TW202126318A - 一種副乾酪乳桿菌gmnl-346用於抗口腔癌之用途 - Google Patents
一種副乾酪乳桿菌gmnl-346用於抗口腔癌之用途 Download PDFInfo
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Abstract
本發明提供一種副乾酪乳桿菌用於製備預防或治療口腔癌之醫藥組合物的用途,其係包含使用副乾酪乳桿菌(Lactobacillus paracasei)或其熱殺菌體上清液作為預防或治療口腔癌的有效成分;本發明另提供一種組合物,其係包含一具抗口腔癌功效的有效成分,其中該有效成分為副乾酪乳桿菌GMNL-346(Lactobacillus paracasei GMNL-346)或其熱殺菌體上清液,該副乾酪乳桿菌GMNL-346的寄存編號為BCRC 910953或CCTCC M 2019983。
Description
本發明係關於乳桿菌分離株,特別係關於副乾酪乳桿菌用於抗口腔癌之技術領域。
根據美國2018年最新統計,口腔癌為男性十大癌症中排名第八位,發生率為女性的2.58倍。口腔癌初期病患的五年存活率雖高達84%,但隨著腫瘤越惡性,病患的五年存活率僅剩39%[1]。在台灣,口腔癌高居男性腫瘤發生率及死亡原因的第四位[2],其與嚼檳榔、抽菸、飲酒等危險因子極為相關。最近多項研究指出,口腔微生物菌叢失調與免疫反應紊亂會引響口腔的健康,例如,牙齦卟啉單胞菌(Porphyromonas gingivalis)除了是牙周病的主要致病菌外,牙齦卟啉單胞菌的慢性感染更可能造成口腔癌的生成及促使口腔癌惡化[3]。口腔癌有90%屬於鱗狀細胞癌,包含舌癌、口腔部位之癌症、口咽癌、下咽癌,其中以舌頭與口腔的頰黏膜為好發區域。傳統口腔癌治療以手術切除與放射治療或合併化學及放射線治療。近年來受到矚目的免疫療法,於口腔癌治療相關的動物實驗與臨床試驗中,也展現了相當的潛力。例如,原位口腔癌小鼠實驗中,可藉由抑制程式性細胞
死亡-1(Programmed cell death protein 1,PD-1)或細胞程式死亡-配體1(Programmed death-ligand 1,PD-L1)來調控T淋巴細胞的功能,增強口腔癌放射治療效果,延長小鼠存活率[4]。
過去研究發現,益生菌具有許多功效,包括平衡腸道微生物菌叢、改善胃腸道屏障、抑制腸道中潛在的病原菌或癌症生成,因此,益生菌被視為癌症預防與治療的新策略。例如,鼠李糖乳桿菌GG株(Lactobacillus rhamnosus GG,LGG)與青春雙歧桿菌SPM0212株(Bifidobacterium adolescentis SPM0212)能抑制胃癌與大腸癌細胞生長;乳酸桿菌(Lactobacillus kefiri)能引起骨髓性白血病細胞的細胞凋亡;乳酸腸球菌IW5株(Enterococcus lactis IW5)能降低多種癌細胞的存活率[5]。又如,長期食用養樂多代田菌(Lactobacillus casei Shirota(BLS)),可降低乳癌、膀胱癌及人類乳突病毒相關的子宮頸癌發生率[6-8]。然而,目前關於益生菌用於口腔癌之研究非常稀少。本發明所屬技術領域尚欠缺一可有效抑制口腔癌之菌株。
參考文獻
[1] CA Cancer J Clin. 2018 Jan; 68(1):7-30.
[2]衛生福利部國民健康署105年癌症登記年報。
[3] J Oral Microbiol. 2019; 11(1): 1563410.
[4] Oncoimmunology. 2017 Aug 3; 6(10):e1356153.
[5] Biomed Res Int. 2018; 2018: 3428437.
[6] Curr Nutr Food Sci. 2013 Aug; 9(3):194-200.
[7] Urologia Internationalis. 2002; 68(4):273-280.
[8] European Journal of Cancer Prevention. 2013; 22(1):46-51.
本案發明人深刻瞭解先前技術之不足,乃亟思加以創新研發,並經多年苦心研究後,終於成功分離出本發明所提供的副乾酪乳桿菌GMNL-346(Lactobacillus paracasei GMNL-346),並證實其具有抗口腔癌之功效。
本發明之目的在於提供一種組合物,其係包含一具抗口腔癌功效的有效成分,其中該有效成分為副乾酪乳桿菌GMNL-346(Lactobacillus paracasei GMNL-346)或其熱殺菌體上清液,該副乾酪乳桿菌GMNL-346的寄存編號為BCRC 910953或CCTCC M 2019983。
為達成前述發明目的,其中該有效成分為該副乾酪乳桿菌GMNL-346的死菌體。
為達成前述發明目的,其中該有效成分為該熱殺菌體上清液依分子量大小分離所得之含有小於3千道爾頓(kDa)之分子的部分。
為達成前述發明目的,其中該組合物為醫藥組合物、營養補充品或保健食品。
為達成前述發明目的,其中該組合物可進一步包
含藥學上可接受之載劑。
為達成前述發明目的,其中該組合物係溶液、懸浮液、乳劑、粉末、錠劑、丸劑、糖漿、口含錠、片劑、口嚼膠、濃漿或膠囊。
為達成前述發明目的,其中該組合物可進一步包含一可食性材料,該可食性材料包含但不限於水、流體乳品、牛奶、濃縮牛奶、優酪乳、酸乳、冷凍優格、乳桿菌發酵飲料、奶粉、冰淇淋、乳酪、乾酪、豆奶、發酵豆奶、蔬果汁、果汁、運動飲料、甜點、果凍、糖果、嬰兒食品、健康食品、動物飼料、中草藥材或膳食補充品。
本發明之另一目的在於提供一種副乾酪乳桿菌用於製備預防或治療口腔癌之醫藥組合物的用途,其係包含使用副乾酪乳桿菌(Lactobacillus paracasei)或其熱殺菌體上清液作為預防或治療口腔癌的有效成分。
為達成前述發明目的,其中該副乾酪乳桿菌為副乾酪乳桿菌GMNL-346,該副乾酪乳桿菌GMNL-346的寄存編號為BCRC 910953或CCTCC M 2019983。
為達成前述發明目的,其中該預防或治療口腔癌係抑制口腔癌細胞的細胞週期進程。
為達成前述發明目的,其中該抑制口腔癌細胞的細胞週期進程係使口腔癌細胞的細胞週期滯留在G0/G1時期。
為達成前述發明目的,其中該預防或治療口腔癌
係抑制口腔癌細胞內的癌幹細胞自我更新能力。
本發明提供了一種副乾酪乳桿菌菌株GMNL-346,該菌株具有抑制口腔癌細胞生長之功效,尤其係具有抑制口腔癌細胞的細胞週期進程或抑制口腔癌細胞內的癌幹細胞自我更新能力之功效。本發明更提供了一種以副乾酪乳桿菌GMNL-346或其熱殺菌體上清液作為抗口腔癌之有效成分的組合物,本發明所提供的組合物因係以益生菌作為有效成分,故具有副作用低之優勢。
第1圖係兩批不同批次培養之副乾酪乳桿菌GMNL-346對口腔癌細胞生長的影響,(A)係口腔癌細胞處理第一批次培養的乾酪乳桿菌GMNL-346,(B)係口腔癌細胞處理第二批次培養的乾酪乳桿菌GMNL-346;
第2圖係副乾酪乳桿菌GMNL-346對正常口腔細胞生長的影響;
第3圖係使用錐藍質排除分析(Trypan blue exclusion assay)分析副乾酪乳桿菌GMNL-346對口腔癌細胞生長的影響;
第4圖係處理副乾酪乳桿菌GMNL-346對口腔癌細胞生長曲線的影響;
第5圖係口腔癌細胞處理副乾酪乳桿菌GMNL-346的細胞
凋亡試驗結果圖;
第6圖係口腔癌細胞處理副乾酪乳桿菌GMNL-346的細胞週期分析實驗結果圖;
第7圖係副乾酪乳桿菌GMNL-346對口腔癌細胞的細胞週期蛋白表現量之影響的結果圖(一);
第8圖係副乾酪乳桿菌GMNL-346對口腔癌細胞的細胞週期蛋白表現量之影響的結果圖(二);
第9圖係副乾酪乳桿菌GMNL-346對口腔癌細胞內的癌幹細胞自我更新能力之影響的結果圖;
第10圖係GMNL-346於小鼠口腔癌模型之治療效果圖,(A)係實驗時間軸,(B)係腫瘤生長實驗結果,(C)係存活率分析實驗結果;
第11圖係GMNL-346於小鼠口腔癌模型之免疫組織化學染色實驗結果圖;
第12圖係GMNL-346熱殺菌體上清液或GMNL-346菌體對口腔癌細胞的抑制效果;
第13圖係GMNL-346熱殺死菌全菌液之不同部分對口腔癌細胞的抑制效果。
本說明書中所述之所有技術性及科學術語,除非另外有所定義,皆為該所屬領域具有通常技藝者可共同瞭解的意義。
本說明書及申請專利範圍中所述之單數用語「一」、「一個」、「該」,除非另有說明,皆可指涉多於一個對象。
本說明書使用之「或」、「以及」、「和」,除非另有說明,皆指涉「或/和」。此外,用語「包含」、「包括」皆非有所限制之開放式連接詞。前述段落僅為系統性之指涉而不應解釋為對發明主體之限制。
本說明書用語「口腔癌」係指口腔部位之惡性腫瘤的總稱,其係包含但不限於鱗狀上皮細胞癌、疣狀癌、腺樣囊狀癌或黏液表皮樣癌。
術語「治療」、「用於治療」以及其類用語係指稱延緩、改善、減少、或逆轉患者所罹患之可診斷病症以及該病症造成之相關症狀的方法以及預防該病症或任何其所屬之相關症狀的方法。
術語「藥學上可接受」係指稱物質或組合物必須與其藥學上調配物之其他成分相容,且不加劇患者之症狀。
本發明提供之組合物係可利用本發明所屬技術領域具有通常知識者所詳知的技術,將本案所提供之有效成分或組合物,與至少一藥學上可接受之載劑(vehicle),製備一適用本發明組合物之劑型。其中該劑型包含但不限於溶液、乳劑、懸浮液、粉末、錠劑、口含錠、藥片、口嚼膠、膠囊以及其他類似或適用本發明之劑型。
術語「藥學上可接受之載劑」包含一種或多種選自於下列的成分類型:溶劑、乳化劑、懸浮劑、分解劑、黏結劑、賦形劑、安定劑、螯合劑、稀釋劑、膠凝劑、防腐劑、潤滑劑、表面活性劑、及其他類似或適用於本發明之載劑。
前述組合物中,亦可依需適宜地添加一種或多種以上製劑領域內通常使用之溶解輔助劑、緩衝劑、著色劑、調味劑等。
術語「藥學上可接受之賦形劑」包括但不限於,聚合物、樹脂、增塑劑、填料、潤滑劑、稀釋劑、黏合劑、崩解劑、溶劑、共一溶劑、界面活性劑、防腐劑、甜味劑、調味劑、藥學級的染料或顏料、及黏度劑至少一者。
術語「醫藥組合物」係指稱一固體或液體組成物,其形式、濃度和純度程度適合投予給患者,在投予之後,其可誘發所欲生理變化;醫藥組成物為無菌及/或非發熱性者(non-pyrogenic)。
術語「有效量」係指稱產生、造成預期之生物體反應所必須之劑量,且非以治療痊癒所需為定量。本發明所屬技術領域具通常知識者可理解,醫藥組合物之有效量可視諸如下列等因素而變化:期望生物終點、擬遞送生物活性劑、囊封基質(encapsulating matrix)之組成、目標組織等等。
本發明所使用之材料,除有特別指明者,皆為市售易於取得之材料。本發明實施例中所使用之副乾酪乳菌為
副乾酪乳桿菌GMNL-346(Lactobacillus paracasei GMNL-346,以下簡稱GMNL-346),其係寄存於台灣食品工業研究所,編號為BCRC 910953、中國典型培養物保藏中心(CCTCC),寄存編號為CCTCC M 2019983。
本發明實施例中的細胞實驗係以人類口腔癌細胞株(SAS,Human tongue squamous carcinoma cell line(RRID:CVCL_1675);以下簡稱口腔癌細胞)作為副乾酪乳桿菌抗口腔癌之功效驗證細胞,並使用人類正常口腔細胞株(SG,Smulow-Glickman(SG)human gingival epithelial cell;以下簡稱正常口腔細胞)作為對照組,該等細胞株皆可於市面上購得。
本發明實施例中的動物實驗係使用8-12周齡大的雄性CAnN.Cg-Foxn1nu/CrlNarl免疫缺陷小鼠,其係購買自國家實驗動物中心,小鼠的飼養環境控制在室溫(24±1℃),溼度為55±5%,並維持各十二小時之白日黑夜光照周期,及允許自由進食及飲水。
本發明之新穎技術特徵,包含特定特徵,係揭示於申請專利範圍,針對本發明之技術特徵,較佳之理解茲配合說明書、依據本發明原理之實施例、和圖式將本發明較佳之實施例詳細說明。
本發明係以下面的實施例予以示範闡明,但本發明不受下述實施例所限制。
實施例一、GMNL-346抑制口腔癌細胞生長測試
將GMNL-346以37℃,5% CO2條件培養於培養基(DeMan-Rogosa-Sharpe,MRS)中,48小時後,經離心去除培養液後,以磷酸鹽緩衝溶液(Phosphate buffer saline,PBS)回溶菌體,再以121℃高溫加熱15分鐘,製成GMNL-346熱殺死菌全菌液。將所得之GMNL-346熱殺死菌全菌液經高速離心後,收集上清液並通過0.22μm濾膜過濾去除菌體後,即為GMNL-346熱殺菌體上清液。
口腔癌細胞或正常口腔細胞分別處理兩批不同批次培養(第1圖A與B)之不同濃度的GMNL-346熱殺死菌全菌液(2.5x101~2.5x108細菌/毫升),72小時後,使用細胞增生呈色分析法(WST-1 assay)測量細胞生長情形,或以錐藍質排除分析(Trypan blue exclusion assay)直接計算細胞數目。
結果如第1~4圖所示,GMNL-346可抑制口腔癌細胞(SAS)生長,但不會對正常口腔細胞(SG)產生毒性。由第1圖可發現,GMNL-346抑制口腔癌細胞生長的效果會隨著處理的菌液濃度增加而提升,其中,2.5x108細菌/毫升的菌液可抑制50%的口腔癌細胞生存;且,由第2圖可發現,GMNL-346對正常口腔細胞沒有明顯毒性,正常口腔細胞在經2.5x108細菌/毫升的菌液處理後,生存力(cell viability)仍大於85%,此結果表示GMNL-346可特異性抑制口腔癌細胞的生長,但不會影響正常細胞,使用GMNL-346作為治療/抗口腔
癌有效成分,具有減低癌症治療之副作用傷害的優勢。另外,由第3圖的錐藍質排除分析結果亦可發現,GMNL-346確實能有效抑制口腔癌細胞生長;且第4圖結果顯示,隨著GMNL-346處理時間越久,口腔癌細胞生長抑制越明顯,在第48小時,GMNL-346便可明顯抑制口腔癌細胞生長,該抑制效果可持續直至96小時。
實施例二、GMNL-346抑制口腔癌細胞生長之機制
利用細胞凋亡試驗及細胞週期分析實驗確認GMNL-346係透過何種機制抑制口腔癌細胞生長。
細胞凋亡試驗:
將口腔癌細胞(SAS),預先處理細胞凋亡抑制劑,包含z-VAD-FMK(廣泛型caspase抑制劑)或z-DEVD-FMK(caspase-3抑制劑),並以DMSO作為未加細胞凋亡抑制劑的對照組(GMNL-346+DMSO),接著加入稀釋後的GMNL-346熱殺死菌全菌液,共同培養72小時後,以細胞增生呈色分析法(WST-1 assay)確認細胞生長情形。
細胞週期分析實驗一:
利用BrdU流式細胞儀試劑組(Cat.No.559619,BD Biosciences,USA)確認細胞週期分佈比例的變化,具體地作法為,以GMNL-346熱殺死菌全菌液(5 x 108細菌/毫升)處理口腔癌細胞,72小時後,使用70%酒精固定該細胞,接
著在固定好的細胞中加入帶有FITC綠色螢光的BrdU抗體,以標定處於S期的細胞,並以7-aminoactinomycin D(7-AAD)DNA染劑標定處於G1與G2時期的細胞,然後使用流式細胞儀分析螢光值。
細胞週期分析實驗二:
細胞週期的調控非常複雜,有大量的調節蛋白參與,其中:
(1)週期蛋白依賴性激酶(CDKs)和週期素蛋白(Cyclins)係決定細胞何時進入下一個週期的關鍵蛋白(細胞週期檢查點,Cell cycle checkpoint);
(2)視網膜母細胞瘤蛋白(Retinoblastoma protein,pRb)為一種可與E2F轉錄因子結合的蛋白,pRb可透過抑制細胞週期進程而防止細胞過度生長。當細胞準備要複製分裂時,在從G1時期進到S時期前,週期素蛋白D(Cyclin D)與CDK4/6所形成複合體會磷酸化pRb,使之成為ppRb,被磷酸化的pRb會失去抑制細胞週期進程的活性,釋放出E2F轉錄因子,而被釋放的E2F轉錄因子則會進一步激活下游其他的週期素蛋白(如cyclin E、cyclin A1和cyclin B)及一系列有關DNA合成複製的基因,使細胞週期進行下去;
(3)細胞週期抑制蛋白(Cell cycle inhibitory protein,CKI)則係可以透過抑制CDK或CDK-cyclin複合物活性,以調節細胞週期之進程的蛋白;p16-INK4a即為G1時期的細胞週期
抑制蛋白,其可與CDK 4/6結合並抑制CDK 4/6的活性。
細胞週期分析實驗二係利用西方墨點法(Western blot)分析細胞週期相關蛋白的表現量,具體地作法為,以GMNL-346熱殺死菌全菌液(5 x 108細菌/毫升)或稀釋20倍的GMNL-346熱殺菌體上清液處理口腔癌細胞後,在不同時間點收集該細胞並萃取蛋白質,以磷酸化-Rb(ppRb)、原型Rb(pRb)、p16-INK4a、週期蛋白依賴性激酶4(CDK4)、或週期蛋白依賴性激酶6(CDK6)的一級抗體確認該等蛋白表現量,並以持家基因(β-actin或GAPDH)作為內部參照(internal control),以無處理的口腔癌細胞作為控制組。
細胞凋亡試驗及細胞週期分析實驗結果:
結果如第5~8圖所示。從第5圖的細胞凋亡試驗結果可發現,GMNL-346即使在細胞凋亡抑制劑的存在下,仍可抑制口腔癌細胞增生,此結果說明GMNL-346不是透過引發細胞凋亡的機制來抑制口腔癌細胞的生長。
在第6圖及表1的細胞週期分析結果中發現,經GMNL-346處理過的口腔癌細胞,其細胞週期的比例分佈明顯改變,G0/G1時期的細胞比例變多,進入DNA複製的合成期(S時期)的細胞比例明顯減少。此結果說明GMNL-346會使口腔癌細胞停滯在G0/G1時期,使之無法複製分裂新的細胞,藉此抑制口腔癌細胞生長。
而由第7圖的西方墨點法結果可知,處理GMNL-346可使口腔癌細胞的ppRb(磷酸化-Rb)表現量明顯下降,且隨著處理時間越久,ppRb表現量下降越多。此結果表示GMNL-346可透過抑制pRb磷酸化,使口腔癌細胞的細胞週期滯留在G0/G1時期,進而導致口腔癌細胞生長被抑制。
另外,在第8圖的西方墨點法結果中發現,GMNL-346熱殺死菌全菌液及稀釋20倍的GMNL-346熱殺菌體上清液(GMNL-346sup 20X diluted)皆能使p16-INK4a表現量明顯上升。此結果表示GMNL-346係藉由提升p16-INK4a表現量,利用p16-INK4a抑制CDK 4/6的活性,使pRb無法磷酸化,造成口腔癌細胞的細胞週期被抑制(G1 arrest)。
實施例三、GMNL-346對口腔癌細胞的自我更新能力之影響
癌症幹細胞或較惡性癌細胞有較好的自我更新能力,能以極少的數量增生分裂形成球體,具有極高形成腫瘤並發展成癌症的潛力。為了解GMNL-346對口腔癌細胞自我
更新能力之影響,利用癌症球體培養,分析口腔癌細胞中癌幹細胞活性。
具體作法為,將口腔癌細胞培養在極致低細胞貼附表面處理培養皿中,以無胎牛血清之DMEM/F12培養基(含20ng/ml表皮生長因子(epidermal growth factor,EGF)、20ng/ml鹼性纖維母細胞生長因子(basic fibroblast growth factor,bFGF)、1X B27補充物(B27 supplement)、1μM氫皮質酮(hydrocortisone)、5μg/ml胰島素(insulin)、4μg/ml肝素(Heparin))進行癌症球體培養,並加入GMNL-346熱殺死菌全菌液(5 x 107或5 x 108細菌/毫升)共同培養7天後,以倒立式顯微鏡觀察並計算口腔癌細胞癌症球體的數目。
結果如第9圖所示,處理GMNL-346的會造成口腔癌細胞的癌症球體數目下降,尤其以處理5 x 108細菌/毫升的GMNL-346效果為佳,此結果顯示GMNL-346具有抑制口腔癌細胞內的癌幹細胞自我更新能力,可降低腫瘤生成的機率。
實施例四、GMNL-346於小鼠口腔癌模型之治療效果
腫瘤生長實驗:
如第10圖A所示方式進行口腔癌動物模型實驗,小鼠在植入口腔癌細胞前先管餵GMNL-346熱殺死菌全菌液(1x109菌量),連續給予兩日。接著將口腔癌細胞以皮下種植方式種植於小鼠背部,30天後腫瘤形成,開始以每週管餵5
日方式給予小鼠GMNL-346熱殺死菌全菌液(1x109菌量),給予4週後,犧牲小鼠,取出腫瘤並量測重量。
存活率分析實驗:
存活率分析實驗流程同前述腫瘤生長實驗,在植入口腔癌細胞至小鼠背部當日視為實驗第0天,待30天腫瘤生長至約50mm3大小後,以每週管餵5日、每日一次方式給予小鼠GMNL-346熱殺死菌全菌液(1x109菌量),連續4個星期餵食,記錄59天中小鼠存活情形。
免疫組織化學染色實驗:
小鼠腫瘤取下後,經福馬林溶液固定後石蠟包埋組織切片,以免疫組織化學染色來分析腫瘤中的腫瘤細胞增生標誌Ki-67、協助細胞分裂的週期素蛋白A2(Cyclin A2)、及原型Rb(pRb)等蛋白質的表現量。
實驗結果:
實驗結果如第10~11圖所示,由第10圖B的腫瘤生長實驗結果可知,給予小鼠GMNL-346有效減緩小鼠的腫瘤生長速度,使生成的腫瘤明顯較小。而第10圖C的小鼠存活率分析實驗結果中,也可看到給予小鼠GMNL-346能有效延長有腫瘤小鼠的存活時間。由該等實驗結果可得知,GMNL-346確實有抗口腔癌之能力。此外,從第11圖的免疫組織化學染色實驗結果可看出,餵食GMNL-346的小鼠,其腫瘤細胞增生標誌Ki-67與協助細胞分裂的週期素蛋白A2,兩種蛋白表現量
降低,且原型Rb(pRb)表現量增加,代表餵食GMNL-346可抑制小鼠腫瘤生長。以上染色結果也與先前細胞實驗結果相符合。
實施例五、GMNL-346之抗口腔癌活性物質分析
為了解GMNL-34能抑制口腔癌細胞生長的活性物質為何,將實施例一之GMNL-346熱殺死菌全菌液(1x1010細菌/毫升)經高速離心後,收集其上清液並通過0.22μm濾膜過濾去除菌體後,得到一GMNL-346熱殺菌體上清液,再進一步分析該熱殺菌體上清液抑制口腔癌細胞生長的效果。
結果由第12圖所示,GMNL-346熱殺菌體上清液不會影響正常口腔細胞(SG)的生長,而10倍稀釋的GMNL-346熱殺菌體上清液與GMNL-346菌體皆能殺死口腔癌細胞(SAS),且,GMNL-346熱殺菌體上清液可殺死高達80%的口腔癌細胞,是GMNL-346菌體的兩倍之多。相似的結果,也可在100倍稀釋的GMNL-346熱殺菌體上清液實驗組中發現。由此結果可推斷,GMNL-346抑制口腔癌細胞生長的活性成份主要存在於熱殺菌體上清液中。
本發明進一步將前述熱殺菌體上清液通過3kDa Amicon濾膜,把熱殺菌體上清液依分子量大小分離成兩部份,並測試其抑制口腔癌細胞生長的效果,結果如第13圖所示,只有含有小於3kDa蛋白質的熱殺菌體上清液才具有抑制口腔癌細胞生長的能力,含大分子量蛋白質的熱殺菌體上清
液則不影響口腔癌細胞生長。
本案發明人在經多年研究後,成功分離出副乾酪乳桿菌GMNL-346,該副乾酪乳桿菌GMNL-346不僅可透過抑制細胞週期進程或抑制癌幹細胞自我更新來抑制口腔癌細胞生長,且對正常口腔細胞不具毒性,非常適合作為預防或治療口腔癌的有效成分。本案發明人另證實除了副乾酪乳桿菌GMNL-346之菌體外,其熱殺菌體之上清液,亦具有抑制口腔癌細胞生長之功效,且以含有小於3kDa分子之部分的抗口腔癌效果為佳。
於本說明書較佳實施例揭示之內容,本發明所屬領域具有通常知識者可明顯得知前述實施例僅為例示;具本發明所屬技術領域通常知識者可藉由諸多變換、替換而實施,而不與本發明之技術特徵有所差異。依據說明書實施例,本發明可有多種變換仍無礙於實施。本說明書提供之請求項界定本發明之範圍,該範圍涵蓋前述方法與結構及與其相等之發明。
上述多項功效,實屬充分符合新穎性及進步性之法定專利要件,爰依法提出申請,懇請 貴局核准本件發明專利申請案,以勵發明。
新竹食品工業發展研究所生物資源保存及研究中心、寄存日期為2019年11月6日、寄存編號為BCRC 910953。
中國、中國典型培養物保藏中心、寄存日期為2019年11月28日、寄存編號為CCTCC M 2019983。
Claims (12)
- 一種組合物,其係包含一具抗口腔癌功效的有效成分,其中該有效成分為副乾酪乳桿菌GMNL-346(Lactobacillus paracasei GMNL-346)或其熱殺菌體上清液,該副乾酪乳桿菌GMNL-346的寄存編號為BCRC 910953或CCTCC M 2019983。
- 如申請專利範圍第1項所述之組合物,其中該有效成分為該副乾酪乳桿菌GMNL-346的死菌體。
- 如申請專利範圍第1項所述之組合物,其中該有效成分為該熱殺菌體上清液依分子量大小分離所得之含有小於3千道爾頓(kDa)之分子的部分。
- 如申請專利範圍第1項所述之組合物,其中該組合物為醫藥組合物、營養補充品或保健食品。
- 如申請專利範圍第4項所述之組合物,其中該組合物可進一步包含藥學上可接受之載劑。
- 如申請專利範圍第4項所述之組合物,其中該組合物係溶液、懸浮液、乳劑、粉末、錠劑、丸劑、糖漿、口含錠、片劑、口嚼膠、濃漿或膠囊。
- 如申請專利範圍第4項所述之組合物,其中該組合物可進一步包含一可食性材料,該可食性材料包含但不限於水、流體乳品、牛奶、濃縮牛奶、優酪乳、酸乳、冷凍優格、乳桿菌發酵飲料、奶粉、冰淇淋、乳酪、乾酪、豆奶、發酵豆奶、蔬果汁、果汁、運動飲料、甜點、果凍、糖果、嬰兒食品、健康食品、動物飼料、中草藥材或膳食補充品。
- 一種副乾酪乳桿菌用於製備預防或治療口腔癌之醫藥組合物的用途,其 係包含使用副乾酪乳桿菌(Lactobacillus paracasei)或其熱殺菌體上清液作為預防或治療口腔癌的有效成分。
- 如申請專利範圍第8項所述之用途,其中該副乾酪乳桿菌為副乾酪乳桿菌GMNL-346,該副乾酪乳桿菌GMNL-346的寄存編號為BCRC 910953或CCTCC M 2019983。
- 如申請專利範圍第8或9項所述之用途,其中該預防或治療口腔癌係抑制口腔癌細胞的細胞週期進程。
- 如申請專利範圍第10項所述之用途,其中該抑制口腔癌細胞的細胞週期進程係使口腔癌細胞的細胞週期滯留在G0/G1時期。
- 如申請專利範圍第8或9項所述之用途,其中該預防或治療口腔癌係抑制口腔癌細胞內的癌幹細胞自我更新能力。
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