TWI430801B - 使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途 - Google Patents
使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途 Download PDFInfo
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- TWI430801B TWI430801B TW100120648A TW100120648A TWI430801B TW I430801 B TWI430801 B TW I430801B TW 100120648 A TW100120648 A TW 100120648A TW 100120648 A TW100120648 A TW 100120648A TW I430801 B TWI430801 B TW I430801B
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Description
本發明係關於一種抑制癌幹細胞生長或癌細胞轉移(cancer stem cells)之醫藥組成物及其應用，尤指一種含小檗鹼化合物(berberine compounds)以抑制癌幹細胞生長或癌細胞轉移之醫藥組成物以及使用小檗鹼化合物製造抑制癌幹細胞生長或癌細胞轉移的藥劑之用途。
癌症係位於十大死因之一，已連續二十七年為居十大死因之榜首。引發癌症起因主要為：細胞變成異常，且持續的自行分裂，形成更多的異常細胞，就是癌症。
一般腫瘤細胞中，潛存些許具有幹細胞特性的癌細胞，此種癌細胞雖然數量不多，但卻類似幹細胞，可以不斷的進行癌細胞分裂及分化，因此稱之為癌幹細胞。由於癌幹細胞具有極高的抗藥性，西方醫學化學治療藥物難以將之毒殺。因此，常聽到許多經過化療的病患，體內癌症復發的情形，目前生物醫學已知的標準癌症療法，對癌幹細胞根本束手無策。
況且，目前西醫療法所使用之手術、放射線治療、化學療法、賀爾蒙療法、生物製劑療法等，常常對於患者身體產生強烈副作用，因此，若能使用比較溫和，且能抑制癌幹細胞生長或癌細胞轉移之療法，進行癌症治療，對於病患而言將是一大福音。
現今，民眾普遍認以中藥對患者進行治療，屬於比較溫和之治療方法，且具有相當高之市場接受度，而成為一種替代性療法(complementary alternative medicines)。因此，自眾多中藥材之中，經篩選實驗後，可證實某中藥材確實可阻止癌幹細胞進行分裂並抑制癌細胞轉移，勢必可對於癌症治療具有相當之幫助。
本發明之主要目的係在提供一種抑制癌幹細胞生長或癌細胞轉移之醫藥組成物，俾能顯著的減低癌細胞株的細胞存活率，如非小細胞型肺癌細胞(non-small-cell lung carcinoma，NSCLC)，但在有效劑量下不會使正常細胞株受到影響，並且能有效抑制癌細胞轉移。
本發明之另一目的係在提供一種使用小檗鹼化合物製造抑制癌幹細胞生長或癌細胞轉移的藥劑之用途，此藥劑能降低癌細胞增生、轉移以及類癌幹細胞的比例，藥劑亦包含預防與治療癌症之保健食品與臨床治療用藥。
為達成上述目的，本發明之一態樣提供一種抑制癌幹細胞生長或癌細胞轉移之醫藥組成物，包括：一小檗鹼化合物；以及一醫藥上可接受性載體。
本發明之另一態樣提供一種使用小檗鹼化合物製造抑制癌幹細胞生長或癌細胞轉移的藥劑之用途。
本發明抑制癌幹細胞生長或癌細胞轉移之醫藥組成物及上述用途中，該小檗鹼化合物可以在市面上購買而得，例如小檗鹼氯化物(berberine chloride)及其水合物、小檗鹼硫酸鹽(berberine sulfate)、小檗鹼半硫酸鹽(berberine hemisulfate)、小檗鹼硫酸氫鹽(berberine bisulfate)等，或者利用黃連藥材萃取而得。
若萃取黃連藥材，則小檗鹼化合物係包含於黃連萃取物中。舉例而言，可以提供黃連藥材，添加50倍至200倍該黃連藥材重量之水，形成一混合物後，對該混合物加熱萃取持續30分鐘至2小時，或直至該混合物係加熱至體積成為原始體積之四分之一至二分之一，便可以得到一黃連水萃取物。如此，該黃連水萃取物便含有小檗鹼化合物，且該黃連水萃取物可經過乾燥製程，如噴霧乾燥法、冷凍乾燥法、科學中藥造粒法等，形成一乾燥形式的萃取物。
由上述可知，含有小檗鹼化合物且用於抑制癌幹細胞生長或癌細胞轉移之醫藥組成物、抑制癌幹細胞生長或癌細胞轉移之治療方法、以及小檗鹼化合物用於製造抑制癌幹細胞生長或癌細胞轉移的藥劑之用途，同樣落於本發明的範疇中，其中該癌幹細胞或該癌細胞可為非小細胞型肺癌細胞。
綜上所述，本發明上述抑制癌幹細胞生長或癌細胞轉移之醫藥組成物、以及使用小檗鹼化合物製造抑制癌幹細胞生長或癌細胞轉移的藥劑之用途，可以突破癌症治療中無法有效抑制癌幹細胞之瓶頸，進而發展成為預防與治療癌症之保健食品與臨床治療用藥。
本發明將黃連藥材萃取而得之黃連萃取物，經過一系列生物性測試實驗，發現此可以抑制癌幹細胞生長或癌細胞轉移，並對此黃連萃取物初步進行成分分析，而發現黃連萃取物中主要成分為小檗鹼，因此推測小檗鹼化合物應該同樣可以達到相同功效，故利用市面上購得的小檗鹼化合物，配製成溶液形式後同樣進行生物性測試實驗，進而確認小檗鹼與黃連萃取物皆可以達到抑制癌幹細胞生長或癌細胞轉移的功效。
本文所使用的「抑制」一詞，係指將一種含小檗鹼化合物之醫藥組成物，投予患有癌症、具有癌症症狀、或朝癌症發展傾向的主體，以期達到治療、治癒、減輕、減緩、改變、醫治、改善、改進、或影響此病症、其症狀、或朝癌症發展之傾向。「有效劑量」一詞係指能夠對於受抑制主體產生預期療效所需的活性藥劑量。對於有效劑量，本領域具有通常知識者可了解到其會根據投藥路徑、使用賦形劑、以及與其它藥劑共同使用的可能性而改變。
本發明的方法可治療的癌症，包含各種器官的實體或血液腫瘤兩者。實體腫瘤舉例包含：胰腺癌；膀胱癌；大腸直腸癌；乳癌，包括轉移性乳癌；腎癌，例如包括轉移性腎細胞癌；肝癌；肺癌，例如包括非小細胞型肺癌(non-small cell lung cacinoma，NSCLC)、細支氣管肺泡癌(bronchioloalveolar carcinoma，BAC)、和肺腺癌；前列腺癌，包括雄激素依賴性和雄激素非依賴性前列腺癌症；卵巢癌，例如包括進行性上皮或原發性腹膜癌；神經內分泌癌，包括轉移性神經內分泌腫瘤；腦腫瘤，例如包括神經膠瘤、退化性寡軸突膠質細胞瘤、多型性神經膠母細胞瘤、以及成人退化性星細胞瘤；子宮頸癌；胃癌；食道癌；頭頸部癌，例如包括頭頸部之鱗狀細胞癌；黑色素瘤；骨癌；以及軟組織肉瘤。惡性血液疾病舉例包括：急性骨髓性白血病(AML)；慢性骨髓性白血病(CML)，包括加速性CML和CML的爆發階段(CML-BP)；骨髓增生不良症候群(myelodysplastic syndromes，MDS)，包括頑抗性貧血(refractory anemia，RA)、伴有環狀含鐵胚細胞之頑抗性貧血(refractory anemia with ringed siderblasts，RARS)、伴有過多胚細胞之頑抗性貧血(refractory anemia with excess blasts，RAEB)、及轉變中的RAEB(RAEB-T)；非霍奇金氏病(non-Hodgkin’s lymphoma，NHL)，包括濾泡型淋巴瘤、和外套細胞淋巴瘤；B細胞淋巴瘤；T細胞淋巴瘤；多發性骨髓瘤(multiple myeloma，MM)；急性淋巴母細胞性白血病(ALL)；慢性淋巴母細胞性白血病(CLL)；霍奇金氏病(Hodgkin’s disease，HD)；華爾登氏巨球蛋白血症(Waldenstrom’s macroglobulinemia)；以及骨髓增生性症候群。
本發明的醫藥組成物可更包含如細胞毒性劑之治療劑，或者與如放射性治療、或免疫性治療之治療法一起施用。舉例而言，此細胞毒性劑可為：抗代謝藥物(antimetabolites)，包含如卡培他濱(capecitibine)、吉西他濱(gemcitabine)、5-氟尿嘧啶(5-fluorouracil)或5-氟尿嘧啶/白葉酸(leucovorin)、氟達拉濱(fludarabine)、阿拉伯糖基胞嘧啶(cytarabine)、巰基嘌呤(mercaptopurine)、硫代鳥嘌呤(thioguanine)、噴司他丁(pentostatin)、和胺甲葉酸(methotrexate)；拓蹼異構酶(topoisomerase)抑制劑，例如包括依妥普賽(etoposide)、坦尼坡賽(teniposide)、喜樹鹼(camptothecin)、拓蹼替康(topotecan)、伊立替康(irinotecan)、阿德力黴素(doxorubcin)、和道諾魯比辛(daunorubicin)；長春花生物鹼(vinca alkaloid)，例如包括長春新鹼(vincristine)、和長春鹼(vinblastin)；紫杉烷類(taxanes)，例如包括紫杉醇(paclitaxel)、和多西紫杉醇(docetaxel)；鉑劑(platinum agents)，例如包括順鉑(cisplatin)、卡鉑定(carboplatin)、和奧沙利鉑(oxaliplatin)；抗生素(antibiotics)，例如包括放線菌素D(actinomycin D)、博來黴素(bleomycin)、絲裂黴素C(mitomycin C)、阿黴素(adriamycin)、道諾魯比辛(daunorubicin)、艾達魯比辛(idarubicin)、阿德力黴素(doxorubicin)、和聚乙二醇脂質體阿德力黴素(pegylated liposomal doxorubicin)；烷基化劑(alkylating agents)，如黴法蘭(melphalan)、氮芥苯丁酸(chlorambucil)、硫酸布他卡因(busulfan)、沙奧特帕(thiotepa)、依弗醯胺(ifosfamide)、卡氮芥(carmustine)、環己亞硝(lomustine)、司莫司汀(semustine)、鏈球黴素(streptozocin)、達卡巴仁(decarbazine)、和環磷醯胺(cyclophosphamide)；沙利竇邁(thalidomide)和相關類似物，例如包括CC-5013和CC-4047；蛋白酪胺酸激酶抑製劑，例如包括甲磺醯伊麻替尼普(imatinib mesylate)、吉非替尼(gefitinib)、達沙替尼(dasatinib)、埃羅替尼(erlotinib)、拉帕替尼(lapatinib)、舒尼替尼(sunitinib)、尼羅替尼(nilotinib)、以及索拉非尼(sorafenib)；抗體，例如包括曲妥珠單抗(trastuzumab)、利妥西單抗(rituximab)、西妥昔單抗(cetuximab)、和貝伐珠單抗(bevacizumab)；邁杜蔥酮(mitoxantrone)；地塞米松(dexamethasone)；普賴松(prednisone)；以及替莫唑胺(temozolomide)。
為實行本發明所述之方法，上述醫藥組成物可經由口服、非口服、噴霧吸入、局部、經直腸、經鼻、舌下、陰道、或經由植入型藥盒(implanted reservoir)等方式投藥。於此使用之「非口服」(parenteral)係指皮下注射、皮內注射、靜脈內注射、肌肉內注射、關節腔內注射、動脈內注射、關節液內注射、胸腔內注射、脊髓內注射、疾病部位內注射、及顱內注射或注入技術。
無菌可注射之組成物，例如無菌可注射水性或油性懸浮液，可根據本領域已知技術，使用適合的分散劑或濕潤劑(如Tween 80)及懸浮劑來配製。無菌可注射之配製液可為無菌可注射的溶液、或是懸浮於無毒的非口服注射稀釋液或溶劑中，例如1,3-丁二醇的溶液。可使用之可接受載體及溶劑為甘露醇(mannitol)、水、林格氏溶液(Ringer’s solution)或等滲透之氯化鈉溶液。除此之外，非揮發油係習用之溶劑或是懸浮介質(例如：合成單甘油酯或雙甘油酯)。脂肪酸如油酸(oleic acid)與其甘油酯衍生物，亦可用於製備注射劑，天然醫藥可接受之用油，例如橄欖油或蓖麻油，特別是其多氧乙基化之型態，同樣可用於製備。這些油酯溶液或懸浮液，可包含長鏈醇類稀釋液或分散劑、羧甲基纖維素、或類似之分散劑。其他常用之界面活性劑，如Tween或Spans、或其他相似乳化劑、或一般醫藥製造業所使用於醫藥可接受之固態、液態或其他可用於劑型開發目的之劑量型式之生物可利用增強劑。
用於口服投藥之組成物可為任何一種口服可接受之劑型，包括膠囊、錠片、乳化液與水懸浮液、分散液與溶液，但不限於此。以錠片為例，一般所使用之載體為乳糖或是玉米澱粉，潤滑劑(如硬脂酸鎂)亦常被添入其中。以口服膠囊投藥型式而言，可用的稀釋劑包括乳糖與乾燥玉米澱粉。當以水懸浮液或乳化液經口投藥時，活性成分可懸浮或是溶解於混有乳化劑或懸浮劑之油狀界面中。如果需要，可添加適度的甜味劑、風味劑或是色素。鼻用氣化噴霧劑或吸入劑組成物，可根據醫藥劑型領域中已知技術進行製備。例如，此組成物可製備為鹽溶液，應用苯甲醇(benzyl alcohol)或其他適合的防腐劑、增強生物可利用性之促吸收劑、碳氟化合物、及/或該領域中其他技藝中已知之溶解劑或分散劑。含小檗鹼化合物之醫藥組成物，亦可以栓劑方式進行直腸投藥。
醫藥組成物之載體必須為「可接受性」，即其必須與組成物之活性成份相容(較佳係能穩定活性成份)，並且不能對被治療之試體造成傷害。一種或多種能與小檗鹼化合物形成溶解性更佳之複合物的溶解劑(如環糊精)，也可用為傳遞活性化合物之醫藥載體。其他載體舉例包括膠質氧化矽、硬脂酸鎂、纖維素、月桂硫酸鈉與D&C黃色10號。
以下係藉由特定的具體實施例說明本發明之實施方式，熟習此技藝之人士，可由本說明書所揭示之內容，輕易地了解本發明之其他優點與功效，亦可瞭解以下實施例僅為說明用，並非用於限制本發明範圍。本發明亦可藉由其他不同的具體實施例加，以施行或應用，本說明書中的各項細節，亦可基於不同觀點與應用，在不悖離本發明之精神下進行各種修飾與變更。
取11.25克黃連藥材(Coptis chinensis
)，加入1.2公升的水，煮沸萃取持續1小時後，大約可得到450 ml的萃取產物，分成數份儲存於4℃。除上述直接儲存水萃產物於4℃之外，亦可使用冷凍乾燥儲存萃取產物。
於進行後續實驗前，儲存於4℃的萃取產物先行使用0.22 μm之濾膜過濾。
使用二甲基亞碸(dimethyl sulfoxide，DMSO)作為溶劑，溶解小檗鹼氯化物(berberine chloride，購自Sigma，B3251)，以製備不同濃度之小檗鹼溶液。
自台灣生物資源保存及研究中心(Bioresource Collection and Research Center，BCRC)購得非小細胞型肺癌(non-small cell lung cacinoma，NSCLC)細胞株A549、NCI-H460與NCI-H520以及正常肺細胞株MRC5，其中A549以F12K培養基(21127，GIBCO，Carlsbad，U.S.A.)培養，NCI-H460與NCI-H520兩者皆以RPMI1640培養基(23400，GIBCO，Carlsbad，U.S.A.)陪養，MRC5則以MEM培養基(41500，GIBCO，Carlsbad，U.S.A.)培養。上述所有培養基皆含有10% FBS(10437，GIBCO，Carlsbad，U.S.A.)，且所有細胞培養皆在37℃、5% CO2
的培養箱(Thermo forma 370，Waltham，U.S.A.)中進行。
使用裝配有逆相管柱(reverse-phase Zorbax ODS II，150 mm x 4.6 mm，5 μm)之高效液相層析系統(High-performance liquid chromatography system，HPLC system，Hitachi)，於管柱溫度為40℃下進行分析。樣本注射體積為10 μl，流速為1.0 ml/min，並測量流出液的UV吸收值(346 nm)。
磷酸氫鉀(Potassium hydrogen phosphate，1.36g)溶解於1000 ml水，並以磷酸(orthophosphoric acid)將pH值調整至pH 2.5，以作為緩衝液A，其中緩衝液A與緩衝液B(乙腈)濃度比例調整為：0.01min，A：B=80：20→
20min，A：B=50：50→
26min，A：B=80：20。
將上述小檗鹼溶液與黃連萃取物進行HPLC分析，其結果顯示小檗鹼吸收峰的滯留時間大約在9.5分，而黃連萃取物在滯留時間大約在9.5分的位置同樣具有一大片吸收峰，此表示本發明之黃連萃取物含有大量的小檗鹼化合物。
以下測試例所得之數據，全數皆以平均值±標準差(mean±SE)表示，並使用SPSS軟體，以學生氏測試法(Student’s test)與變異數分析法(Analysis of variance，ANOVA)判定各群組之差異顯著與否，其中當p
值小於0.05時，則視為顯著差異。
於24孔盤中，每孔培養1×104
個待測細胞，待培養16小時後，將黃連萃取物或不同濃度之小檗鹼溶液等待測樣本直接加入24孔盤內，再於37℃下培養24小時、48小時與72小時。
使用經0.22 μm過濾膜過濾之PBS，配置出濃度為5.5 mg/ml之溴噻唑藍溴化四唑(Thiazolyl blue tetrazolium bromide，MTT，m5655，Sigma，St. Louis，U.S.A.)溶液。配置所得之MTT溶液，取50 μl加入經過24小時、48小時與72小時培養之A549、NCI-H460、NCI-H520與MRC5等細胞株之24孔盤內，再於37℃下培養2小時後，移除所有的培養液。每孔再加入500 μl DMSO，以溶解MTT與粒線體中去氫酶反應所得之產物甲臢(formazan)。以吸液器反覆吸吐使甲臢完全溶解，將200 μl所得溶液轉至96孔ELISA盤，使用微孔盤測量儀(Microplate Autoreader EL311，Bio-Tek Instruments，Winooski，U.S.A.)偵測吸光值(O.D. 570 nm)，其結果如圖1、圖2A、圖2B及圖2C所示。
參考圖1，其為黃連萃取物(0.6% v/v)對A549、NCI-H460、NCI-H520與MRC5等細胞株之測試結果，其中*代表p
<0.05。由圖1可知添加黃連萃取物經過48小時培養後，便可以明顯看到相較於正常細胞之存活率，癌細胞之存活率明顯下降，持續培養至72小時後，癌細胞之存活率更是顯著下降，此表示本發明之黃連萃取物可以在不影響正常細胞的前提下毒殺癌細胞，使其存活率下降。
參考圖2A，其為小檗鹼溶液(3 μM、6 μM、9 μM、12 μM)與A549細胞株培養48小時後之測試結果。如圖2A所示，對於A549細胞株的抑制隨著小檗鹼溶液之濃度增加而增加，且其半抑制濃度(half maximal inhibitory concentration，IC50
)約為7 μM。
參考圖2B，其為小檗鹼溶液(10 μM、20 μM、30 μM、40 μM)與NCI-H460細胞株培養48小時後之測試結果。如圖2B所示，對於NCI-H460細胞株的抑制隨著小檗鹼溶液之濃度增加而增加，且其半抑制濃度(half maximal inhibitory concentration，IC50
)約為40 μM。
參考圖2C，其為小檗鹼溶液(10 μM、20 μM、30 μM、40 μM)與NCI-H520細胞株培養48小時後之測試結果。如圖2C所示，對於NCI-H520細胞株的抑制隨著小檗鹼溶液之濃度增加而增加，且其半抑制濃度(half maximal inhibitory concentration，IC50
)約為20 μM。
由圖2A、圖2B與圖2C可知小檗鹼化合物類似於本發明黃連萃取物，同樣可以毒殺癌細胞，使其存活率下降。
使用萘胺藍染劑(Trypan blue，T10282，Invitrogen，Carlsbad，U.S.A.)，對經過黃連萃取物(0.6% v/v)處理之A549細胞株染色，然後將細胞染色液轉至細胞計數腔室玻片上(Cell Counting Chamber Slide，C10228，Invitrogen，Carlsbad，U.S.A.)，再使用自動化細胞計數器(CountessAutomated Cell Counter，C10227，Invitrogen，Carlsbad，U.S.A.)測量細胞數目，其結果如圖3所示。
參考圖3，其為黃連萃取物(0.6% v/v)對A549細胞株之測試結果，其中*代表p
<0.05。由圖3可知添加黃連萃取物經過48小時培養後，便可以明顯看到相較於無處理組(控制組，ctrl)之存活率，處理組癌細胞之存活率明顯下降，持續培養至72小時後，癌細胞之存活率更是顯著下降，此結果同於圖1，因此更加證明本發明之黃連萃取物可以在不影響正常細胞的前提下毒殺癌細胞，使其存活率下降。
於10 cm培養皿中，培養3×105
個A549細胞株，當細胞進入對數(logarithmical)生長期時，細胞數目便足以進行分析。待16小時後，此細胞以黃連萃取物處理24小時、48小時與72小時，再以胰蛋白酶處理(trypsinization)以收集細胞。使用冰乙醇(70%)於-20℃下將細胞固定過夜後，使用PBS清洗細胞以移除乙醇。將PI染色緩衝液(PBS：RNase(10μg/ml)：PI(1 μg/ml)=97：1：2)加入細胞液，其中每1×106
個細胞添加1 ml PI染色緩衝液，以確保DNA完全染色，於37℃下避光持續震盪染色30分鐘。使用尼龍篩(35 μm)過濾細胞，防止細胞群集。然後，將樣本移入圓底管並盡快以流式細胞儀(FACSCalibur)分析，並制訂單細胞閘以排除聚集的細胞。每樣本收集一萬五千個細胞，以完成細胞週期分佈，再使用Modfit軟體(Verity Software House，Topsham，U.S.A.)，計算不同細胞週期階段的百分比，其結果如圖4所示。
參考圖4，其為黃連萃取物處理後A549細胞株之細胞週期分析結果，其中*代表p
<0.05，***代表p
<0.001。由圖4可知黃連萃取物處理24小時後，A549細胞株的細胞週期明顯阻斷在G1階段，而黃連萃取物處理48小時後，A549細胞株的細胞週期則明顯阻斷於G2階段，此表示本發明之黃連萃取物可抑制癌細胞持續分裂。
於10 cm培養皿中，培養3×105
個A549細胞株，當細胞進入對數(logarithmical)生長期時，細胞數目便足以進行分析。細胞以IC50
劑量的黃連萃取物或小檗鹼處理48小時，收集細胞並以RIPA緩衝液(10mM Tris(pH 7.4)，150mM NaCl，5mM EDTA(pH 8.0)，0.1% SDS，1% DOS，1% NP40)溶解，再混入蛋白酶抑制劑混合組(protease inhibitor cocktail，Pierce，Rockford，U.S.A.)、磷酸酶抑制劑混合組(phosphatase inhibitor cocktail，Sigma，St. Louis，U.S.A.)，而後以13,000 g、4℃離心30分鐘，以將細胞殘渣離心而沉降於底部，離心後收集上清液，再混入樣本緩衝液(100mM Tris-Cl(pH 6.8)，4%(w/v) SDS，0.2%(w/v)溴酚藍，20%(v/v)甘油，200 mM β-巰基乙醇，儲存於-80℃直至使用為止)。
根據製造商操作手冊，以BCA蛋白質分析套組(BCA protein assay kit，23250，Thermo Scientific，Waltham，U.S.A.)定量蛋白質濃度，每一樣本取20 μg的蛋白質，以10%至15%的SDS-PAGE進行電泳，SDS-PAGE的濃度係根據與偵測之蛋白質的分子量決定。而後將SDS-PAGE，以400 mA轉印至硝酸纖維(nitrocellulose，NC)膜，持續1至2小時。
轉印膜置於含5%脫脂奶粉之TBST(Tris Buffered Saline with 0.05% Tween-20)中，在室溫下浸泡1小時。而後，轉印膜以TBST清洗兩次，每次五分鐘，以去除多餘的牛奶，而後在4℃下，將轉印膜泡在適當稀釋的一級抗體並緩和震盪持續過夜。轉印膜以TBST清洗三次，去除過多一級抗體後，再將轉印膜浸泡於對應HRP鍵結之二級抗體持續1小時。最後，膜上添加HRP基質(WBKLS0050,Millipore,Billerica,U.S.A.)，以顯現蛋白質表現圖型，再利用影像系統(Fuji LAS-3000 imaging system)抓取影像，而後使用軟體(Multi Gauge software(FUJIFILM,Tokyo,Japan)對墨點影像定量，其結果如圖5A、圖5B、圖5C、圖5D、圖5E、圖5F、圖5G、圖5H所示。
參考圖5A、圖5B、圖5C、圖5D、圖5E、圖5F、圖5G、圖5H，其分別為黃連萃取物處理後CDK4、CDK6、cyclin D3(G1/S調控蛋白)、cyclin B1(G2/M調控蛋白)、Vimentin(間葉標幟蛋白)與ALDH1A1、β-catenin、ABCG2(三者為癌幹細胞標幟蛋白)的表現結果，其中*代表p
<0.05，**代表p
<0.01，***代表p
<0.001，胞內控制組(internal ctrl)為β-肌動蛋白。由圖5A、圖5B、圖5C、圖5D、圖5E、圖5F、圖5G、圖5H可知黃連萃取物處理後，上述調控蛋白與標幟蛋白的表現量皆顯著減少，此表示本發明之黃連萃取物可以抑制癌幹細胞及其轉移作用。
於24孔穿孔盤(Corning,Lowell,U.S.A.)中，每孔使用不含血清的培養基100 μl培養2×104
個A549細胞，每一6.5 mm嵌插件之上方部分設有孔，尺寸為8 μm，底間隔填滿有500 μl含10% FBS之F12K培養基。以黃連萃取物(0.6% v/v)處理四小時後，以對甲醛(paraformaldehyde，PFA)固定細胞10分鐘，然後使用4',6-二脒-2-苯基吲哚(DAPI：PBST，=1：10000，PBST：Phosphate Buffered Saline with 0.2% Tween-20)染色10分鐘。嵌插件以PBST清洗三次每次10分鐘，而後以活細胞影像系統(Leica,Wetzlar,Germany)觀察，並用MetaXpress軟體(Molecular Devices,Sunnyvale,U.S.A.)定出細胞數量，其結果如圖6所示。
參考圖6，其為黃連萃取物處理後全數15個顯微鏡觀察視野中單位視野的細胞數量，其中***代表p
<0.001。由圖6結合圖5E，可知相較於控制組，黃連萃取物可以明顯減少癌細胞轉移。
於10 cm培養皿中，培養3×105
個A549細胞株，獲得足以進行分析之細胞數目。細胞以IC50
劑量的黃連萃取物或小檗鹼處理48小時，以胰蛋白酶處理收集細胞後離心，細胞重新懸浮於含2% FBS之培養基，其中每一毫升含有1×106
個細胞。將50 μM作為阻斷劑之reserpine(Sigma,St. Louis,U.S.A.)連同Hoechst33342染劑(Invitrogen,Carlsbad,U.S.A.，5 μg/ml)加入細胞，或上述染劑單獨加入細胞。所得樣本在37℃下緩和震盪培養2小時，以確保染色均勻。以PBS清洗細胞後，使用PI染色(20 ng/ml)判定活/死細胞。為了設定螢光補償，亦製備單染色及無染色群組。以35 μm尼龍篩過濾樣本，防止細胞群聚。PI陽性反應之死細胞首先排除，以避免偽陽性，然後赫斯特藍(Hoechst blue)與赫斯特紅點繪製可判定側族群。對於樣本兩組群(reserpine添加族群與無reserpine添加組群)減少之區域則定亦為側族群，側族群的百分比則以Flowjo軟體(TreeStar,Ashland,U.S.A.)分析，其結果如圖7A與7B所示。
參考圖7A與圖7B，其分別為黃連萃取液與小檗鹼溶液處理後之SP分析結果。由圖7A與圖7B可知經過黃連萃取液與小檗鹼溶液處理後，側族群大幅減少；結合參考圖5F、圖5G、圖5H，可知黃連萃取液可以抑制癌幹細胞。
上述實施例僅係為了方便說明而舉例而已，本發明所主張之權利範圍自應以申請專利範圍所述為準，而非僅限於上述實施例。
圖1係黃連萃取物對A549、NCI-H460、NCI-H520與MRC5等細胞株之測試結果。
圖2A係小檗鹼溶液與A549細胞株培養48小時後之MTT測試結果。
圖2B係小檗鹼溶液與NCI-H460細胞株培養48小時後之MTT測試結果。
圖2C係小檗鹼溶液與NCI-H520細胞株培養48小時後之MTT測試結果。
圖3為黃連萃取物對A549細胞株之萘胺藍染劑測試結果。
圖4為黃連萃取物處理後A549細胞株之細胞週期分析結果。
圖5A為黃連萃取物處理後CDK4之表現結果。
圖5B為黃連萃取物處理後CDK6之表現結果。
圖5C為黃連萃取物處理後cyclin D3之表現結果。
圖5D為黃連萃取物處理後cyclin B1之表現結果。
圖5E為黃連萃取物處理後Vimentin之表現結果。
圖5F為黃連萃取物處理後ALDH1A1之表現結果。
圖5G為黃連萃取物處理後β-catenin之表現結果。
圖5H為黃連萃取物處理後ABCG2之表現結果。
圖6為穿孔分析中黃連萃取物處理後全數15個顯微鏡觀察視野中單位視野的細胞數量。
圖7A為黃連萃取液處理後之SP分析結果。
圖7B為小檗鹼溶液處理後之SP分析結果。
Claims (8)
- 一種使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途。
- 如申請專利範圍第1項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該小檗鹼化合物係小檗鹼氯化物。
- 如申請專利範圍第1項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該小檗鹼化合物係包含於一黃連萃取物中。
- 如申請專利範圍第3項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該黃連萃取物係一黃連水萃取物或由該黃連水萃取物乾燥而得。
- 如申請專利範圍第4項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該黃連水萃取物係提供一黃連藥材，添加50倍至200倍該黃連藥材重量之水，形成一混合物後，對該混合物加熱萃取而得。
- 如申請專利範圍第5項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該萃取之時間為30分鐘至2小時。
- 如申請專利範圍第5項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該混合物係加熱至體積成為原始體積之四分之一至二分之一。
- 如申請專利範圍第1項所述之使用小檗鹼化合物製造抑制癌幹細胞生長或轉移的藥劑之用途，其中，該癌幹細胞係非小細胞型肺癌幹細胞。
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| US13/137,711 US20120321726A1 (en) | 2011-06-14 | 2011-09-07 | Berberine-containing pharmaceutical composition for inhibiting cancer stem cell growth or carcinoma metastasis and application thereof |
| US14/790,154 US20150320738A1 (en) | 2011-06-14 | 2015-07-02 | Berberine-containing pharmaceutical composition for inhibiting cancer stem cell growth or carcinoma metastasis and application thereof |
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| CN103860960B (zh) * | 2014-03-21 | 2017-06-06 | 哈尔滨市固元科技发展有限公司 | 一种治疗乳腺癌的胶囊及其制备方法 |
| EP3250235A1 (en) * | 2015-01-29 | 2017-12-06 | International Society for Drug Development S.r.l. | Combination anticancer endowed with antitumor activity, comprising alkaloids of chelidonium majus |
| CN109925313A (zh) * | 2017-12-18 | 2019-06-25 | 清华大学 | 小檗碱作为制备阻断炎癌转化和/或预防肿瘤发生药物的应用 |
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