CN113151036A - 具有预防或治疗癌症的效果的新型菌株 - Google Patents
具有预防或治疗癌症的效果的新型菌株 Download PDFInfo
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Abstract
本发明涉及新型两歧双歧杆菌MG731(Bifidobacterium bifidum MG731)菌株及包含其的癌症预防或治疗用组合物。具体而言,本发明的两歧双歧杆菌MG731菌株具有抑制癌细胞增殖、降低癌细胞移动性、抑制新血管生成、增强抗癌免疫反应的效果,同时降低炎性因子的表达,从而具有预防或治疗癌症或炎性疾病的效果。并且,当与其他抗癌剂或免疫抗癌剂并用时,本发明的两歧双歧杆菌MG731菌株表现出更优秀的抗癌效果。并且,本发明涉及新型乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株及包含其的癌症预防或治疗用组合物。具体而言,本发明的乳酸乳球菌GEN3033菌株表现出直接的癌细胞增殖抑制及免疫增强效果,具有预防或治疗癌症的效果。并且,当与其他抗癌剂或免疫抗癌剂组合使用时,本发明的乳酸乳球菌GEN3033菌株表现出更优秀的抗癌效果。
Description
技术领域
本发明涉及具有预防或治疗癌症的优秀效果的新型两歧双歧杆菌MG731(Bifidobacterium bifidum MG731)菌株及乳酸乳球菌GEN3033(Lactococcus lactisGEN3033)菌株。
具体而言,本发明的两歧双歧杆菌MG731菌株不仅具有抑制癌细胞的增 殖的效果,而且具有降低癌细胞的移动性并调节参与新血管生成的基因的效 果,从而具有比现有的两歧双歧杆菌菌株显著优秀的效果。不仅如此,本发明 的两歧双歧杆菌MG731菌株具有抗炎、抗氧化及增强免疫效果。
并且,本发明的乳酸乳球菌GEN3033菌株不仅具有癌细胞自身的增殖抑 制效果,而且增强免疫活性,由此具有比现有的乳酸乳球菌菌株显著优秀的效 果。
背景技术
人体的肠道具有通过与多种细菌之间的共生来吸收因食物的消化所带来 的营养素的吸收及将体内不必要的物质排泄至体外的重要功能。并且,肠道内 细菌的环境变化与肠道免疫直接联系,这最终还影响到体内免疫力。通过这几 年持续对这种有益于肠内健康的微生物的研究,世界各地正在积极发表有关乳 酸菌的肠道功能、免疫力及体内代谢活动的研究结果。益生菌(probiotics)是 指存活的微生物,其起到如下功能,通过改善消化道内的不平衡,抑制有害细 菌并增强自然防御效果来提高体内免疫反应。过去,用于提高肠道免疫功能的 益生菌的功能研究利用乳酸菌属(Lactobacillus)、乳球菌(Lactococcus)、双歧杆菌属(Bifidobacterium)等,根据种(species)和属(genus)的分类学 形式进行研究。
乳酸菌的研究始于1900年代由梅奇尼科夫发表乳酸菌延长寿命的效果,1946年将酿脓链球菌(Streptococcus pyogenes)和粘质沙雷氏菌(Serratia marcescen)以骨肉瘤(Osteosarcoma)患者为对象直接注入肿瘤内时,一部分 患者出现了肿瘤治疗反应,以此为基础,关于乳酸菌的抗癌治疗的研究正在全 面展开,目前为止,多项临床前研究一直在活跃进行。
2016年El-Nezami研究组表明当给小鼠同种异体肿瘤模型口服给药按规 定比例混合的鼠李糖乳杆菌GG(L.rhamnosus GG)、大肠杆菌尼斯勒1917 (E.coli Nissle 1917)以及热处理的VSL#3时,与作为抗癌剂的顺铂(cisplatin) 相比,具有通过抑制新血管生成过程而带来的抗癌效果。并且,给药了抗癌剂 的组出现因抗癌剂的毒性而导致的小鼠的体重减轻,相反,给药了益生菌的组 却未出现这种情况,从而证明益生菌可具有作为抗癌治疗剂的功能。然而,上 述多项研究中所使用的益生菌含有多种复合微生物,并且缺乏对于每种微生物 的功能性研究。
与普通细胞不同,癌症是可怕的疾病之一,癌症细胞增殖能力无限,其增 殖速度也快,并且利用围绕癌细胞的血管、淋巴管及成纤维细胞等来形成肿瘤 微环境,诱导向其他组织的转移及普通细胞的功能丧失等而导致死亡。
为了治疗这些癌症,世界各地的研究人员正在开展关于癌细胞的细胞内信 号机制及转移、药物的副作用等的多种主题的多项研究,每年开发出新药,并 进行着使许多癌症患者期待治疗效果的多种临床试验。
除了通过手术切除肿瘤组织和放射线治疗之外,用于抗癌治疗的当前多种 抗癌剂根据各个癌症种类而不同地应用。通常,给癌症患者所开处方中的化学 抗癌剂并非以癌细胞作为靶,因此虽然具有杀死癌细胞的效果,但也影响正常 细胞,因此患者身上出现脱发、腹泻、发烧、免疫力低下等副作用。此后,基 于癌症的遗传研究等开发出由各种癌症中产生的基因突变作为目标的靶向抗 癌剂,虽然大大改善了因现有的化学抗癌剂产生的副作用,但快速适应环境的 癌细胞为了脱离靶向抗癌剂的攻击而诱发对抗癌剂的抗药性,因此存在无法 100%期待靶向抗癌剂的持续性癌症治疗效果的问题。
近年来,积极开展着抗癌剂和肿瘤微环境的研究,并开发出保持抗癌效果 的同时调节患者的免疫力的诸多免疫检查点抑制剂的免疫抗癌剂,并作为治疗 剂来使用于患者。据悉,其中,对PD-1/PD-L1的治疗对皮肤癌、肺癌等的患 者呈现出较高的治疗反应。这种免疫抗癌剂在肿瘤微环境内调节免疫细胞的功 能,从而具有癌细胞的增殖抑制及提高免疫细胞的活性的功能。然而,还存在 如下问题:免疫抗癌剂也并非对所有患者呈现出相同的抗癌效果,并且还未明 确披露对于免疫抗癌剂的生物标记(biomarker),JAK-STAT基因突变时未呈 现出药物的效果,可导致因抗体合成物的特性引起的自身免疫疾病,产生昂贵的治疗费用。
基于这些研究结果,本发明人进行过实质性地对癌症患者可呈现出治疗改 善效果的微生物的研究,发现两歧双歧杆菌MG731(Bifidobacterium bifidum MG731)菌株和乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株分别 对癌细胞的增殖抑制等呈现出优秀的效果的事实,从而完成了本发明。
发明内容
需要解决的问题
本发明用于将呈现出抗癌及抗炎效果的益生菌或其提取物适用于新型抗 癌剂、炎性疾病治疗剂或免疫疾病治疗剂等的开发。
因此,本发明的目的之一在于,提供具有优秀的癌症预防或治疗效果的两 歧双歧杆菌MG731(Bifidobacterium bifidum MG731)菌株。
本发明的另一目的在于,提供包含两歧双歧杆菌MG731(Bifidobacteriumbifidum MG731)菌株的癌症预防或治疗用药物组合物。
并且,本发明的目的在于,提供包含两歧双歧杆菌MG731(Bifidobacteriumbifidum MG731)菌株的癌症预防或改善用食品组合物或动物用饲料组合物。
并且,本发明用于提供具有优秀的癌症预防或治疗效果的新型乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株。
本发明的另一目的在于,提供包含乳酸乳球菌GEN3033(Lactococcus lactisGEN3033)菌株的癌症预防或治疗用药物组合物。
并且,本发明的目的在于,提供包含乳酸乳球菌GEN3033(Lactococcus lactisGEN3033)菌株的癌症预防或改善用食品组合物或动物用饲料组合物。
解决问题的方法
为了实现上述目的,本发明提供新型两歧双歧杆菌MG731 (Bifidobacteriumbifidum MG731)菌株。上述菌株于2018年01月04日以保 藏号KCTC13452BP保藏在韩国典型培养物保藏中心(韩国生命工学研究院,韩 国全罗北道井邑市,56212)。
并且,本发明提供包含两歧双歧杆菌MG731菌株的癌症预防或治疗用药 物组合物。具体而言,上述两歧双歧杆菌MG731菌株可意指包含菌株本身或 破碎菌株而获得的细胞质部分(cytoplasmic fraction)。
尤其,本发明的两歧双歧杆菌MG731菌株的特征在于,均呈现出抗癌、 抗炎、抗氧化及免疫增强效果。
在本发明中,癌症可以为黑色素瘤、鳞状细胞癌、乳腺癌、头颈部癌、甲 状腺癌、软组织肉瘤、骨肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、皮肤癌、 脑癌、血管肉瘤、肥大细胞瘤、白血病、淋巴瘤、肝癌、肺癌、胰腺癌、胃癌、 肾癌、结肠直肠癌、造血系统肿瘤、神经母细胞瘤、表皮癌或其的转移癌,但 不限定于此。优选地,在本发明中,癌症可以为肺癌、结肠直肠癌、胃癌、乳 腺癌或肝癌。
在本发明中,炎性疾病可以为骨关节炎、类风湿性关节炎、痛风、强直性 脊柱炎、肌腱炎、腱膜炎、风湿热、狼疮、纤维肌痛(Fibromyalgia)、牛皮 癣性关节炎、哮喘、特应症、克罗恩病或溃疡性结肠炎,但不限定于此。
本发明的两歧双歧杆菌MG731菌株抑制癌细胞的增殖,并降低癌细胞的 移动性,从而可呈现出抗癌效果。并且,本发明的两歧双歧杆菌MG731菌株 抑制作为血管生成因子的血管内皮生长因子(VEGF;vascular endothelial growth factor)、血管生成素1(Ang1;angiopoetin1)、血管生成素2(Ang2;angiopoetin2) 的表达,从而可呈现出抗癌效果。
并且,本发明的两歧双歧杆菌MG731菌株抑制TNF-α的表达,从而可呈 现出抗炎或抗癌效果。肿瘤坏死因子-α(TNF-α)为人体内感染、外伤、败血 症、类风湿性关节炎等的慢性或急性炎症反应时从免疫细胞分泌的细胞因子, 当肿瘤坏死因子-α(TNF-α)的浓度增加时,细胞内脂质及糖代谢过程中会诱 发损伤。据悉,肿瘤坏死因子-α(TNF-α)为诱导细胞坏死的细胞因子,但据 研究结果发表,持续的TNF-α的刺激传递至细胞时,反而因影响到细胞内代谢 而产生肿瘤形成基因,从而产生细胞的异常增殖而促进癌症的诱发。
本发明涉及一种癌症预防或治疗用药物组合物,其特征在于,包含两歧双 歧杆菌MG731菌株及化学抗癌剂或免疫抗癌剂。
上述化学抗癌剂可以为奥沙利铂(Oxaliplatin)、培美曲塞(Pemetrexed)、 顺铂(Cisplatin)、吉西他滨(Gemcitabine)、卡铂(Carboplatin)、氟尿嘧 啶(5-FU)、环磷酰胺(Cyclophosphamide)、紫杉醇(Paclitaxel)、长春新 碱(Vincristine)、依托泊甙(Etoposide),多柔比星(Doxorubicin)等,但 不限定于此。
并且,上述免疫抗癌剂可以为抗-PD1(anti-PD1,程序性死亡受体1抗体)、 抗-PDL1(anti-PDL1,细胞程序性死亡配体1抗体)、抗-CTLA(anti-CTLA, 细胞毒性T淋巴细胞相关抗原)、抗-Tim3(anti-Tim3,T淋巴细胞膜蛋白3 抗体)、抗-LAG3(anti-LAG3,淋巴细胞活化基因-3抗体)等具有免疫检查 点抑制功能的免疫抗癌剂,但不限定于此。
本发明的两歧双歧杆菌MG731菌株及抗癌剂或免疫抗癌剂可依次或同时 给药于需要它的患者。
并且,本发明涉及包含两歧双歧杆菌MG731(Bifidobacterium bifidum MG731)菌株的用于预防或改善癌症的食品组合物或动物用饲料组合物。
上述食品组合物可以为保健功能食品、乳制品、发酵产品或食品添加剂, 但不限定于此。
本发明提供新型乳酸乳球菌GEN3033(Lactococcus lactis GEN3033)菌株。 上述乳酸乳球菌GEN3033菌株于2018年10月25日以保藏号KCTC13684BP 保藏于韩国典型培养物保藏中心。
并且,本发明提供包含乳酸乳球菌GEN3033(Lactococcus lactis GEN3033) 菌株的癌症预防或治疗用药物组合物。具体而言,上述乳酸乳球菌GEN3033 (Lactococcuslactis GEN3033)菌株可包含菌株本身或破碎菌株而获得的细胞 质部分(cytoplasmicfraction)。
尤其,本发明的乳酸乳球菌GEN3033菌株的特征在于,均呈现出抗癌效 果及免疫增强效果。
上述癌症可以为黑色素瘤、鳞状细胞癌、乳腺癌、头颈部癌、甲状腺癌、 软组织肉瘤、骨肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、皮肤癌、脑癌、 血管肉瘤、肥大细胞瘤、白血病、淋巴瘤、肝癌、肺癌、胰腺癌、胃癌、肾癌、 结肠直肠癌、造血系统肿瘤、神经母细胞瘤、表皮癌或其的转移癌,但不限定 于此。
本发明的乳酸乳球菌GEN3033菌株直接抑制癌细胞的增殖,并激活免疫 细胞,从而可呈现出抗癌效果。并且,本发明的乳酸乳球菌GEN3033菌株可 根据肠道定植来调节代谢产物,从而可呈现出抗癌效果。
具体而言,本发明的乳酸乳球菌GEN3033菌株可增加神经节苷脂GM3(Ganglioside GM3;monosialodihexosylganglioside,单唾液酸二己糖神经节苷 脂)。神经节苷脂GM3(Ganglioside GM3)为具有以下化学式I结构的化合 物,其为[(2S,4S,5R)-2-{[(2S,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-{[(2S,3R)-2- 二十二烷酰氨基-3-羟基十八烷基]氧基}-4,5-二羟基-2-(羟甲基)氧杂环己-3-基] 氧基}-3,5-二羟基-6-(羟甲基)氧杂环己-4-基]氧基-5-乙酰氨基-4-羟基 -6-[(1R,2R)-1,2,3-三羟基丙基]氧杂环己烷-2-甲酸] ([(2S,4S,5R)-2-{[(2S,3R,4S,5S,6R)-2-{[(2R,3S,4R,5R,6R)-6-{[(2S,3R)-2-docosa namido-3-hydroxyoctadecyl]oxy}-4,5-dihydroxy-2-(hydroxymethyl)oxan-3-yl]oxy }-3,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy}-5-acetamido-4-hydroxy-6-[(1R, 2R)-1,2,3-trihydroxypropyl]oxane-2-carboxylic acid])。
化学式I
据悉,糖鞘脂类(Glycosphingolipids)之一的神经节苷脂GM3(Ganglioside GM3)为细胞膜的组成成分,抑制血管内皮生长因子(VEGF;vascular endothelial growthfactor),从而阻止新血管生成并调节淋巴细胞的花生四烯酸级联反应 (arachidonicacid cascade),通过调节免疫作用而呈现出抗癌功效。进而,据 悉,用顺铂(cisplatin)处理神经节苷脂GM3(Ganglioside GM3)时更增加癌 细胞的凋亡(apoptosis)。
因此,本发明涉及一种癌症预防或治疗用药物组合物,其特征在于,上述 乳酸乳球菌GEN3033菌株增加神经节苷脂GM3(GangliosideGM3)。
并且,本发明的乳酸乳球菌GEN3033菌株增加基于记忆性T细胞(memory T cell)活性的γ-干扰素(IFN-γ)的生成,并且增加诱发T细胞(T cell)的激 活的白细胞介素-15(IL-15)和白细胞介素-7(IL-7)的表达,从而可呈现出抗 癌及增强免疫效果。
因此,本发明涉及一种癌症预防或治疗用药物组合物,其特征在于,上述 乳酸乳球菌GEN3033菌株增加γ-干扰素(IFN-γ)的生成。
并且,本发明涉及一种癌症预防或治疗用药物组合物,其特征在于,上述 乳酸乳球菌GEN3033菌株增加白细胞介素-15(IL-15)或白细胞介素-7(IL-7) 的表达。
本发明涉及一种癌症预防或治疗用药物组合物,其特征在于,包含乳酸乳 球菌GEN3033菌株及化学抗癌剂或免疫抗癌剂。
上述化学抗癌剂可以为奥沙利铂(Oxaliplatin)、培美曲塞(Pemetrexed)、 顺铂(Cisplatin)、吉西他滨(Gemcitabine),卡铂(Carboplatin)、氟尿嘧 啶(5-FU)、环磷酰胺(Cyclophosphamide)、紫杉醇(Paclitaxel)、长春新 碱(Vincristine)、依托泊甙(Etoposide)、多柔比星(Doxorubicin)等,但 不限定于此。
并且,上述免疫抗癌剂可以为抗-PD1、抗-PDL1、抗-CTLA、抗-Tim3, 抗-LAG3等具有免疫检查点抑制功能的免疫抗癌剂,但不限定于此。
本发明的乳酸乳球菌GEN3033菌株及抗癌剂或免疫抗癌剂可依次或同时 给药于需要它的患者。
并且,本发明涉及包含乳酸乳球菌GEN3033(Lactococcus lactis GEN3033) 菌株的用于预防或改善癌症的食品组合物或动物用饲料组合物。
上述食品组合物可以为保健功能食品、乳制品、发酵产品或食品添加剂, 但不限定于此。
发明效果
本发明的新型两歧双歧杆菌MG731菌株对多种癌细胞株具有增殖抑制效 果。并且,本发明的两歧双歧杆菌MG731菌株减少癌细胞的移动性,同时还 具有抑制新血管的生成的效果,相比于以往已知的两歧双歧杆菌,具有显著优 秀的效果。
并且,本发明的两歧双歧杆菌MG731菌株具有抗炎、抗氧化或增强免疫 效果,从而还可使用于炎症疾病或免疫疾病。
尤其,当单独给药本发明的两歧双歧杆菌MG731菌株时,不仅可呈现出 优秀的抗癌效果,而且与其他抗癌剂或免疫抗癌剂组合给药时,与单独给药相 比,具有更优秀的抗癌效果。
本发明的新型乳酸乳球菌GEN3033菌株不仅对多种癌细胞株具有抑制增 殖的效果,而且呈现出免疫活性,由此相比于现有的乳酸乳球菌菌株具有显著 优秀的效果。
尤其,就本发明的乳酸乳球菌GEN3033菌株而言,单独给药时不仅呈现 出优秀的抗癌效果,而且与其他抗癌剂或免疫抗癌剂组合给药时,与单独给药 相比,具有更优秀的抗癌效果。
附图说明
图1用图表示出在人源癌细胞株中根据MG731处理的细胞增殖抑制情况。
图2a及图2b为示出通过MG731的癌细胞株的移动性降低的结果。
图3示出MG731抑制作为新血管生成相关因子的血管内皮生长因子 (VEGF;vascular endothelial growth factor)的表达。
图4a及图4b为确认抑制血管内皮生长因子(VEGF;vascular endothelial growthfactor)之外的作为新血管生成相关因子的血管生成素1(Ang1; angiopoetin1)、血管生成素2(Ang2;angiopoetin2)的表达的MG731的功效 的结果。
图5示出MG731抑制通过LPS的炎症反应诱导因子中肿瘤坏死因子-α (TNF-α)的表达。
图6示出根据MG731的不同浓度的活性氧的减少。
图7为示出根据抗癌剂(奥沙利铂(oxaliplatin)或培美曲塞(pemetrexed)) 和MG731的组合处理的癌细胞的增殖抑制效果的结果。
图8示出对图7中染色的细胞进行脱色之后将癌细胞的增殖抑制效果进行 数值化。
图9为利用小鼠同种异体移植模型来示出根据抗癌剂(oxaliplatin)和 MG731的组合给药的肿瘤增殖抑制效果的结果。
图10为利用小鼠同种异体移植模型来示出根据免疫抗癌剂(抗-PD1)和 MG731的组合给药的肿瘤增殖抑制效果的结果。
图11为渗透至根据抗癌剂(奥沙利铂,oxaliplatin)和MG731的组合给 药的小鼠同种异体移植模型的肿瘤组织内的免疫细胞的分布的分析结果。
图12为渗透至根据免疫抗癌剂(抗-PD1)和MG731的组合给药的小鼠 同种异体移植模型的肿瘤组织内的免疫细胞的分布的分析结果。
图13为利用酶联免疫吸附测定试剂盒(ELISA kit)来确认GEN3033菌 株的γ-干扰素(IFN-γ)生成增加效果的结果。
图14为通过将GEN3033菌株给药到小鼠肿瘤模型来确认肿瘤增殖抑制效 果的结果。
图15为给药GEN3033菌株的小鼠肿瘤模型的大肠和肿瘤组织中测定白细 胞介素-15(IL-15)的表达的结果。
图16为给药GEN3033菌株的小鼠肿瘤模型的大肠和肿瘤组织中测定白细 胞介素-7(IL-7)的表达的结果。
图17为在小鼠肿瘤模型给药GEN3033菌株时,给药免疫抗癌剂(抗-PD1) 时及将其组合给药时确认肿瘤增殖抑制效果的结果。
图18至图20示出对给药GEN3033菌株或给药免疫抗癌剂(抗-PD1)或 将其组合给药的小鼠的血清中分析代谢产物的结果。
图21至图25为GEN3033菌株和抗癌剂(顺铂、奥沙利铂、氟尿嘧啶、 环磷酰胺、紫杉醇)在癌细胞株中起到的细胞存活率减少效果的测定结果。
图26为GEN3033菌株和免疫抗癌剂(抗-PDL1)在癌细胞株中起到的细 胞生存率减少效果的测定结果。
具体实施方式
本发明人为了发掘具有优秀的抗癌治疗或预防效果的益生菌而进行研究 的结果,确认新型两歧双歧杆菌MG731菌株及乳酸乳球菌GEN3033菌株具有 优秀的抗癌效果,由此完成了本发明。
令人惊讶的是,MG731菌株对肺癌、结肠直肠癌、胃癌、乳腺癌及肝癌 等的多种癌细胞株具有优秀的癌细胞增殖抑制效果。
并且,用MG731菌株处理癌细胞株的情况下,癌细胞的移动性明显降低。 癌细胞不同于正常细胞,具有即使细胞受损也能增殖和移动的特征,所谓癌细 胞的移动性减少是指癌症癌症转移可能性降低,因此MG731菌株具有癌症转 移抑制效果。
并且,MG731菌株均可抑制作为血管生成相关主要因子的血管内皮生长 因子(VEGF;vascular endothelial growth factor)、血管生成素1(Ang1;angiopoetin1)及血管生成素2(Ang2;angiopoetin2)的表达。新血管的生成 为癌细胞的特征之一,通过抑制它来阻碍通过血管向癌细胞供给营养成分,从 而可抑制癌细胞的增殖。
炎性疾病中的一个明显的状态之一为活性氧(Reactive oxygen species; ROS)的增加。中等程度的活性氧浓度通过调节细胞信号传递系统来发挥效果, 但实际上若长期暴露于高浓度的活性氧,则对蛋白质、脂质及核酸导致非特异 性损伤。活性氧在如蛋白质磷酸化、离子通道及转录因子的氧化还原调节之类 的正常生理过程中起到重要作用,并且在包括甲状腺激素生成及细胞外基质的 交联的生物合成过程中也具有主要功能。并且,众所周知,在大部分的癌细胞 中,这种活性氧也具有高活性,从而诱发异常的细胞增殖。因此,本发明的 MG731菌株具有通过减少活性氧来抑制癌细胞的增殖,并预防发生各种疾病的效果。
并且,本发明的MG731菌株诱导具有抑制肿瘤细胞的增殖的功能的细胞 毒性T细胞(cytotoxic T cells)(CD8+效应T细胞)及自然杀伤细胞(NK cells; Natural killercells)更多地渗透到肿瘤组织内,减少用于抑制细胞毒性T细胞 (cytotoxic T cell)的功能的调节性T细胞(T regulatory cell)的数量,从而调 节免疫细胞的功能,并呈现出优秀的抗癌效果。
分别用MG731菌株及公知的化学抗癌剂或免疫抗癌剂处理多种癌细胞 株,或者用MG731菌株及公知的化学抗癌剂或免疫抗癌剂组合处理多种癌细 胞株时,经MG731处理的癌细胞株相比于经抗癌剂处理的癌细胞株具有更优 秀的细胞增殖抑制效果,用MG731及抗癌剂组合处理的癌细胞株相比于仅用 MG731或抗癌剂处理的癌细胞株具有突出的细胞增殖抑制效果,因此MG731 与现有的抗癌剂组合给药时具有得以提高的抗癌效果。
因此,本发明的两歧双歧杆菌MG731菌株同时呈现出抑制癌细胞增殖、 降低癌细胞移动性及抑制新血管生成效果,由此可用作优秀的抗癌剂,并可与 现有的化学抗癌剂或免疫抗癌剂组合给药。
并且,通过显著减少由作为炎症诱导因子的脂多糖(LPS, lipopolysaccharide)而诱导的肿瘤坏死因子-α(TNF-α)的表达,MG731菌株 可同时预防或治疗炎性疾病及癌症。
本发明提供通过向体内给药两歧双歧杆菌MG731菌株来预防或治疗癌 症、炎性疾病、免疫疾病等的方法。
本发明的包含两歧双歧杆菌MG731菌株的组合物可使用于药品、保健功 能食品、乳制品、发酵产品,食品添加剂或动物用饲料等。
并且,本发明的乳酸乳球菌GEN3033菌株对多种癌细胞株具有优秀的增 殖抑制效果。
当处理本发明的乳酸乳球菌GEN3033菌株时,癌细胞的增殖直接降低, 根据记忆性T细胞(memory T cell)的活性的γ-干扰素(IFN-γ)的生成被增 加,并且诱发T细胞(Tcell)的激活的白细胞介素-15(IL-15)和白细胞介素 -7(IL-7)的表达被增加,从而呈现出抗癌及增强免疫效果。
并且,本发明的乳酸乳球菌GEN3033菌株根据肠道定植来调节代谢产物, 从而呈现出抗癌效果。尤其,乳酸乳球菌GEN3033菌株抑制血管内皮生长因 子(VEGF;vascularendothelial growth factor),由此阻碍新血管生成并调节 淋巴细胞的花生四烯酸级联反应(arachidonic acid cascade),由此增加公知为 通过调节免疫作用来呈现出抗癌功效的神经节苷脂GM3(Ganglioside GM3), 可呈现出优秀的抗癌效果。并且,确认乳酸乳球菌GEN3033菌株增加通过使 巨噬细胞(macrophage)激活而调节免疫反应的磷脂酰肌醇(Phosphatidylinositol)(PI)18:1及20:4,并减少公知为表示细胞膜的损伤 和炎症反应的标记的花生四烯酸硫代磷酸胆碱 (Arachidonoylthiophosphorylcholine)和PC16:0/22:6,来缓解炎症反应。
当多种癌细胞株中分别处理或组合处理GEN3033菌株及公知的化学抗癌 剂或免疫抗癌剂时,GEN3033与抗癌剂组合处理的癌细胞株相比于仅处理 GEN3033或抗癌剂的癌细胞株具有更优秀的细胞增殖抑制效果,故而 GEN3033在与现有的抗癌剂组合给药时呈现出得以提高的抗癌效果。
因此,本发明的乳酸乳球菌GEN3033菌株同时呈现出癌细胞增殖抑制效 果和免疫增强效果,由此可用作优秀的抗癌剂,并且可与现有的化学抗癌剂或 免疫抗癌剂组合给药。
本发明提供通过向体内给药乳酸乳球菌GEN3033菌株来预防或治疗癌 症、炎性疾病、免疫疾病等的方法。
本发明的包含乳酸乳球菌GEN3033菌株的组合物可使用于药品、保健功 能食品、乳制品、发酵产品,食品添加剂或动物用饲料等。
以下,通过实施例来更详细说明本发明。这些实施例仅用于更具体说明本 发明,本发明的范围不限定于这些实施例。
实施例1
两歧双歧杆菌MG731的分离及培养
MG731利用对于双岐杆菌属(Bifidobacterium spp.)的选择性培养基,从 健康的幼儿的粪便中分离出菌株。
将收集的粪便试样在0.85%NaCl中分阶段稀释10倍之后,涂抹于添加有 50mg/L莫匹罗星锂(lithium mupirocin)的TOS丙酸盐琼脂(TOS-propionate agar)(默克集团(Merck KGaA),达姆施塔特(Darmstadt),德国(Germany)) 中,并在37℃的温度下厌氧培养48小时后,筛选出菌落(colony)的形态不 同的菌株。被筛选的菌株在胆盐乳糖培养基(BLbroth)中进行继代培养之后, 在-80℃下,在含有20%甘油的胆盐乳糖培养基(BL broth)中冷冻保管。
分析所得的菌株的rRNA的碱基序列,并以序列号1(SEQ ID NO:1)表 示,其鉴定结果确认MG731为两歧双歧杆菌(Bifidobacterium bifidum)。上 述MG731菌株于2018年1月04日以保藏号KCTC13452BP保藏于韩国典型 培养物保藏中心。
将本实验中要使用的两歧双歧杆菌MG731接种在MRS broth(Difco, USA)培养基,在37℃及厌氧条件下培养并在乳酸菌的增殖为OD=1时结束 培养。培养结束的培养物通过离心分离来回收菌体,所回收的菌体用磷酸盐缓 冲液(PBS)清洗之后,在磷酸盐缓冲液中悬浮并以超声波粉碎法粉碎了菌体。 所粉碎的菌体通过离心分离而获得上清液,并通过0.42μm滤网进行过滤,从 而制备了两歧双歧杆菌MG731的提取物。
实施例2
两歧双歧杆菌MG731菌株的肿瘤增殖抑制效果
为了确认两歧双歧杆菌MG731是否在多种癌细胞株中呈现出抗癌功效, 利用人源癌细胞株来进行细胞存活率分析(MTT测定)。
细胞存活率分析(MTT测定)中所使用的癌细胞株为利用肺癌(A549, H1975,HCC827,H1299,SW900)、结肠直肠癌(HCT116,LoVo,SNU-C2A, SNU-C1,Colo205)、胃癌(SNU216,AGS,MKN-28,MKN-1,SNU-601, SNU-1)、乳腺癌(Hs578T,BT20,MDA-MB-231,MCF7)、肝癌(HepG2, Hep3B)的总计5种癌症种类来进行实验。
以1-5×103细胞/孔的方式,将癌细胞株分注于96-孔板(96-well plate)中, 经过24小时后添加乳酸菌试样1%(1%=12.147μg,通过BCA分析测定提取 物的浓度),培养72小时之后,用MTT(3-(4,5-二甲基噻唑-2-基)-2,5-二苯基 四唑溴化噻唑蓝(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide thiazolyl blue)试剂处理各个孔(well),反应2小时。
此后,与存活的细胞的线粒体反应,经过从黄色的MTT变成紫色的过程。 此后,加入MTT的培养液均被去除,向各个孔(well)中添加100μl的二甲 基亚砜(DMSO),利用酶标仪(microplate reader)设备在540nm吸光度下 测定紫色的浓度,并且将对人源癌细胞株的实验结果在图1中示出。
实施例3
两歧双歧杆菌MG731菌株的癌细胞移动性降低效果
由于癌细胞不同于正常细胞,具有即使细胞受损也增殖并移动的特征,因 此为了确认是否因MG731菌株而导致癌细胞的移动性降低,进行伤口愈合试 验(wound healingassay)。将A549(5×105个细胞)及HCT116(6×105个 细胞)菌株附着于6孔板(well plate),若细胞处于90%-95%增殖的状态,则 利用tip以规定间隔使细胞受损。24小时处理磷酸盐缓冲液或MG731菌株, 用显微镜观察了细胞是否移动,其结果在图2中示出。
如图2所示,基于使细胞受损的A549(图2a)和HCT116(图2b)细胞 株的0时间段的细胞状态,24小时后,A549为65.31±1.69%,HCT116为33.82 ±5.86%,表示癌细胞的移动性活跃,反之,用MG731处理的A549和HCT116 分别为42.59±4.01%及22.63±3.11%,由此可确认细胞的移动性被降低。
最终,可知MG731菌株抑制癌症转移,具有优秀的抗癌效果。
实施例4
两歧双歧杆菌MG731菌株的新血管生成抑制效果
为了确认MG731菌株是否抑制癌细胞的特征之一的新血管生成过程,对 新血管生成相关因子如下进行表达试验。
HCT116细胞株中用MG731处理24小时之后,获得RNA来合成cDNA, 利用其,通过普通聚合酶链式反应(PCR,Polymerase Chain Reaction)确认作 为血管生成因子的血管内皮生长因子(VEGF;vascular endothelial growth factor)的表达,通过实时聚合酶链式反应(real-time PCR)确认了血管生成素 1(Ang1;angiopoetin1)和血管生成素2(Ang2;angiopoetin2)的表达,其结 果分别在图3及图4中示出。
如图3所示,确认到MG731的处理组相比于对照组,血管内皮生长因子 (VEGF;vascular endothelial growth factor)的121同种型(isoform)及165 同种型的表达明显减少。
并且,如图4所示,除了血管内皮生长因子(VEGF;vascular endothelial growthfactor)之外,当比较参与新血管生成的因子血管生成素1(Ang1; angiopoetin1)(图4a)及Ang2(图4b)的表达时,确认到血管生成素1(Ang1; angiopoetin1)和血管生成素2(Ang2;angiopoetin2)的表达在MG731的处理 组中,相比于对照组,表达率明显降低70%以上。
最终,MG731抑制新血管生成来阻碍通过血管向癌细胞供给营养成分, 由此可知对异常的癌细胞的增殖具有优秀的抑制效果。
实施例5
两歧双歧杆菌MG731菌株的抗炎效果
为了确认MG731菌株的抗炎效果,用MG731菌株处理18小时作为小鼠 巨噬细胞的RAW264.7细胞之后,将作为炎症诱导因子的LPS 100ng/ml处理 6小时,获得RNA。
用1μg的上述RNA合成了cDNA,由此通过实时PCR确认了公知为炎性 因子的肿瘤坏死因子-α(TNF-α)是否表达,在图5中示出了其结果。
如图5所示,当因LPS而增加的肿瘤坏死因子-α(TNF-α)的表达程度作 为相对指数而被设定为1时,确认到MG731处理组的肿瘤坏死因子-α(TNF-α) 的表达增加的程度为0.5以下。肿瘤坏死因子-α(TNF-α)还被公知为诱发癌 症的因子,因此因MG731而使肿瘤坏死因子-α(TNF-α)的表达明显减少,由 此可知,MG731同时具有抗炎及抗癌功能。
实施例6
两歧双歧杆菌MG731菌株的抗氧化活性效果
为了确认MG731的抗氧化活性,A549癌细胞株中用MG731处理24小 时之后,用0.5μM的H2O2处理4小时,通过DCFDA荧光染料,利用FACs 设备测定了细胞内活性氧量,并将其结果在图6中示出。
如图6所示,仅处理磷酸盐缓冲液的组呈现出4.66%的活性氧量,仅处理 H2O2的组增加了64.8%活性氧。反之,分别处理0.1%、0.5%、1%的MG731 的组的活性氧的量减少为57.8%、39.3%及32.5%。因此,确认到MG731呈现 出减少活性氧的量的效果,若MG731的浓度增加,则抑制活性氧的效果也增 加。
最终,通过上述实验结果可知,MG731具有抗氧化效果。即,在正常细 胞中可起到保护因活性氧而致使细胞损伤的作用,在癌细胞中可起到通过减少 异常的活性氧的浓度来控制线粒体的异常功能的作用。
实施例7
基于两歧双歧杆菌MG731菌株和抗癌剂的组合处理的癌细胞增殖抑制效果 (体外(in vitro)实验)
在A549人肺癌细胞(human lung cancer cells)、HCT116人结肠癌细胞 (humancolon cancer cells)中,进行基于MG731和抗癌剂组合处理的癌细胞 增殖抑制实验。利用奥沙利铂(oxaliplatin)或培美曲塞(pemetrexed)来作为 抗癌剂,通过以下方法进行实验。
以1-2×103的方式,将上述两种癌细胞株向6孔板(well plate)的各个孔 (well)中稀释分注,附着24小时之后,在每个孔处理乳酸菌和抗癌剂,隔着 2-3天,更换培养基,诱导7天细胞增殖。
用4%福尔马林,将孔板处理30分钟,使细胞定植并停止细胞增殖之后, 经过2次的磷酸盐缓冲液清洗过程,用结晶紫(crystal violet)溶液染色5分钟 之后,用蒸馏水清洗,并观察了是否发生细胞的增殖。其结果在图7中示出。
如图7所示,可知将MG731菌株和抗癌剂组合处理的癌细胞株,相比于 仅处理MG731或抗癌剂的癌细胞株,呈现更优秀的细胞增殖抑制效果。
并且,对于染色的细胞的菌落(colony)的数值通过用醋酸(acetic acid) 溶解结晶紫(crystal violet)并利用酶标仪(microplate reader)设备测定了浓度, 其结果在图8中示出。并确认到在图8中也呈现出与图7相同的效果。
实施例8
基于两歧双歧杆菌MG731菌株和抗癌剂的组合给药的肿瘤增殖抑制效果(体 内(in vivo)实验)
在建立肿瘤模型之前,向小鼠给药乳酸菌试样2周,以实现肠道定植及提 高免疫力之后,每组C57BL/6小鼠(mouse)8只的右屁股附近皮下注射2×105 MC38癌细胞(cancercells),从而建立了肿瘤诱发模型。注入肿瘤细胞的同 时,将乳酸菌试样给上述动物模型口服给药3周(星期一-星期六)。经给药 的乳酸菌的试样在200μl的磷酸盐缓冲液中稀释后口服给药,使得每只给药 CFU 1×109。癌症诱发后,将奥沙利铂(3mg/kg,蓝木化工有限公司 (Sellekchem))或抗-PD1(2mg/kg,欣博盛生物科技有限公司(BioXCell)) 作为抗癌剂,每周星期一和星期四进行腹腔注射。
对于仅处理了乳酸菌的组、仅处理了奥沙利铂或抗-PD1的组及两者都处 理的组观察了肿瘤抑制效果之后,在图9及图10中示出。
如图9及10所示,确认到单独给药MG731的情况相比于单独给药奥沙利 铂或抗-PD1的情况,肿瘤抑制效果更突出,当将MG731与奥沙利铂或抗-PD1 组合给药的情况下,肿瘤抑制效果更为优秀。
实施例9
基于两歧双歧杆菌MG731菌株和抗癌剂的组合给药的抗肿瘤免疫反应增强效 果(体内(in vivo)实验)
基于上述实施例8的结果,为了确认渗透至肿瘤内的免疫细胞的分布,要 进行FACs实验,如下进行了动物实验。
通过与实施例8相同的方法,建立肿瘤诱发模型并给药乳酸菌试样及抗癌 剂后,分离肿瘤和脾,并确认小鼠的免疫细胞分布图,粉碎组织并分离了免疫 细胞。所分离的免疫细胞利用各个功能的免疫细胞的标记所属的荧光抗体来进 行反应之后,利用FACs设备进行确认。上述实验结果在图11和图12中示出。
如图11及图12所示,确认到给药了MG731的组与对照组相比,在抗癌 免疫反应中呈现重要功能的CD4T细胞、CD8 T细胞、CD8效应T细胞的分 布增加了1.5-2倍以上,可知用于调节T细胞(T cell)的功能的调节性T细胞 (regulatory T cells)的数量明显减少。
并且,在MG731和抗癌剂组合给药的组中,确认到抗肿瘤免疫反应明显 增加。
从上述结果可知,基于MG731的免疫细胞功能的调节还对肿瘤增殖的抑 制也带来影响。
实施例10
乳酸乳球菌GEN3033菌株的分离及鉴定
为了分离GEN3033菌株,接收到满41岁的正常人女性提供的粪便。将约 4g所收集的新鲜粪便试样添加至磷酸盐缓冲液(PBS;phosphate buffered saline) 80ml中,涡流(vortexing)之后再悬浮(re-suspension)。经均质化的试样在 相同溶液中连续稀释10倍,其中,将稀释为10-5、10-6、10-7、10-8倍的试样 200μl涂抹于作为乳酸菌选择培养基的De ManRogosa,Sharpe琼脂(MRS培 养基;迪福库(Difco),美国)培养基中,并在37℃温度、好氧条件下培养 了48小时。利用菌落PCR方法从固体培养基中所生成的各个菌落获得了所扩 增的16S rRNA基因(1.5kb)。纯化PCR试样之后,通过测序(sequencing) 获得的各个16S rRNA基因碱基序列代入NCBI blast程序并搜索相关物种。
其中,将与乳酸乳球菌亚种乳酸菌(Lactococcus lactis subsp.lactis strain)41MoQuesillo的相似度高的菌株(1448/1448bp,100%)命名为GEN3033,为 了纯分离,固体培养基中进行6次菌落再划线(restreaking)工作之后,重新 确认了16S rRNA基因碱基序列。所筛选的GEN3033菌株进行液体培养之后, 添加20%甘油,在-80℃温度下冷冻保管。
对所获得的菌株的rRNA的碱基序列进行分析,以序列号2(SEQ ID NO: 2)表示,对其进行鉴定的结果,确认到GEN3033为乳酸乳球菌(Lactococcus lactis)。上述GEN3033菌株于2018年10月25日以保藏号KCTC13684BP保 藏于韩国典型培养物保藏中心。
1.糖发酵特性的确认
对于GEN3033菌株,使用API CHL试剂盒(法国生物梅里埃公司 (BioMetrieuxCo.France)来调查了糖发酵特性,其结果在下列表1中示出。
表1
+:呈现糖发酵效果;-:未呈现糖发酵效果
2.酶活性的确认
为了调查GEN3033菌株的生化特性,利用API ZYM试剂盒(法国生物 5梅里埃公司)来调查酶活性特性,并将其结果在表2中示出。
表2
*0:0纳摩尔(nanomol);1:5纳摩尔;2:10纳摩尔;3:20纳摩尔;4:30 纳摩尔;5:>40纳摩尔
实施例11
乳酸乳球菌GEN3033菌株的免疫细胞活性效果
为了确认GEN3033的免疫活性,通过以下方法对基于记忆性T细胞的活 性的γ-干扰素(IFN-γ)的分泌变化进行实验。
通过Ficoll,从人体血液(human blood)中分离外周血单个核细胞(PBMC) 之后,用红细胞裂解液(RBC lysis buffer)去除红细胞,并利用LS柱(column) 和MACS缓冲液(buffer)来分离单核细胞(monocyte)。GEN3033被分注的 96孔板(well plate)中放入单核细胞使得每孔达到5×103,以使GEN3033将 单核细胞分化为巨噬细胞(macrophage)的方式反应2小时。
在单核细胞和GEN3033进行反应期间,利用MACS缓冲液和LS柱从剩 余的PBMC细胞中分离了CD4及CD8被表达的T细胞(T cell),上述分离 的T细胞用100μl的RPMI培养基稀释,使得成为5×104个细胞,并分注于具 有单核细胞和GEN3033的上述孔之后,以培养成48小时期间产生免疫活性。 在经过规定时间之后,各孔的细胞培养液均收集于1.5ml的试管(tube)中, 仅分离上清液,利用ELISA试剂盒(ELISA kit)来测定γ-干扰素(IFN-γ)的 生成度,将其结果在图13中示出。
如图13所示,确认到仅具有单核细胞和T细胞(T cell)的孔板不生成γ- 干扰素(IFN-γ),反之,使大肠杆菌(E.coli)反应的孔板生成了50pg/mL的 γ-干扰素(IFN-γ),使GEN3033反应的孔板生成约210pg/mL的γ-干扰素(IFN-γ)。
即,GEN3033使巨噬细胞(macrophages)激活,从而刺激记忆性T细胞 (memory Tcell)来诱导γ-干扰素(IFN-γ)的生成。最终可知,GEN3033显 著增加记忆性T细胞(memory T cell)的活性,并诱发优秀的免疫活性。
实施例12
乳酸乳球菌GEN3033的抗肿瘤效果(体外,in vitro)
为了确认GEN3033在多种癌细胞株中是否呈现抗癌功效,利用人源癌症 细胞株11种,进行CCK-8测定。
将癌细胞株分注于96-孔板中,以使达到1-5×103细胞/孔,稳定化24小 时之后,将破碎的乳酸菌试样添加为1%(1%=4.965μg,通过BCA分析来测 定提取物的浓度),培养72小时,利用CCK-8(美国东仁化学科技有限公司 (DOJINDO,USA))确认癌细胞存活率并在下列表3中示出。
表3
如上述表3所示,根据癌细胞所具有的特性,虽然呈现出GEN3033中的 细胞存活率之差,但处理GEN3033的所有细胞株与未处理的对照组(100%的 细胞存活率)相比,确认到细胞存活率被减少的共同点。
实施例13
乳酸乳球菌GEN3033菌株的肿瘤增殖抑制效果(体内,in vivo)
同种异体的小鼠肿瘤模型在短时间内肿瘤极速产生,因肿瘤的坏死而无法 确认正确的功效,在建立肿瘤模型之前,给小鼠给药乳酸菌试样2周,并诱导 了基于GEN3033的肠道定植的免疫活性。
之后,将2×105的MC38癌细胞株皮下注射至小鼠的右腿并进行肿瘤移 植,之后,将乳酸菌试样口服给药到上述动物模型3周(星期一-星期六), 给药的乳酸菌的试样稀释于200μl的磷酸盐缓冲液,使得每只给药CFU 1× 109。此后,在小鼠中测定肿瘤的大小,并在图14中示出。
如图14所示,对给药作为阴性对照组的磷酸盐缓冲液的组根据时间经过, 肿瘤快速增加,反之,GEN3033的给药组相比于上述对照组,可确认到肿瘤 的增殖速度显著减少。最终,可知GEN3033呈现出抗肿瘤治疗效果。
实施例14
乳酸乳球菌GEN3033菌株的免疫因子表达效果
巨噬细胞(macrophages)和树突状细胞(dendritic cells)受到刺激会分泌 用于诱发T细胞(T cell)的激活的白细胞介素-15(IL-15)和白细胞介素-7 (IL-7)。因此,通过qPCR从上述实施例13的小鼠的大肠和肿瘤组织中确认 了诱发T细胞的活性的白细胞介素-15(IL-15)和白细胞介素-7(IL-7)的表 达。其结果在图15及图16中示出。
如图15及图16所示,在GEN3033的给药组的小鼠中确认到与阴性对照 组相比,肿瘤和大肠组织均增加了白细胞介素-15(IL-15)和白细胞介素-7(IL-7) 的表达。
并且,确认大肠组织呈现出比肿瘤更高的免疫因子的表达,这表明在肠道 中定植的GEN3033激活大肠组织的免疫细胞,并参与肿瘤微环境内的免疫细 胞的渗透。
实施例15
乳酸乳球菌GEN3033菌株和免疫抗癌剂的组合给药
将GEN3033和作为免疫抗癌剂的抗-PD1组合给药时,为了确认肿瘤的增 殖抑制效果,进行如下的实验。
以实施例13的肿瘤模型为对象,作为对于抗-PD1及GEN3033的阴性对 照组,分为免疫球蛋白G(IgG)(腹腔给药)和磷酸盐缓冲液(口服给药) 的给药组、GEN3033的给药组、抗-PD1的给药组、抗-PD1和GEN3033的组 合给药组来确认其功效,将抗-PD1(2mg/kg,BioXCell)诱发癌症后,在第3 天、第7天、第10天、第14天、第17天、第21天时进行腹腔注射。在图17 中示出各实验组的肿瘤增殖速度。
如图17所示,GEN3033的给药组和抗-PD1的给药组相比于阴性对照组, 确认到肿瘤的增殖速度被减少。并且,确认到抗-PD1及GEN3033的组合给药 组相比于单独给药组,肿瘤增殖速度更减少。
最终,GEN3033不仅单独抑制肿瘤增殖,而且在与抗-PD1组合给药的情 况下,相比于单独给药抗-PD1的情况,可知呈现出提高的肿瘤增殖抑制效果。
实施例16
乳酸乳球菌GEN3033的代谢产物调节
通过肠道定植,乳酸菌帮助消化道中所分解的食物的分解及吸收并供给到 体内各个器官。因此,为了确认因GEN3033引起的代谢产物的变化,将实施 例15的肿瘤模型中确保的小鼠的血清以如下方法进行分析。
为了分析给药GEN3033的小鼠的血清内所存在的代谢产物,利用了由 Cortex C18+(2.1mm×100mm,2.7um)柱形成的HPLC-MS/MS系统(戴安 (DIONEX)UltiMate 3000,戴安公司(Dionex Corporation),森尼韦尔 (Sunnyvale),加利福尼亚(CA),美国(USA)),为了检测从柱分离的 物质,利用了Triple TOF 5600+(美国应用生物系统公司(AB Sciex,USA))。作为移动相,利用了0.1%的甲酸水溶液和0.1%的甲酸乙腈,所有试样以对两 种离子转导进行分析的多反应监测(MRM)模式(multiple reaction monitoring (MRM)mode)进行分析,其结果在图18至图20中示出。
如图18所示,与对照组相比,确认到GEN3033的给药组中显著增加白皮 杉醇4’-没食子酰基葡萄糖苷(Piceatannol 4’-galloylglucoside)、神经节苷脂 GM3(GangliosideGM3),灯笼草内酯(Perulactone)、辛酸辛酯(Octyl octanoate)。
如图19所示,就抗-PD1给药组而言,相比于对照组,呈现出灯笼草内酯、 白皮杉醇4’-没食子酰葡萄糖苷、辛酸辛酯、邻苯二酚硫酸盐(Pyrocatechol sulfate)、神经节苷脂GM3增加的态势。
并且,如图20所示,将GEN3033和抗-PD1一同给药的组相比于对照组, 呈现灯笼草内酯、神经节苷脂GM3、白皮杉醇4’-没食子酰基葡萄糖苷、辛酸 辛酯相同地增加的态势。并且,与将GEN3033单独给药的组相比,确认到花 生四烯酸硫代磷酸胆碱(Arachidonoylthiophosphorylcholine)、PC16:0/22:6 增加。并且,与将抗-PD1单独给药的组相比,确认到十二烷基硫酸盐(Dodecyl sulfate)、花生四烯酸硫代磷酸胆碱、PC16:0/22:6增加。
并且,作为类固醇的一种的灯笼草内酯,主要用于食品添加剂的环肽生物 碱C、白皮杉醇4’-没食子酰基葡萄糖苷、辛酸辛酯的情况下,与对照组相比, GEN3033的单独给药的组、抗-PD1的单独给药的组、GEN3033和抗-PD1组 合给药的组中同样较高。
尤其,神经节苷脂GM3与抗-PD1单独给药的组相比,GEN3033单独给 药的组及GEN3033和抗-PD1组合给药的组中更增加。
磷脂酰肌醇(PI;Phosphatidylinositol)18:1及20:4的情况下,GEN3033 单独给药的组(相对于对照组1.32倍)和GEN3033和抗-PD1组合给药的组中 增加,但已知,上述PI20:4为激活巨噬细胞(macrophage)来帮助调节免疫 反应。并且,据悉,与正常人相比,癌症患者中呈现出较低的上述PI18:1、 PI20:4、PI20:2的3种磷脂酰肌醇的血液中含量。因此,上述磷脂酰肌醇可 成为用于区分正常人和癌症患者的重要生物标记。花生四烯酸硫代磷酸胆碱和 PC 16:0/22:6为属于磷脂(phospholipid)的代谢产物,当引起如炎症反应等 的刺激时,胆碱代谢出现异常而诱发细胞膜的损伤,从而磷脂数值减少,因此 这种花生四烯酸硫代磷酸胆碱及PC 16:0/22:6的减少被认知为表示细胞膜的 损伤及炎症反应的标记。
如图20所示,当对GEN3033和抗-PD1进行组合给药时,与对照组相比, 花生四烯酸硫代磷酸胆碱及PC 16:0/22:6数值显著增加,这意味着GEN3033 和抗-PD1的组合给药使细胞内的炎症反应缓解。
通过分析这种代谢产物,根据GEN3033的肠道定植的代谢产物的变化对 免疫反应及抗癌功效起到重要作用。
实施例17
乳酸乳球菌GEN3033和其他抗癌剂的组合给药
为了确认GEN3033和除了抗-PD1之外的其他化学抗癌剂或免疫抗癌剂的 组合处理中抗肿瘤效果是否也显著增加,进行以下实验。
作为化学抗癌剂,使用了顺铂、奥沙利铂、氟尿嘧啶、环磷酰胺、紫杉醇, 作为结肠直肠癌细胞株的HCT116中,当各个浓度的抗癌剂和0.5%浓度的 GEN3033进行组合给药时,确认到的细胞存活率的结果示于图21至图25中。
如图21所示,可知,与单独处理7μM顺铂的情况相比,当对GEN3033 进行组合处理时,细胞存活率显著减少。并且如图22至图25所示,与单独处 理HCT116中呈现90%以上的细胞存活率的各个浓度的奥沙利铂、氟尿嘧啶、 环磷酰胺及紫杉醇的情况相比,对GEN3033进行组合处理时,癌细胞的死亡 明显高。
即,GEN3033与所有抗癌剂的组合给药中显著降低癌细胞存活率,因此 可知具有提高的抗癌效果。
并且,通过与作为其他免疫抗癌剂的抗-PDL1的组合处理,免疫细胞的活 性及根据其的肿瘤细胞的生存率降低,进行以下实验。小鼠的脾和骨髓中分离 PBMC及T细胞,PBMC通过与GEN3033之间的反应来诱导巨噬细胞的分化 之后,刺激了T细胞的活性。分离激活的免疫细胞的上清液并与抗-PDL1一同 放入MC38肿瘤细胞中,反应24小时之后,用FACs设备确认了MC38的生 存率。其结果在图26中示出。
如图26所示,确认了即使未处理免疫抗癌剂,也随着与GEN3033之间的 反应癌细胞株的生存率减少12.82%、22.02%。并且,确认了通过单独处理抗 -PDL1(1mg/mL)而使癌细胞株的生存率减少18.33%,反之,对抗-PDL1 (1mg/mL)和GEN3033进行组合处理时,癌细胞株的生存率减少25.44%、 41.23%。由此,确认了除了抗-PD1之外,在与如抗-PDL1等的其他免疫抗癌 剂的组合给药中GEN3033也具有优秀的抗癌功效。
保藏号
两歧双歧杆菌MG731(Bifidobacterium bifidum MG731)
保藏机构名称:韩国典型培养物保藏中心
保藏号:KCTC13452BP
保藏日:2018年01月04日
乳酸乳球菌GEN3033(Lactococcus
lactis
GEN3033)
保藏机构名称:韩国典型培养物保藏中心
保藏号:KCTC13684BP
保藏日:2018年10月25日
序列表
<110> 韩国亿诺生物有限公司 (GENOME AND COMPANY)
<120> 具有预防或治疗癌症的效果的新型菌株
<130> 190114 1KRCN
<150> KR 10-2018-0054195
<151> 2018-05-11
<150> KR 10-2018-0133030
<151> 2018-11-01
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 1447
<212> RNA
<213> 两歧双歧杆菌(Bifidobacterium bifidum) MG731
<400> 1
agacgctggc ggcgtgctta acacatgcaa gtcgaacggg atccatcggg ctttgcttgg 60
tggtgagagt ggcgaacggg tgagtaatgc gtgaccgacc tgccccatgc tccggaatag 120
ctcctggaaa cgggtggtaa tgccggatgt tccacatgat cgcatgtgat tgtgggaaag 180
attctatcgg cgtgggatgg ggtcgcgtcc tatcagcttg ttggtgaggt aacggctcac 240
caaggcttcg acgggtagcc ggcctgagag ggcgaccggc cacattggga ctgagatacg 300
gcccagactc ctacgggagg cagcagtggg gaatattgca caatgggcgc aagcctgatg 360
cagcgacgcc gcgtgaggga tggaggcctt cgggttgtaa acctcttttg tttgggagca 420
agccttcggg tgagtgtacc tttcgaataa gcgccggcta actacgtgcc agcagccgcg 480
gtaatacgta gggcgcaagc gttatccgga tttattgggc gtaaagggct cgtaggcggc 540
tcgtcgcgtc cggtgtgaaa gtccatcgct taacggtgga tctgcgccgg gtacgggcgg 600
gctggagtgc ggtaggggag actggaattc ccggtgtaac ggtggaatgt gtagatatcg 660
ggaagaacac cgatggcgaa ggcaggtctc tgggccgtca ctgacgctga ggagcgaaag 720
cgtggggagc gaacaggatt agataccctg gtagtccacg ccgtaaacgg tggacgctgg 780
atgtggggca cgttccacgt gttccgtgtc ggagctaacg cgttaagcgt cccgcctggg 840
gagtacggcc gcaaggctaa aactcaaaga aattgacggg ggcccgcaca agcggcggag 900
catgcggatt aattcgatgc aacgcgaaga accttacctg ggcttgacat gttcccgacg 960
acgccagaga tggcgtttcc cttcggggcg ggttcacagg tggtgcatgg tcgtcgtcag 1020
ctcgtgtcgt gagatgttgg gttaagtccc gcaacgagcg caaccctcgc cccgtgttgc 1080
cagcacgtta tggtgggaac tcacggggga ccgccggggt taactcggag gaaggtgggg 1140
atgacgtcag atcatcatgc cccttacgtc cagggcttca cgcatgctac aatggccggt 1200
acagcgggat gcgacatggc gacatggagc ggatccctga aaaccggtct cagttcggat 1260
cggagcctgc aacccggctc cgtgaaggcg gagtcgctag taatcgcgga tcagcaacgc 1320
cgcggtgaat gcgttcccgg gccttgtaca caccgcccgt caagtcatga aagtgggcag 1380
cacccgaagc cggtggccta accccttgtg ggatggagcc gtctaaggtg aggctcgtga 1440
ttgggac 1447
<210> 2
<211> 1470
<212> RNA
<213> 乳酸乳球菌(Lactococcus lactis) GEN3033
<400> 2
gacgaacgct ggcggcgtgc ctaatacatg caagttgagc gctgaaggtt ggtacttgta 60
ccgactggat gagcagcgaa cgggtgagta acgcgtgggg aatctgcctt tgagcggggg 120
acaacatttg gaaacgaatg ctaataccgc ataaaaactt taaacacaag ttttaagttt 180
gaaagatgca attgcatcac tcaaagatga tcccgcgttg tattagctag ttggtgaggt 240
aaaggctcac caaggcgatg atacatagcc gacctgagag ggtgatcggc cacattggga 300
ctgagacacg gcccaaactc ctacgggagg cagcagtagg gaatcttcgg caatggacga 360
aagtctgacc gagcaacgcc gcgtgagtga agaaggtttt cggatcgtaa aactctgttg 420
gtagagaaga acgttggtga gagtggaaag ctcatcaagt gacggtaact acccagaaag 480
ggacggctaa ctacgtgcca gcagccgcgg taatacgtag gtcccgagcg ttgtccggat 540
ttattgggcg taaagcgagc gcaggtggtt tattaagtct ggtgtaaaag gcagtggctc 600
aaccattgta tgcattggaa actggtagac ttgagtgcag gagaggagag tggaattcca 660
tgtgtagcgg tgaaatgcgt agatatatgg aggaacaccg gtggcgaaag cggctctctg 720
gcctgtaact gacactgagg ctcgaaagcg tggggagcaa acaggattag ataccctggt 780
agtccacgcc gtaaacgatg agtgctagat gtagggagct ataagttctc tgtatcgcag 840
ctaacgcaat aagcactccg cctggggagt acgaccgcaa ggttgaaact caaaggaatt 900
gacgggggcc cgcacaagcg gtggagcatg tggtttaatt cgaagcaacg cgaagaacct 960
taccaggtct tgacatactc gtgctattcc tagagatagg aagttccttc gggacacggg 1020
atacaggtgg tgcatggttg tcgtcagctc gtgtcgtgag atgttgggtt aagtcccgca 1080
acgagcgcaa cccctattgt tagttgccat cattaagttg ggcactctaa cgagactgcc 1140
ggtgataaac cggaggaagg tggggatgac gtcaaatcat catgcccctt atgacctggg 1200
ctacacacgt gctacaatgg atggtacaac gagtcgcgag acagtgatgt ttagctaatc 1260
tcttaaaacc attctcagtt cggattgtag gctgcaactc gcctacatga agtcggaatc 1320
gctagtaatc gcggatcagc acgccgcggt gaatacgttc ccgggccttg tacacaccgc 1380
ccgtcacacc acgggagttg ggagtacccg aagtaggttg cctaaccgca aggagggcgc 1440
ttcctaaggt aagaccgatg actggggtga 1470
Claims (14)
1.一种两歧双歧杆菌MG731菌株(KCTC13452BP)。
2.一种癌症预防或治疗用组合物,其特征在于,包含两歧双歧杆菌MG731菌株(KCTC13452BP)。
3.一种癌症预防或治疗用组合物,其特征在于,包含两歧双歧杆菌MG731菌株(KCTC13452BP),所述两歧双歧杆菌MG731菌株表现出抗癌、抗炎、抗氧化及增强免疫的效果。
4.根据权利要求2所述的癌症预防或治疗用组合物,其特征在于,所述癌症为选自由黑色素瘤、鳞状细胞癌、乳腺癌、头颈部癌、甲状腺癌、软组织肉瘤、骨肉瘤、睾丸癌、前列腺癌、卵巢癌、膀胱癌、皮肤癌、脑癌、血管肉瘤、肥大细胞瘤、白血病、淋巴瘤、肝癌、肺癌、胰腺癌、胃癌、肾癌、结肠直肠癌、造血系统肿瘤、神经母细胞瘤、表皮癌及其的转移癌组成的组中的一种以上。
5.根据权利要求4所述的癌症预防或治疗用组合物,其特征在于,所述癌症为选自由肺癌、结肠直肠癌、胃癌、乳腺癌及肝癌组成的组中的一种以上。
6.根据权利要求2所述的癌症预防或治疗用组合物,其特征在于,所述两歧双歧杆菌MG731菌株通过降低癌细胞的移动性来表现出抗癌效果。
7.根据权利要求2所述的癌症预防或治疗用组合物,其特征在于,所述两歧双歧杆菌MG731菌株通过抑制作为血管生成因子的血管内皮生长因子、血管生成素1及血管生成素2的表达来表现出抗癌效果。
8.根据权利要求3所述的癌症预防或治疗用组合物,其特征在于,所述两歧双歧杆菌MG731菌株抑制肿瘤坏死因子-α的表达。
9.根据权利要求2所述的癌症预防或治疗用组合物,其特征在于,还包含抗癌剂或免疫抗癌剂。
10.根据权利要求9所述的癌症预防或治疗用组合物,其特征在于,所述抗癌剂为选自由奥沙利铂、培美曲塞、顺铂、吉西他滨、卡铂、氟尿嘧啶、环磷酰胺、紫杉醇、长春新碱、依托泊甙及多柔比星组成的组中的一种以上。
11.根据权利要求9所述的癌症预防或治疗用组合物,其特征在于,所述免疫抗癌剂为选自由抗-PD1、抗-PDL1、抗-CTLA、抗-Tim3及抗-LAG3组成的组中的一种以上。
12.一种用于预防或改善癌症的食品组合物,其特征在于,包含两歧双歧杆菌MG731菌株(KCTC13452BP)。
13.根据权利要求12所述的用于预防或改善癌症的食品组合物,其特征在于,所述食品组合物为保健功能食品、乳制品、发酵产品或食品添加剂。
14.一种用于预防或改善癌症的动物用饲料组合物,其特征在于,包含两歧双歧杆菌MG731菌株(KCTC13452BP)。
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Publication number | Priority date | Publication date | Assignee | Title |
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CN115011518A (zh) * | 2022-06-13 | 2022-09-06 | 东北农业大学 | 一种具有缓解结肠炎相关结直肠癌作用的乳酸菌混合物及其应用 |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115702908A (zh) * | 2021-08-05 | 2023-02-17 | 香港中文大学 | 用于治疗和预防结肠直肠癌的益生菌组合物 |
KR20230092708A (ko) | 2021-12-16 | 2023-06-26 | 주식회사 엔테로바이옴 | 암 또는 염증성 질환 예방 또는 치료용 약학적 조성물 |
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KR102645456B1 (ko) * | 2023-04-24 | 2024-03-13 | 주식회사 메디오젠 | 면역 증진 및 장 건강 증진 활성을 가진 락토코쿠스 락티스 mg5474 균주 및 이를 포함하는 조성물 |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002534113A (ja) * | 1999-01-15 | 2002-10-15 | エンタープライズ・アイルランド(トレイディング・アズ・バイオリサーチ・アイルランド) | 炎症性疾患治療におけるビフィドバクテリウム(Bifidobacterium) |
WO2009049932A1 (en) * | 2007-10-20 | 2009-04-23 | Universite De Liege | Bifidobacterial species |
CN101575582A (zh) * | 2008-05-08 | 2009-11-11 | 景岳生物科技股份有限公司 | 具有抗炎活性的乳杆菌分离株及其用途 |
US20170354697A1 (en) * | 2016-06-14 | 2017-12-14 | Vedanta Biosciences, Inc. | Treatment of clostridium difficile infection |
CN107629988A (zh) * | 2017-11-03 | 2018-01-26 | 江南大学(扬州)食品生物技术研究所 | 一种可缓解结直肠癌的两歧双歧杆菌及其用途 |
CN108430482A (zh) * | 2015-11-10 | 2018-08-21 | 伊丽莎白·麦克纳 | 细胞氧化还原水平的控制 |
WO2018230960A2 (ko) * | 2017-06-14 | 2018-12-20 | 기초과학연구원 | 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체 |
CN112312920A (zh) * | 2018-06-22 | 2021-02-02 | 合成制剂有限公司 | 非存活两歧双歧杆菌及其用途 |
CN115261426A (zh) * | 2022-09-26 | 2022-11-01 | 东北农业大学 | 一种具有抗氧化能力的两歧双歧杆菌e3胞外多糖 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3841495B2 (ja) * | 1995-09-14 | 2006-11-01 | サンエイ糖化株式会社 | L−乳酸生産能及びtnf産生誘導活性を有する乳酸菌 |
US20130302380A1 (en) * | 2010-12-28 | 2013-11-14 | Daisuke Fujiwara | Agent for inducing interferon production containing lactic acid bacteria |
KR101599769B1 (ko) * | 2012-08-10 | 2016-03-04 | 한국생명공학연구원 | 신규한 락토코쿠스 종 균주 및 이의 용도 |
JP6479685B2 (ja) * | 2013-02-04 | 2019-03-06 | セレス セラピューティクス インコーポレイテッド | 病原性細菌生育の抑制のための組成物および方法 |
US20140341853A1 (en) * | 2013-05-14 | 2014-11-20 | Vanna Hovanky | Bacteria-Mediated Therapy for Cancer |
CN107603921B (zh) * | 2017-11-03 | 2020-08-11 | 江南大学(扬州)食品生物技术研究所 | 一种可调节结肠肿瘤信号通路的乳酸乳球菌乳酸亚种及其用途 |
CN113151036A (zh) * | 2018-05-11 | 2021-07-23 | 韩国亿诺生物有限公司 | 具有预防或治疗癌症的效果的新型菌株 |
US20240209081A1 (en) * | 2021-04-29 | 2024-06-27 | Genome And Company | Anti-cntn4-specific antibodies and use thereof |
-
2019
- 2019-01-14 CN CN202110013498.5A patent/CN113151036A/zh active Pending
- 2019-01-14 CN CN201910030979.XA patent/CN110468061B/zh active Active
- 2019-05-08 CA CA3099906A patent/CA3099906C/en active Active
- 2019-05-08 WO PCT/KR2019/005518 patent/WO2019216649A1/ko active Application Filing
- 2019-05-08 EP EP19799157.3A patent/EP3792343A4/en active Pending
- 2019-05-08 KR KR1020190053963A patent/KR102148223B1/ko active IP Right Grant
- 2019-05-08 AU AU2019267042A patent/AU2019267042B8/en active Active
- 2019-05-08 US US17/054,433 patent/US20210322490A1/en active Pending
- 2019-05-08 JP JP2021513739A patent/JP7119220B2/ja active Active
- 2019-05-08 CA CA3104023A patent/CA3104023C/en active Active
- 2019-05-09 TW TW110103672A patent/TWI791190B/zh active
- 2019-05-09 TW TW108116028A patent/TWI791111B/zh active
-
2020
- 2020-11-12 US US17/096,031 patent/US20210138003A1/en active Pending
- 2020-11-23 AU AU2020277103A patent/AU2020277103B2/en active Active
-
2021
- 2021-01-19 JP JP2021006383A patent/JP7119143B2/ja active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002534113A (ja) * | 1999-01-15 | 2002-10-15 | エンタープライズ・アイルランド(トレイディング・アズ・バイオリサーチ・アイルランド) | 炎症性疾患治療におけるビフィドバクテリウム(Bifidobacterium) |
WO2009049932A1 (en) * | 2007-10-20 | 2009-04-23 | Universite De Liege | Bifidobacterial species |
CN101575582A (zh) * | 2008-05-08 | 2009-11-11 | 景岳生物科技股份有限公司 | 具有抗炎活性的乳杆菌分离株及其用途 |
CN108430482A (zh) * | 2015-11-10 | 2018-08-21 | 伊丽莎白·麦克纳 | 细胞氧化还原水平的控制 |
US20170354697A1 (en) * | 2016-06-14 | 2017-12-14 | Vedanta Biosciences, Inc. | Treatment of clostridium difficile infection |
WO2018230960A2 (ko) * | 2017-06-14 | 2018-12-20 | 기초과학연구원 | 신규한 비피도박테리움 비피덤 균주 및 균주 유래 다당체 |
CN107629988A (zh) * | 2017-11-03 | 2018-01-26 | 江南大学(扬州)食品生物技术研究所 | 一种可缓解结直肠癌的两歧双歧杆菌及其用途 |
CN112312920A (zh) * | 2018-06-22 | 2021-02-02 | 合成制剂有限公司 | 非存活两歧双歧杆菌及其用途 |
CN115261426A (zh) * | 2022-09-26 | 2022-11-01 | 东北农业大学 | 一种具有抗氧化能力的两歧双歧杆菌e3胞外多糖 |
Non-Patent Citations (4)
Title |
---|
PARK 等: "Potentiation of hydrogen peroxide, nitric oxide, and cytokine production in RAW 264.7 macrophage cells exposed to human and commercial isolates of Bifidobacterium", INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY, vol. 46, pages 231 - 241 * |
WEI 等: "Antitumor mechanisms of bifidobacteria", ONCOLOGY LETTERS, vol. 16, pages 3 - 8, XP055919457, DOI: 10.3892/ol.2018.8692 * |
YOU 等: "Anticancerogenic effect of a novel chiroinositol-containing polysaccharide from Bifidobacterium bifidum BGN4", FEMS MICROBIOLOGY LETTERS, vol. 240, pages 131 - 136, XP004797115, DOI: 10.1016/j.femsle.2004.09.020 * |
绵贯雅章 等: "发挥乳酸菌在疾病预防中的作用", 日本医学介绍, vol. 22, no. 3, pages 101 - 103 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115011518A (zh) * | 2022-06-13 | 2022-09-06 | 东北农业大学 | 一种具有缓解结肠炎相关结直肠癌作用的乳酸菌混合物及其应用 |
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