전하게 약학적 조성물 및 건강기능식품에 포함되어 유용하게 사용될 수 있다.Since the melatonin of the present invention is a natural plant as a raw material, even when used as a pharmaceutical composition or a food composition, side effects may be less than that of a general synthetic compound, so it can be safely included in pharmaceutical compositions and health functional foods and used usefully.
본 발명의 멜라토닌은 시험관(in vitro)내에서 다발성 골수종 세포주에 처리시 PARP 절단 증가, GADD153/CHOP의 발현 증가 및 활성산소의 발생을 증가시키는 방법을 제공할 수 있으며, 본 발명에 따라 PARP 절단 증가, p-eIF2α 발현 증가 및 활성산소 발생을 증가시켜 다발성 골수종 세포의 소포체 스트레스 유발을 통한 세포사멸을 유도할 수 있다. Melatonin of the present invention can provide a method of increasing PARP cleavage, increasing the expression of GADD153/CHOP, and increasing the generation of reactive oxygen species when treated with multiple myeloma cell lines in vitro, and increasing PARP cleavage according to the present invention. , By increasing the expression of p-eIF2α and the generation of free radicals, it is possible to induce apoptosis by inducing endoplasmic reticulum stress in multiple myeloma cells.
하기의 실시예를 통하여 본 발명을 보다 상세하게 설명한다. 그러나 하기 실시예는 본 발명의 내용을 구체화하기 위한 것일 뿐 이에 의해 본 발명이 한정되는 것은 아니다.The present invention will be described in more detail through the following examples. However, the following examples are only for embodiing the contents of the present invention and the present invention is not limited thereto.
실시예 1: 생체 외 세포주 모델 제작Example 1: In vitro cell line model construction
멜라토닌의 세포 독성을 시험하고자, 다발성 골수종 세포주인 U937, THP-1와 대장암 정상세포인 CCD-18Co, 신장정상세포 MDBK(한국세포주 은행)를 하기와 같이 배양하였다. To test the cytotoxicity of melatonin, multiple myeloma cell lines U937, THP-1, colon cancer normal cells CCD-18Co, and kidney normal cells MDBK (Korea Cell Line Bank) were cultured as follows.
다발성 골수종 세포주인 U937세포주, THP-1 (한국세포주은행) 50㎕를 96웰-플레이트에 1×104세포/웰이 되도록 분주한 뒤, 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 RPMI 배지에서, 37℃의 5% CO2인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다.Multiple myeloma cell line U937 cell line, THP-1 (Korea Cell Line Bank) 50µl was dispensed into a 96-well plate at 1×10 4 cells/well, and then 10% inactivated fetal bovine serum and 1% penicillin-streptomycin were added. In one RPMI medium, it was cultured in a 5% CO 2 incubator at 37°C (MCO-15AC, Sanyo, Osaka, Japan).
대장암 정상세포인 CCD-18Co세포는 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 DMEM high glucose 배지에서, 신장정상세포 MDBK(한국세포주 은행)는 inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 RPMI 배지에서 37℃의 5% CO2인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였다.CCD-18Co cells, which are normal colon cancer cells, were in DMEM high glucose medium supplemented with 10% inactivated fetal bovine serum and 1% penicillin-streptomycin, and kidney normal cells MDBK (Korea Cell Line Bank) were inactivated fetal bovine serum and 1% penicillin- It was cultured in a 5% CO 2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37°C in RPMI medium to which streptomycin was added.
실시예 2: 멜라토닌의 다발성 골수종에 대한 세포 독성 확인Example 2: Confirmation of cytotoxicity of melatonin to multiple myeloma
멜라토닌의 다발성 골수종에 대한 세포 독성을 확인하고자, 다발성 골수종 세포주 U937, THP-1 세포에 본 발명의 멜라토닌을 처리하고 세포 독성을 확인하였다. In order to confirm the cytotoxicity of melatonin to multiple myeloma, multiple myeloma cell lines U937, THP-1 cells were treated with melatonin of the present invention and cytotoxicity was confirmed.
상기 실시예 1에서 배양한 세포주 U937, THP-1 세포에 상기 실시예 1에서 제조한 멜라토닌을 0, 0.6, 1.25, 2.5, 5, 10mM의 농도로 각각 50㎕씩 처리하였다. The cell lines U937 and THP-1 cells cultured in Example 1 were treated with melatonin prepared in Example 1 at a concentration of 0, 0.6, 1.25, 2.5, 5, and 10 mM, respectively.
다발성 골수종 세포 독성 확인을 위하여 CCD-18Co, MDBK 세포를 대조군으로 실험을 진행하였다. In order to confirm the cytotoxicity of multiple myeloma cells, CCD-18Co and MDBK cells were used as controls.
상기 실시예 1에서 배양한 대장암 정상세포인 CCD-18Co 세포는 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 DMEM high glucose 배지에서, 신장정상세포 MDBK(한국세포주 은행)는 inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 RPMI 배지에서 37℃의 5% CO2인큐베이터 (MCO-15AC, Sanyo, Osaka, Japan)로 배양하였고 멜라토닌 처리 하루 전에 100㎕를 96웰-플레이트에 1×104 세포/웰이 되도록 분주하여서 세포가 부착이 되도록 안정화 시킨 후 그 다음날 배지를 모두 suction하여 버린 후 새로운 배지에 멜라토닌을 0, 0.3, 0.6, 1.25, 2.5, 5㎜의 농도로 처리한 것을, 각각 100㎕를 처리하였다. 대장암 정상세포인 CCD-18Co, 신장정상세포 MDBK (한국세포주은행) 는 멜라토닌 처리 하루 전에 10% inactivated fetal bovine serum 및 1% penicillin-streptomycin을 첨가한 DMEM HG와 RPMI 배지 100㎕를 96웰-플레이트에 1×104세포/웰이 되도록 분주하여서 세포가 부착이 되도록 안정화 시킨 후 그 다음날 배지를 모두 suction으로 버린 후 새로운 배지에 멜라토닌을 0, 0.3, 0.6, 1.25, 2.5, 5mM의 농도로 처리한 후, 각각 100㎕를 넣었다. 그리고 다발성 골수종 세포주인 U937, THP-1, 정상세포인 CCD-18Co, MDBK 세포들 각각 모두 멜라토닌을 처리 하고 하루 동안 인큐베이션 하였다. 멜라토닌을 처리 한 후 24시간 뒤 세포에 EZ-Cytox 시약 (DoGen)을 10㎕ 처리하고 암상태에서 30분 내지 4시간 동안 인큐베이션한 뒤, 마이크로플, 레이트 리더기 (Bio-rad Model 680) 흡광도 450nm에서 세포 생존율을 확인하였다. The CCD-18Co cells, which are normal colon cancer cells cultured in Example 1, were in DMEM high glucose medium to which 10% inactivated fetal bovine serum and 1% penicillin-streptomycin were added, and kidney normal cells MDBK (Korea Cell Line Bank) were inactivated fetal. In RPMI medium supplemented with bovine serum and 1% penicillin-streptomycin, it was incubated in a 5% CO 2 incubator (MCO-15AC, Sanyo, Osaka, Japan) at 37°C, and 100 μl was added to a 96-well plate one day before melatonin treatment. 10 4 After dispensing into cells/well, stabilizing the cells to adhere, suction off all the media the next day, and treated with melatonin at concentrations of 0, 0.3, 0.6, 1.25, 2.5, 5㎜ in a new medium. Each 100 µl was treated. Colorectal cancer normal cells, CCD-18Co, and kidney normal cells MDBK (Korea Cell Line Bank) are 96-well plates of DMEM HG and RPMI medium added with 10% inactivated fetal bovine serum and 1% penicillin-streptomycin the day before melatonin treatment. After stabilizing the cells to adhere to 1×10 4 cells/well, the next day, all the medium was suctioned away, and melatonin was treated with a concentration of 0, 0.3, 0.6, 1.25, 2.5, and 5 mM in a new medium. After that, each 100 μl was added. In addition, multiple myeloma cell lines U937 and THP-1, normal cells CCD-18Co, and MDBK cells were all treated with melatonin and incubated for one day. After 24 hours after melatonin treatment, the cells were treated with 10 µl of EZ-Cytox reagent (DoGen) and incubated for 30 minutes to 4 hours in the dark state, and the microfluid, rate reader (Bio-rad Model 680) absorbance at 450 nm Cell viability was confirmed.
그 결과, 도 1에 나타낸 바와 같이, U937, THP-1 세포에서는 멜라토닌 농도 의존적으로 세포 독성을 나타냄을 확인하였다. 반면, 정상세포주인 CCD-18Co, MDBK 세포에서는 다발성 골수종에서 유의한 세포 독성 효과를 나타낸 저농도에서 세포 독성 효과가 미미함을 확인하였다.As a result, as shown in FIG. 1, it was confirmed that U937 and THP-1 cells exhibited cytotoxicity in a melatonin concentration-dependent manner. On the other hand, it was confirmed that in the normal cell lines, CCD-18Co and MDBK cells, the cytotoxic effect was insignificant at a low concentration showing a significant cytotoxic effect in multiple myeloma.
실시예 3: 멜라토닌의 다발성 골수종에 대한 세포사멸 유발 효과 확인Example 3: Confirmation of the effect of melatonin inducing apoptosis on multiple myeloma
멜라토닌이 다발성 골수종에서의 세포사멸에 미치는 영향을 확인하기 위해, 세포사멸 진행 시 절단되는 것으로 알려진 PARP(Poly ADP ribose polymerase)와, DNA 손상을 유도하고 소포체 스트레스 단백질 발현을 위하여 리보솜의 tRNAiMet 에 결합하여 GTP-dependent manner로 translation 단계 개시에 주요인자로 작용하는 p-eIF2α (Eukaryotic Initiation Factor 2α)발현 정도를 웨스턴 블롯으로 확인하였다. To confirm the effect of melatonin on apoptosis in multiple myeloma, PARP (Poly ADP ribose polymerase), which is known to be cleaved during apoptosis, induces DNA damage and binds to ribosomal tRNAiMet for expression of endoplasmic reticulum stress protein. The expression level of p-eIF2α (Eukaryotic Initiation Factor 2α), which acts as a major factor in the initiation of the translation phase in a GTP-dependent manner, was confirmed by Western blot.
구체적으로, 다발성 골수종 세포주인 THP-1 세포주에서 상기 실시예 1에서 멜라토닌을 THP-1은 0.125, 0.25mM 로 각각 처리하고 24시간 동안 37℃의 5% CO2 에 인큐베이션 하였다. 그 후, 세포를 수집하여 PBS로 워싱하고, 세포 파쇄 버퍼 RIPA (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM NaEDTA, 1mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1mM beta-glycerophosphate, 1mM Na3VO4 및 1㎍/ml leupeptin (Cell signaling)를 첨가하여 30분간 4℃에서 세포를 파쇄하였다. 세포파쇄물을 12000rpm 4℃에서 20분간 원심 분리하여 세포막 성분 등을 제거한 후, RC DC™ Protein Assay Kit II(protein assay kit) (Bio-rad, USA)를 사용하여 단백질을 정량 하여 준비된 단백질 시료에 5×로딩 다이를 넣고 5분 동안 95℃로 가열하여 단백질을 변성시켰다. 그 후 8~10% SDS-PAGE 젤에 시료를 로딩하여 100 내지 120V로 2시간 전기영동을 수행하였으며, 젤 위에서 분리된 단백질들을 320mA로 2시간 동안 멤브레인으로 트랜스퍼하였다. 단백질이 트랜스퍼 된 멤브레인을 5% 스킴 밀크가 포함된 TBST (tris buffered saline, pH 7.5) 용액으로 상온에서 2시간 동안 블로킹한 뒤 1차 항체 항-PARP (Cell signaling) 1:1000및 항-eIF2α (Cell signaling)를 각각 1:500으로 희석하여 블로킹한 멤브레인에 넣어서 안티바디들이 단백질의 특이적인 위치에 부착하도록 4℃에서 12시간 내지 오버나잇으로 반응시켰다. 다음날 멤브레인을 TBST로 3회 세정한 뒤 horseradish peroxidase가 결합된 항-rabbit IgG를 1:10,000으로 희석하여 상온에서 멤브레인과 1시간 동안 반응시킨 다음 TBST로 3회 세정하였다. 세정한 멤브레인을 chemiluminescent reagent와 1분 동안 반응시키고 필름에 감광하여 단백질 밴드를 가시화하였다. Specifically, in the THP-1 cell line, which is a multiple myeloma cell line, melatonin in Example 1 was treated with 0.125 and 0.25 mM of THP-1, respectively, and incubated in 5% CO 2 at 37° C. for 24 hours. Then, the cells were collected and washed with PBS, and cell disruption buffer RIPA (20mM Tris-HCL (pH 7.5), 150mM NaCl, 1mM NaEDTA, 1mM EGTA, 1% NP-40, 1% sodium pyrpphophate, 1mM beta-glycerophosphate) , 1mM Na3VO4 and 1㎍/ml leupeptin (Cell signaling) were added to disrupt the cells at 4° C. For 30 minutes, the cell lysate was centrifuged at 12000 rpm 4° C. for 20 minutes to remove cell membrane components, etc., and then RC DC™ Protein Assay Protein was quantified using Kit II (protein assay kit) (Bio-rad, USA), put a 5× loading die in the prepared protein sample, and heated at 95° C. for 5 minutes to denature the protein, then 8-10%. A sample was loaded on an SDS-PAGE gel and electrophoresis was performed for 2 hours at 100 to 120 V, and the proteins separated on the gel were transferred to the membrane for 2 hours at 320 mA. The protein-transferred membrane was transferred to the membrane containing 5% skim milk. After blocking with TBST (tris buffered saline, pH 7.5) solution at room temperature for 2 hours, the primary antibodies anti-PARP (Cell signaling) 1:1000 and anti-eIF2α (Cell signaling) were diluted 1:500 and blocked. The membrane was put into a membrane and reacted for 12 hours to overnight at 4° C. The next day, the membrane was washed three times with TBST, and the anti-rabbit IgG conjugated with horseradish peroxidase was 1:10,000. After diluting and reacting with the membrane for 1 hour at room temperature, it was washed 3 times with TBST The washed membrane was reacted with a chemiluminescent reagent for 1 minute, and the protein band was visualized by sensitizing the film.
그 결과, 도 2에 나타낸 바와 같이, 멜라토닌 농도에 의존적으로 PARP의 절단이 증가하고, p-eIF2α의 발현이 증가하여 세포사멸과 소포체 스트레스가 멜라토닌에 의해 증가함을 확인하였다.As a result, as shown in FIG. 2, it was confirmed that the cleavage of PARP was increased depending on the melatonin concentration, and the expression of p-eIF2α was increased, thereby increasing apoptosis and endoplasmic reticulum stress by melatonin.
실시예 4: 멜라토닌의 다발성 골수종에서의 활성산소 유발 효과 확인Example 4: Confirmation of active oxygen-inducing effect of melatonin in multiple myeloma
활성 산소는 세포사멸 관련 유전자를 자극하여 세포사멸을 유도 하는 바, 멜라토닌의 다발성 골수종에서의 활성 산소 유발 효과를 확인하였다. As active oxygen stimulates apoptosis-related genes to induce apoptosis, the effect of melatonin inducing active oxygen in multiple myeloma was confirmed.
다발성 골수종 세포주인 U937, THP-1 세포주들을 2×104개를 PBS로 세정한 뒤, DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam)를 20㎛처리하여 37℃에서 암상태로 30분 동안 인큐베이션하고, 다시 PBS로 세정하였다. 이 후, 2×104개의 세포 (50㎕)를 96월-플레이트에 분주하고, 상기 실시예 1에서 제조한 멜라토닌을 U937은 0.25 0.5mM, THP-1은 0.125, 0.25mM로 각각 처리한 뒤, 6시간 동안 암상태에서 인큐베이션하였다. 그 후, 마이크로플레이트 리더기를 이용하여 485/535nm에서 흡광도를 측정하였다. After washing 2×10 4 cells of multiple myeloma cell lines, U937 and THP-1 cells, with PBS, DCFDA Cellular Reactive Oxygen Species Detection Assay kit (abcam) was treated with 20 μm, and incubated at 37° C. in cancer for 30 minutes. , Washed again with PBS. Thereafter, 2×10 4 cells (50 μl) were dispensed on a 96 wall-plate, and the melatonin prepared in Example 1 was treated with 0.25 0.5 mM for U937, 0.125 and 0.25 mM for THP-1, respectively. , Incubated in the dark for 6 hours. Thereafter, absorbance was measured at 485/535 nm using a microplate reader.
그 결과, 도 3에 나타낸 바와 같이, U937 세포에서 멜라토닌을 0.5mM, THP-1 세포에서 멜라토닌을 0.25mM 로 처리 시 활성산소(ROS) 생성이 유의적으로 증가되는 것을 확인 하였다. As a result, as shown in FIG. 3, it was confirmed that the production of reactive oxygen species (ROS) was significantly increased when melatonin was treated with 0.5mM in U937 cells and 0.25mM in THP-1 cells.
Claims (6)
상기 조성물은 다발성 골수종 세포의 소포체(endoplasmic reticulum, ER) 스트레스로 인한 세포사멸을 유도하는 것인 조성물.The method of claim 1,
The composition is to induce apoptosis due to endoplasmic reticulum (ER) stress of multiple myeloma cells.
상기 조성물은 PARP(Poly ADP ribose polymerase) 절단을 증가시키고, p-eIF2α(Eukaryotic Initiation Factor 2α) 발현을 증가시킴으로서 세포사멸과 소포체-스트레스를 증가시키는 조성물. The method of claim 1,
The composition increases apoptosis and endoplasmic reticulum-stress by increasing PARP (Poly ADP ribose polymerase) cleavage and p-eIF2α (Eukaryotic Initiation Factor 2α) expression.
In vitro, a method of increasing PARP cleavage, increasing the expression of p-eIF2α, and increasing the generation of reactive oxygen species (ROS) by treating melatonin in multiple myeloma cells U937 and THP-1 cell lines.
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