CN113116940A - 一种副干酪乳杆菌gmnl-346用于抗口腔癌之用途 - Google Patents
一种副干酪乳杆菌gmnl-346用于抗口腔癌之用途 Download PDFInfo
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Abstract
本发明提供一种副干酪乳杆菌用于制备预防或治疗口腔癌之医药组合物的用途,其系包含使用副干酪乳杆菌(Lactobacillus paracasei)或其热杀菌体上清液作为预防或治疗口腔癌的有效成分;本发明另提供一种组合物,其系包含一具抗口腔癌功效的有效成分,其中该有效成分为副干酪乳杆菌GMNL‑346(Lactobacillus paracasei GMNL‑346)或其热杀菌体上清液,该副干酪乳杆菌GMNL‑346的寄存编号为BCRC 910953或CCTCC M 2019983。
Description
技术领域
本发明系关于乳杆菌分离株,特别系关于副干酪乳杆菌用于抗口腔癌之技 术领域。
背景技术
根据美国2018年最新统计,口腔癌为男性十大癌症中排名第八位,发生 率为女性的2.58倍。口腔癌初期病患的五年存活率虽高达84%,但随着肿瘤 越恶性,病患的五年存活率仅剩39%[1]。在台湾,口腔癌高居男性肿瘤发生率 及死亡原因的第四位[2],其与嚼槟榔、抽烟、饮酒等危险因子极为相关。最近 多项研究指出,口腔微生物菌丛失调与免疫反应紊乱会影响口腔的健康,例如, 牙龈卟啉单胞菌(Porphyromonas gingivalis)除了是牙周病的主要致病菌外,牙 龈卟啉单胞菌的慢性感染更可能造成口腔癌的生成及促使口腔癌恶化[3]。口腔 癌有90%属于鳞状细胞癌,包含舌癌、口腔部位之癌症、口咽癌、下咽癌,其 中以舌头与口腔的颊黏膜为好发区域。传统口腔癌治疗以手术切除与放射治疗 或合并化学及放射线治疗。近年来受到瞩目的免疫疗法,于口腔癌治疗相关的 动物实验与临床试验中,也展现了相当的潜力。例如,原位口腔癌小鼠实验中, 可藉由抑制程序性细胞死亡-1(Programmed cell death protein 1,PD-1)或细胞 程序死亡-配体1(Programmed death-ligand 1,PD-L1)来调控T淋巴细胞的功能, 增强口腔癌放射治疗效果,延长小鼠存活率[4]。
过去研究发现,益生菌具有许多功效,包括平衡肠道微生物菌丛、改善胃 肠道屏障、抑制肠道中潜在的病原菌或癌症生成,因此,益生菌被视为癌症预 防与治疗的新策略。例如,鼠李糖乳杆菌GG株(Lactobacillus rhamnosus GG, LGG)与青春双歧杆菌SPM0212株(Bifidobacterium adolescentis SPM0212)能 抑制胃癌与大肠癌细胞生长;乳酸杆菌(Lactobacillus kefiri)能引起骨髓性白 血病细胞的细胞凋亡;乳酸肠球菌IW5株(Enterococcus lactis IW5)能降低多 种癌细胞的存活率[5]。又如,长期食用养乐多代田菌(Lactobacillus casei Shirota(BLS)),可降低乳癌、膀胱癌及人类乳突病毒相关的子***发生率 [6-8]。然而,目前关于益生菌用于口腔癌之研究非常稀少。本发明所属技术领 域尚欠缺一可有效抑制口腔癌之菌株。
参考文献
[1]CA Cancer J Clin.2018Jan;68(1):7-30.
[2]卫生福利部国民健康局105年癌症登记年报。
[3]J Oral Microbiol.2019;11(1):1563410.
[4]Oncoimmunology.2017Aug 3;6(10):e1356153.
[5]Biomed Res Int.2018;2018:3428437.
[6]Curr Nutr Food Sci.2013Aug;9(3):194-200.
[7]Urologia Internationalis.2002;68(4):273–280.
[8]European Journal of Cancer Prevention.2013;22(1):46–51.
发明内容
本案发明人深刻了解先前技术之不足,乃亟思加以创新研发,并经多年苦 心研究后,终于成功分离出本发明所提供的副干酪乳杆菌GMNL-346 (Lactobacillus paracaseiGMNL-346),并证实其具有抗口腔癌之功效。
本发明之目的在于提供一种组合物,其系包含一具抗口腔癌功效的有效成 分,其中该有效成分为副干酪乳杆菌GMNL-346(Lactobacillus paracasei GMNL-346)或其热杀菌体上清液,该副干酪乳杆菌GMNL-346的寄存编号为BCRC 910953或CCTCC M 2019983。
为达成前述发明目的,其中该有效成分为该副干酪乳杆菌GMNL-346的 死菌体。
为达成前述发明目的,其中该有效成分为该热杀菌体上清液依分子量大小 分离所得之含有小于3千道尔顿(kDa)之分子的部分。
为达成前述发明目的,其中该组合物为医药组合物、营养补充品或保健食 品。
为达成前述发明目的,其中该组合物可进一步包含药学上可接受之载剂。
为达成前述发明目的,其中该组合物系溶液、悬浮液、乳剂、粉末、锭剂、 丸剂、糖浆、***锭、片剂、口嚼胶、浓浆或胶囊。
为达成前述发明目的,其中该组合物可进一步包含一可食性材料,该可食 性材料包含但不限于水、流体乳品、牛奶、浓缩牛奶、酸奶、酸乳、冷冻优格、 乳杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆奶、发酵豆奶、蔬果汁、果 汁、运动饮料、甜点、果冻、糖果、婴儿食品、健康食品、动物饲料、中草药 材或膳食补充品。
本发明之另一目的在于提供一种副干酪乳杆菌用于制备预防或治疗口腔 癌之医药组合物的用途,其系包含使用副干酪乳杆菌(Lactobacillus paracasei) 或其热杀菌体上清液作为预防或治疗口腔癌的有效成分。
为达成前述发明目的,其中该副干酪乳杆菌为副干酪乳杆菌GMNL-346, 该副干酪乳杆菌GMNL-346的寄存编号为BCRC 910953或CCTCC M 2019983。
为达成前述发明目的,其中该预防或治疗口腔癌系抑制口腔癌细胞的细胞 周期进程。
为达成前述发明目的,其中该抑制口腔癌细胞的细胞周期进程系使口腔癌 细胞的细胞周期滞留在G0/G1时期。
为达成前述发明目的,其中该预防或治疗口腔癌系抑制口腔癌细胞内的癌 干细胞自我更新能力。
本发明提供了一种副干酪乳杆菌菌株GMNL-346,该菌株具有抑制口腔癌 细胞生长之功效,尤其系具有抑制口腔癌细胞的细胞周期进程或抑制口腔癌细 胞内的癌干细胞自我更新能力之功效。本发明更提供了一种以副干酪乳杆菌 GMNL-346或其热杀菌体上清液作为抗口腔癌之有效成分的组合物,本发明所 提供的组合物因系以益生菌作为有效成分,故具有副作用低之优势。
附图说明
图1系两批不同批次培养之副干酪乳杆菌GMNL-346对口腔癌细胞生长的 影响,(A)系口腔癌细胞处理第一批次培养的干酪乳杆菌GMNL-346,(B)系口 腔癌细胞处理第二批次培养的干酪乳杆菌GMNL-346;
图2系副干酪乳杆菌GMNL-346对正常口腔细胞生长的影响;
图3系使用锥蓝质排除分析(Trypan blue exclusion assay)分析副干酪乳杆菌GMNL-346对口腔癌细胞生长的影响;
图4系处理副干酪乳杆菌GMNL-346对口腔癌细胞生长曲线的影响;
图5系口腔癌细胞处理副干酪乳杆菌GMNL-346的细胞凋亡试验结果图;
图6系口腔癌细胞处理副干酪乳杆菌GMNL-346的细胞周期分析实验结果 图;
图7系副干酪乳杆菌GMNL-346对口腔癌细胞的细胞周期蛋白表现量之影 响的结果图(一);
图8系副干酪乳杆菌GMNL-346对口腔癌细胞的细胞周期蛋白表现量之影 响的结果图(二);
图9系副干酪乳杆菌GMNL-346对口腔癌细胞内的癌干细胞自我更新能力 之影响的结果图;
图10系GMNL-346于小鼠口腔癌模型之治疗效果图,(A)系实验时间轴, (B)系肿瘤生长实验结果,(C)系存活率分析实验结果;
图11系GMNL-346于小鼠口腔癌模型之免疫组织化学染色实验结果图;
图12系GMNL-346热杀菌体上清液或GMNL-346菌体对口腔癌细胞的抑 制效果;
图13系GMNL-346热杀死菌全菌液之不同部分对口腔癌细胞的抑制效果。
具体实施方式
本说明书中所述之所有技术性及科学术语,除非另外有所定义,皆为该所 属领域具有通常技艺者可共同了解的意义。
本说明书及申请专利范围中所述之单数用语「一」、「一个」、「该」,除非 另有说明,皆可指涉多于一个对象。
本说明书使用之「或」、「以及」、「和」,除非另有说明,皆指涉「或/和」。 此外,用语「包含」、「包括」皆非有所限制之开放式连接词。前述段落仅为系 统性之指涉而不应解释为对发明主体之限制。
本说明书用语「口腔癌」系指口腔部位之恶性肿瘤的总称,其系包含但不 限于鳞状上皮细胞癌、疣状癌、腺样囊状癌或黏液表皮样癌。
术语「治疗」、「用于治疗」以及其类用语系指称推迟、改善、减少、或逆 转患者所罹患之可诊断病症以及该病症造成之相关症状的方法以及预防该病 症或任何其所属之相关症状的方法。
术语「药学上可接受」系指称物质或组合物必须与其药学上调配物之其他 成分兼容,且不加剧患者之症状。
本发明提供之组合物系可利用本发明所属技术领域具有通常知识者所详 知的技术,将本案所提供之有效成分或组合物,与至少一药学上可接受之载剂 (vehicle),制备一适用本发明组合物之剂型。其中该剂型包含但不限于溶液、 乳剂、悬浮液、粉末、锭剂、***锭、药片、口嚼胶、胶囊以及其他类似或适 用本发明之剂型。
术语「药学上可接受之载剂」包含一种或多种选自于下列的成分类型:溶 剂、乳化剂、悬浮剂、分解剂、黏结剂、赋形剂、安定剂、螯合剂、稀释剂、 胶凝剂、防腐剂、润滑剂、表面活性剂、及其他类似或适用于本发明之载剂。
前述组合物中,亦可依需适宜地添加一种或多种以上制剂领域内通常使用 之溶解辅助剂、缓冲剂、着色剂、调味剂等。
术语「药学上可接受之赋形剂」包括但不限于,聚合物、树脂、增塑剂、 填料、润滑剂、稀释剂、黏合剂、崩解剂、溶剂、共一溶剂、界面活性剂、防 腐剂、甜味剂、调味剂、药学级的染料或颜料、及黏度剂至少一者。
术语「医药组合物」系指称一固体或液体组成物,其形式、浓度和纯度程 度适合投予给患者,在投予之后,其可诱发所欲生理变化;医药组成物为无菌 及/或非发热性者(non-pyrogenic)。
术语「有效量」系指称产生、造成预期之生物体反应所必须之剂量,且非 以治疗痊愈所需为定量。本发明所属技术领域具通常知识者可理解,医药组合 物之有效量可视诸如下列等因素而变化:期望生物终点、拟递送生物活性剂、 囊封基质(encapsulatingmatrix)之组成、目标组织等等。
本发明所使用之材料,除有特别指明者,皆为市售易于取得之材料。本发 明实施例中所使用之副干酪乳菌为副干酪乳杆菌GMNL-346(Lactobacillus paracasei GMNL-346,以下简称GMNL-346),其系寄存于台湾食品工业研究所, 编号为BCRC 910953、中国典型培养物保藏中心(CCTCC),寄存编号为CCTCC M 2019983。
本发明实施例中的细胞实验系以人类口腔癌细胞株(SAS,Human tonguesquamous carcinoma cell line(RRID:CVCL_1675);以下简称口腔癌细胞)作为 副干酪乳杆菌抗口腔癌之功效验证细胞,并使用人类正常口腔细胞株(SG, Smulow-Glickman(SG)human gingival epithelial cell;以下简称正常口腔细胞) 作为对照组,该等细胞株皆可于市面上购得。
本发明实施例中的动物实验系使用8-12周龄大的雄性 CAnN.Cg-Foxn1nu/CrlNarl免疫缺陷小鼠,其系购买自台湾实验动物中心,小 鼠的饲养环境控制在室温(24±1℃),湿度为55±5%,并维持各十二小时之白 日黑夜光照周期,及允许自由进食及饮水。
本发明之新颖技术特征,包含特定特征,系揭示于申请专利范围,针对本 发明之技术特征,较佳之理解兹配合说明书、依据本发明原理之实施例、和图 式将本发明较佳之实施例详细说明。
本发明系以下面的实施例予以示范阐明,但本发明不受下述实施例所限制。
实施例一、GMNL-346抑制口腔癌细胞生长测试
将GMNL-346以37℃,5%CO2条件培养于培养基 (DeMan-Rogosa-Sharpe,MRS)中,48小时后,经离心去除培养液后,以磷酸 盐缓冲溶液(Phosphate buffer saline,PBS)回溶菌体,再以121℃高温加热15 分钟,制成GMNL-346热杀死菌全菌液。将所得之GMNL-346热杀死菌全菌 液经高速离心后,收集上清液并通过0.22μm滤膜过滤去除菌体后,即为 GMNL-346热杀菌体上清液。
口腔癌细胞或正常口腔细胞分别处理两批不同批次培养(图1中A与B) 之不同浓度的GMNL-346热杀死菌全菌液(2.5x101~2.5x108细菌/毫升),72小 时后,使用细胞增生呈色分析法(WST-1assay)测量细胞生长情形,或以锥蓝 质排除分析(Trypan blueexclusion assay)直接计算细胞数目。
结果如图1~4所示,GMNL-346可抑制口腔癌细胞(SAS)生长,但不会 对正常口腔细胞(SG)产生毒性。由图1可发现,GMNL-346抑制口腔癌细胞 生长的效果会随着处理的菌液浓度增加而提升,其中,2.5x108细菌/毫升的菌 液可抑制50%的口腔癌细胞生存;且,由图2可发现,GMNL-346对正常口腔 细胞没有明显毒性,正常口腔细胞在经2.5x108细菌/毫升的菌液处理后,生存 力(cell viability)仍大于85%,此结果表示GMNL-346可特异性抑制口腔癌细 胞的生长,但不会影响正常细胞,使用GMNL-346作为治疗/抗口腔癌有效成分,具有减低癌症治疗之副作用伤害的优势。另外,由图3的锥蓝质排除分析 结果亦可发现,GMNL-346确实能有效抑制口腔癌细胞生长;且图4结果显示, 随着GMNL-346处理时间越久,口腔癌细胞生长抑制越明显,在第48小时, GMNL-346便可明显抑制口腔癌细胞生长,该抑制效果可持续直至96小时。
实施例二、GMNL-346抑制口腔癌细胞生长之机制
利用细胞凋亡试验及细胞周期分析实验确认GMNL-346系透过何种机制 抑制口腔癌细胞生长。
细胞凋亡试验:
将口腔癌细胞(SAS),预先处理细胞凋亡抑制剂,包含z-VAD-FMK(广泛 型caspase抑制剂)或z-DEVD-FMK(caspase-3抑制剂),并以DMSO作为未加 细胞凋亡抑制剂的对照组(GMNL-346+DMSO),接着加入稀释后的GMNL-346 热杀死菌全菌液,共同培养72小时后,以细胞增生呈色分析法(WST-1assay) 确认细胞生长情形。
细胞周期分析实验一:
利用BrdU流式细胞仪试剂组(Cat.No.559619,BD Biosciences,USA)确 认细胞周期分布比例的变化,具体地作法为,以GMNL-346热杀死菌全菌液(5 x 108细菌/毫升)处理口腔癌细胞,72小时后,使用70%酒精固定该细胞,接 着在固定好的细胞中加入带有FITC绿色荧光的BrdU抗体,以标定处于S期 的细胞,并以7-aminoactinomycin D(7-AAD)DNA染剂标定处于G1与G2时 期的细胞,然后使用流式细胞仪分析荧光值。
细胞周期分析实验二:
细胞周期的调控非常复杂,有大量的调节蛋白参与,其中:
周期蛋白依赖性激酶(CDKs)和周期素蛋白(Cyclins)系决定细胞何时 进入下一个周期的关键蛋白(细胞周期检查点,Cell cycle checkpoint);
视网膜母细胞瘤蛋白(Retinoblastoma protein,pRb)为一种可与E2F转录 因子结合的蛋白,pRb可透过抑制细胞周期进程而防止细胞过度生长。当细胞 准备要复制***时,在从G1时期进到S时期前,周期素蛋白D(Cyclin D)与 CDK4/6所形成复合体会磷酸化pRb,使之成为ppRb,被磷酸化的pRb会失去 抑制细胞周期进程的活性,释放出E2F转录因子,而被释放的E2F转录因子 则会进一步激活下游其他的周期素蛋白(如cyclin E、cyclinA1和cyclin B)及 一系列有关DNA合成复制的基因,使细胞周期进行下去;
细胞周期抑制蛋白(Cell cycle inhibitory protein,CKI)则系可以透过抑制CDK或CDK-cyclin复合物活性,以调节细胞周期之进程的蛋白;p16-INK4a 即为G1时期的细胞周期抑制蛋白,其可与CDK 4/6结合并抑制CDK 4/6的活 性。
细胞周期分析实验二系利用西方墨点法(Western blot)分析细胞周期相关 蛋白的表现量,具体地作法为,以GMNL-346热杀死菌全菌液(5x 108细菌/ 毫升)或稀释20倍的GMNL-346热杀菌体上清液处理口腔癌细胞后,在不同 时间点收集该细胞并萃取蛋白质,以磷酸化-Rb(ppRb)、原型Rb(pRb)、 p16-INK4a、周期蛋白依赖性激酶4(CDK4)、或周期蛋白依赖性激酶6(CDK6) 的一级抗体确认该等蛋白表现量,并以持家基因(β-actin或GAPDH)作为内 部参照(internal control),以无处理的口腔癌细胞作为控制组。
细胞凋亡试验及细胞周期分析实验结果:
结果如图5~8所示。从图5的细胞凋亡试验结果可发现,GMNL-346即使 在细胞凋亡抑制剂的存在下,仍可抑制口腔癌细胞增生,此结果说明 GMNL-346不是透过引发细胞凋亡的机制来抑制口腔癌细胞的生长。
在图6及表1的细胞周期分析结果中发现,经GMNL-346处理过的口腔癌 细胞,其细胞周期的比例分布明显改变,G0/G1时期的细胞比例变多,进入 DNA复制的合成期(S时期)的细胞比例明显减少。此结果说明GMNL-346会 使口腔癌细胞停滞在G0/G1时期,使之无法复制***新的细胞,藉此抑制口腔 癌细胞生长。
表1
而由图7的西方墨点法结果可知,处理GMNL-346可使口腔癌细胞的ppRb (磷酸化-Rb)表现量明显下降,且随着处理时间越久,ppRb表现量下降越多。 此结果表示GMNL-346可透过抑制pRb磷酸化,使口腔癌细胞的细胞周期滞 留在G0/G1时期,进而导致口腔癌细胞生长被抑制。
另外,在图8的西方墨点法结果中发现,GMNL-346热杀死菌全菌液及稀 释20倍的GMNL-346热杀菌体上清液(GMNL-346sup 20X diluted)皆能使 p16-INK4a表现量明显上升。此结果表示GMNL-346系藉由提升p16-INK4a表 现量,利用p16-INK4a抑制CDK 4/6的活性,使pRb无法磷酸化,造成口腔 癌细胞的细胞周期被抑制(G1 arrest)。
实施例三、GMNL-346对口腔癌细胞的自我更新能力之影响
癌症干细胞或较恶性癌细胞有较好的自我更新能力,能以极少的数量增生 ***形成球体,具有极高形成肿瘤并发展成癌症的潜力。为了解GMNL-346 对口腔癌细胞自我更新能力之影响,利用癌症球体培养,分析口腔癌细胞中癌 干细胞活性。
具体作法为,将口腔癌细胞培养在极致低细胞贴附表面处理培养皿中,以 无胎牛血清之DMEM/F12培养基(含20ng/ml表皮生长因子(epidermal growth factor,EGF)、20ng/ml碱性纤维母细胞生长因子(basic fibroblast growth factor, bFGF)、1X B27补充物(B27 supplement)、1μM氢皮质酮(hydrocortisone)、5μg/ml胰岛素(insulin)、4μg/ml肝素(Heparin))进行癌症球体培养,并加 入GMNL-346热杀死菌全菌液(5x 107或5x 108细菌/毫升)共同培养7天后, 以倒立式显微镜观察并计算口腔癌细胞癌症球体的数目。
结果如图9所示,处理GMNL-346的会造成口腔癌细胞的癌症球体数目下 降,尤其以处理5x 108细菌/毫升的GMNL-346效果为佳,此结果显示 GMNL-346具有抑制口腔癌细胞内的癌干细胞自我更新能力,可降低肿瘤生成 的机率。
实施例四、GMNL-346于小鼠口腔癌模型之治疗效果
肿瘤生长实验:
如图10中A所示方式进行口腔癌动物模型实验,小鼠在植入口腔癌细胞 前先管喂GMNL-346热杀死菌全菌液(1x109菌量),连续给予两日。接着将口 腔癌细胞以皮下种植方式种植于小鼠背部,30天后肿瘤形成,开始以每周管喂 5日方式给予小鼠GMNL-346热杀死菌全菌液(1x109菌量),给予4周后,牺 牲小鼠,取出肿瘤并量测重量。
存活率分析实验:
存活率分析实验流程同前述肿瘤生长实验,在植入口腔癌细胞至小鼠背部 当日视为实验第0天,待30天肿瘤生长至约50mm3大小后,以每周管喂5日、 每日一次方式给予小鼠GMNL-346热杀死菌全菌液(1x109菌量),连续4个星 期喂食,记录59天中小鼠存活情形。
免疫组织化学染色实验:
小鼠肿瘤取下后,经***溶液固定后石蜡包埋组织切片,以免疫组织 化学染色来分析肿瘤中的肿瘤细胞增生标志Ki-67、协助细胞***的周期素蛋 白A2(Cyclin A2)、及原型Rb(pRb)等蛋白质的表现量。
实验结果:
实验结果如图10~图11所示,由图10中B的肿瘤生长实验结果可知, 给予小鼠GMNL-346有效减缓小鼠的肿瘤生长速度,使生成的肿瘤明显较小。 而图10中C的小鼠存活率分析实验结果中,也可看到给予小鼠GMNL-346 能有效延长有肿瘤小鼠的存活时间。由该等实验结果可得知,GMNL-346确实 有抗口腔癌之能力。此外,从图11的免疫组织化学染色实验结果可看出,喂 食GMNL-346的小鼠,其肿瘤细胞增生标志Ki-67与协助细胞***的周期素蛋 白A2,两种蛋白表现量降低,且原型Rb(pRb)表现量增加,代表喂食 GMNL-346可抑制小鼠肿瘤生长。以上染色结果也与先前细胞实验结果相符合。
实施例五、GMNL-346之抗口腔癌活性物质分析
为了解GMNL-34能抑制口腔癌细胞生长的活性物质为何,将实施例一之 GMNL-346热杀死菌全菌液(1x1010细菌/毫升)经高速离心后,收集其上清液 并通过0.22μm滤膜过滤去除菌体后,得到一GMNL-346热杀菌体上清液,再 进一步分析该热杀菌体上清液抑制口腔癌细胞生长的效果。
结果由图12所示,GMNL-346热杀菌体上清液不会影响正常口腔细胞(SG) 的生长,而10倍稀释的GMNL-346热杀菌体上清液与GMNL-346菌体皆能杀 死口腔癌细胞(SAS),且,GMNL-346热杀菌体上清液可杀死高达80%的口腔 癌细胞,是GMNL-346菌体的两倍之多。相似的结果,也可在100倍稀释的 GMNL-346热杀菌体上清液实验组中发现。由此结果可推断,GMNL-346抑制 口腔癌细胞生长的活性成份主要存在于热杀菌体上清液中。
本发明进一步将前述热杀菌体上清液通过3kDa Amicon滤膜,把热杀菌 体上清液依分子量大小分离成两部份,并测试其抑制口腔癌细胞生长的效果, 结果如图13所示,只有含有小于3kDa蛋白质的热杀菌体上清液才具有抑制 口腔癌细胞生长的能力,含大分子量蛋白质的热杀菌体上清液则不影响口腔癌 细胞生长。
本案发明人在经多年研究后,成功分离出副干酪乳杆菌GMNL-346,该副 干酪乳杆菌GMNL-346不仅可透过抑制细胞周期进程或抑制癌干细胞自我更 新来抑制口腔癌细胞生长,且对正常口腔细胞不具毒性,非常适合作为预防或 治疗口腔癌的有效成分。本案发明人另证实除了副干酪乳杆菌GMNL-346之 菌体外,其热杀菌体之上清液,亦具有抑制口腔癌细胞生长之功效,且以含有 小于3kDa分子之部分的抗口腔癌效果为佳。
于本说明书较佳实施例揭示之内容,本发明所属领域具有通常知识者可明 显得知前述实施例仅为例示;具本发明所属技术领域通常知识者可藉由诸多变 换、替换而实施,而不与本发明之技术特征有所差异。依据说明书实施例,本 发明可有多种变换仍无碍于实施。本说明书提供之请求项界定本发明之范围, 该范围涵盖前述方法与结构及与其相等之发明。
生物材料寄存
台湾,新竹食品工业发展研究所生物资源保存及研究中心、寄存日期为 2019年11月6日、寄存编号为BCRC 910953。
中国典型培养物保藏中心、寄存日期为2019年11月28日、寄存编号为 CCTCC M2019983。
Claims (12)
1.一种组合物,其特征在于,包含一具抗口腔癌功效的有效成分,其中所述有效成分为副干酪乳杆菌GMNL-346或其热杀菌体上清液,所述副干酪乳杆菌GMNL-346的寄存编号为BCRC 910953或CCTCC M 2019983。
2.根据权利要求1所述的组合物,其特征在于,所述有效成分为所述副干酪乳杆菌GMNL-346的死菌体。
3.根据权利要求1所述的组合物,其特征在于,所述有效成分为所述热杀菌体上清液依分子量大小分离所得之含有小于3千道尔顿之分子的部分。
4.根据权利要求1所述的组合物,其特征在于,所述组合物为医药组合物、营养补充品或保健食品。
5.根据权利要求4所述的组合物,其特征在于,所述组合物可进一步包含药学上可接受之载剂。
6.根据权利要求4所述的组合物,其特征在于,所述组合物系溶液、悬浮液、乳剂、粉末、锭剂、丸剂、糖浆、***锭、片剂、口嚼胶、浓浆或胶囊。
7.根据权利要求4所述的组合物,其特征在于,所述组合物可进一步包含一可食性材料,所述可食性材料包含但不限于水、流体乳品、牛奶、浓缩牛奶、酸奶、酸乳、冷冻优格、乳杆菌发酵饮料、奶粉、冰淇淋、奶酪、干酪、豆奶、发酵豆奶、蔬果汁、果汁、运动饮料、甜点、果冻、糖果、婴儿食品、健康食品、动物饲料、中草药材或膳食补充品。
8.一种副干酪乳杆菌用于制备预防或治疗口腔癌之医药组合物的用途,其特征在于,包含使用副干酪乳杆菌或其热杀菌体上清液作为预防或治疗口腔癌的有效成分。
9.根据权利要求8所述的用途,其特征在于,所述副干酪乳杆菌为副干酪乳杆菌GMNL-346,所述副干酪乳杆菌GMNL-346的寄存编号为BCRC 910953或CCTCC M 2019983。
10.根据权利要求8或9所述的用途,其特征在于,所述预防或治疗口腔癌系抑制口腔癌细胞的细胞周期进程。
11.根据权利要求10所述的用途,其特征在于,所述抑制口腔癌细胞的细胞周期进程系使口腔癌细胞的细胞周期滞留在G0/G1时期。
12.根据权利要求8或9所述的用途,其特征在于,所述预防或治疗口腔癌系抑制口腔癌细胞内的癌干细胞自我更新能力。
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