丁浩淼, 洪嘉瑤, 陳雪佳, 李沁清, 李貴鋒, 汪財(cái)生, 錢國(guó)英

羊棲菜多糖抗腫瘤及其作用機(jī)制研究進(jìn)展

丁浩淼, 洪嘉瑤, 陳雪佳, 李沁清, 李貴鋒, 汪財(cái)生, 錢國(guó)英

(浙江萬(wàn)里學(xué)院 生物與環(huán)境學(xué)院, 浙江 寧波 315100)

羊棲菜()多糖在多種腫瘤細(xì)胞系中表現(xiàn)出良好的抗癌活性, 具有針對(duì)腫瘤細(xì)胞的選擇活性和較小的毒副作用, 可以作為現(xiàn)有腫瘤化療藥物的替代品進(jìn)行開(kāi)發(fā)。羊棲菜多糖主要通過(guò)誘導(dǎo)細(xì)胞凋亡作用于腫瘤細(xì)胞, 其通過(guò)細(xì)胞周期停滯, 增強(qiáng)機(jī)體免疫功能, 改變細(xì)胞膜鈣通道與流動(dòng)性, 破壞線粒體膜和產(chǎn)生一氧化氮來(lái)殺死癌細(xì)胞并防止轉(zhuǎn)移。本文就國(guó)內(nèi)外發(fā)表的羊棲菜多糖抗腫瘤功能及作用機(jī)制進(jìn)行系統(tǒng)的歸納和總結(jié), 旨在為羊棲菜多糖抗腫瘤藥物的深入研究、開(kāi)發(fā)提供理論依據(jù)。

羊棲菜(); 多糖; 抗腫瘤作用機(jī)制

腫瘤是以細(xì)胞異常增殖為特點(diǎn)的一類疾病, 常在機(jī)體中形成腫塊, 有些腫瘤生長(zhǎng)迅速, 侵襲性強(qiáng), 可以從原發(fā)部位播散到身體的其他部位, 對(duì)人體的危害大, 醫(yī)學(xué)上稱為惡性腫瘤, 其又稱為癌癥, 是嚴(yán)重威脅人類健康的常見(jiàn)病、多發(fā)病、慢性病[1-3]。天然產(chǎn)物已被廣泛用作治療有效藥物的重要來(lái)源, 當(dāng)前的趨勢(shì)是將研究對(duì)象轉(zhuǎn)向海洋生物。最近, 已發(fā)現(xiàn)源自海藻的多糖具有抗腫瘤作用, 例如: 從臺(tái)灣海帶(s)、海帶()、鈍型凹頂藻()、墨角藻()等提取的多糖可抑制淋巴癌或髓系細(xì)胞增殖[4-7]。

羊棲菜()隸屬褐藻門(Phaeo-phuta)墨角藻目(Fucales)馬尾藻科(Sargassaceae), 又名玉草、六角菜、鹿角尖, 在我國(guó)遼東半島、山東、浙江、福建、廣東淺海域均有分布, 日本和韓國(guó)也有生長(zhǎng), 其含有豐富的多糖[8-10]。羊棲菜多糖(SFPS)的主要成分是褐藻酸、褐藻多糖硫酸酯、褐藻淀粉; 其中, 褐藻多糖硫酸酯生物活性豐富, 因其具有抗輻射[11]、抗病毒[12]、調(diào)節(jié)血糖[13]、提高記憶力[14]、免疫調(diào)節(jié)[15]、清除自由基[16]的多種藥理性質(zhì), 這些功效與褐藻糖膠這類硫酸酯多糖密切相關(guān)。國(guó)內(nèi)外文獻(xiàn)資料表明羊棲菜多糖對(duì)腫瘤細(xì)胞具有抑制效果, 因此, 本文著重研究介紹了羊棲菜多糖對(duì)腫瘤細(xì)胞抗癌機(jī)理分類研究, 為羊棲菜多糖在抗腫瘤作用類藥物的開(kāi)發(fā)提供參考。

1 羊棲菜多糖的抗腫瘤作用

羊棲菜多糖已經(jīng)通過(guò)多種腫瘤細(xì)胞系和合適的動(dòng)物模型體內(nèi)研究證明其具有抗腫瘤的作用, 如表1所示。許多疾病如腫瘤、風(fēng)濕病和某些類型的炎癥導(dǎo)致紅細(xì)胞的電遷移率增加, Ji等[17]通過(guò)灌胃S180腫瘤小鼠各種劑量SFPS, 測(cè)量其紅細(xì)胞的遷移率, 發(fā)現(xiàn)高劑量組, 中劑量組和低劑量組的紅細(xì)胞遷移時(shí)間短于陰性對(duì)照組, 表明SFPS可能改變腫瘤小鼠體內(nèi)紅細(xì)胞表面電荷密度。Yu等[18]從羊棲菜中提取SFPS, 并對(duì)SFPS采用氯磺酸吡啶法增加其硫酸化程度, 通過(guò)MTT法檢測(cè)多糖化學(xué)修飾前后對(duì)HepG2細(xì)胞體外增殖的抑制作用, 實(shí)驗(yàn)結(jié)果發(fā)現(xiàn)兩種多糖對(duì)HepG2細(xì)胞均有一定的抑制效果, 改性多糖對(duì)HepG2細(xì)胞生長(zhǎng)的抑制作用與從羊棲菜中提取SFPS相比有所提高。Cong等[19]從羊棲菜中分離出多糖組分04S2P, 通過(guò)硫酸化反應(yīng)獲得04S2P-S, 在5種不同的腫瘤細(xì)胞系測(cè)試其抗腫瘤活性, 發(fā)現(xiàn)04S2P-S僅在Bel7402細(xì)胞系上顯示出明顯的抗腫瘤作用, 而對(duì)SMMC7721細(xì)胞、HT-29細(xì)胞、Huh7細(xì)胞和Caco-2細(xì)胞沒(méi)有明顯的抗腫瘤作用。況煒等[20]采用不同組分的SFPS濃度梯度對(duì)人肺癌細(xì)胞SPC-A-1進(jìn)行藥物刺激, 后用MTT法檢測(cè)腫瘤細(xì)胞增殖情況, 結(jié)果表明, SFPS具有抗腫瘤效果, 初步測(cè)得300 mg/L及1 000 mg/L的SFPS可以有效對(duì)人肺癌細(xì)胞的增殖活性產(chǎn)生抑制作用。Chen等[21]通過(guò)SFPS對(duì)體內(nèi)外腫瘤細(xì)胞的生長(zhǎng)進(jìn)行了研究, 發(fā)現(xiàn)SFPS具有抑制腫瘤生長(zhǎng)作用; 體外研究主要針對(duì)SFPS對(duì)A549細(xì)胞系的細(xì)胞毒性以及對(duì)細(xì)胞生長(zhǎng)的影響, 體內(nèi)研究中將接種A549細(xì)胞的小鼠按100 μg/kg和200 μg/kg體重的劑量口服SFPS, 觀察攜帶A549癌細(xì)胞的小鼠體內(nèi)腫瘤的生長(zhǎng)情況, 發(fā)現(xiàn)小鼠體內(nèi)的腫瘤生長(zhǎng)受到抑制。岑穎洲等[22]用熱水提取, 乙醇、氯化鈣沉淀分離及酸水解制備了6種羊棲菜多糖樣品, 發(fā)現(xiàn)各羊棲菜多糖樣品對(duì)肝細(xì)胞HepG2均有一定的抑制作用, 抑制率均未超過(guò)40%。早在1998年, Shan等[23]從6種海藻中獲得粗提物, 發(fā)現(xiàn)羊棲菜水提物能夠顯著刺激人體淋巴細(xì)胞增殖, 而這種功能與SFPS活性有關(guān)。

羊棲菜多糖通過(guò)多種途徑起作用, 一些作用機(jī)制尚未明確定義, 確定的常見(jiàn)機(jī)制是阻滯細(xì)胞周期, 線粒體膜電位去極化, 一氧化氮途徑和免疫調(diào)節(jié)[24], 如圖1所示。

表1 羊棲菜多糖抗腫瘤實(shí)例

圖1 羊棲菜多糖抗腫瘤作用機(jī)制

2 羊棲菜多糖抗腫瘤機(jī)制

2.1 細(xì)胞周期阻滯

在多細(xì)胞生物中, 細(xì)胞增殖和細(xì)胞死亡是由機(jī)體精確調(diào)節(jié)以維持組織穩(wěn)態(tài)。大多數(shù)的腫瘤細(xì)胞都有一個(gè)共同特點(diǎn), 即與細(xì)胞增殖相關(guān)的基因被開(kāi)啟或激活, 而與細(xì)胞分化有關(guān)的基因被關(guān)閉或抑制, 從而表現(xiàn)為不受機(jī)體約束的無(wú)限增值狀態(tài)。已有報(bào)道羊棲菜多糖通過(guò)使細(xì)胞周期停滯在G2/M期、S期或G0/G1期起作用。胡晨熙等[25]分離純化獲得羊棲菜褐藻糖膠(CSFP-1)并作用于肺癌細(xì)胞A549、宮頸癌細(xì)胞HeLa和肝癌細(xì)胞Hep3B, 結(jié)果發(fā)現(xiàn)CSFP-1具有選擇性細(xì)胞毒性, 對(duì)A549和Hep3B細(xì)胞無(wú)明顯影響, 但對(duì)HeLa細(xì)胞具有顯著抑制作用, 當(dāng)劑量為300 μg/mL CFPS-1處理Hela細(xì)胞時(shí), 其抑制率達(dá)到35.1%。HeLa細(xì)胞經(jīng)過(guò)CSFP-1處理24 h后, G1期細(xì)胞比例明顯減少, 48 h后S期比例顯著增加, G2期細(xì)胞比例顯著減少。Chen等[26]通過(guò)體外研究發(fā)現(xiàn)SFPS抑制人肺腺癌SPC-A-1細(xì)胞的增殖呈濃度依賴性, 低濃度(30 mg/L)至高濃度(300 mg/L)的SFPS都能有效誘導(dǎo)細(xì)胞周期阻滯于G2/M期, 并顯著增加人臍靜脈內(nèi)皮細(xì)胞HUVECs的凋亡, 并能抑制HUVEC細(xì)胞中VEGF-A的表達(dá)。季宇彬等[27]通過(guò)體外抗腫瘤實(shí)驗(yàn)觀察SFPS對(duì)6種不同腫瘤細(xì)胞的抑制作用, 發(fā)現(xiàn)SFPS對(duì)人胃癌細(xì)胞SGC-7901和直腸癌COLO-205有較好的療效, 可以阻滯SGC-7901人胃癌細(xì)胞由G0/G1期進(jìn)入S期。梁倩[28]和張華芳[29]等研究SFPS對(duì)人白血病HL-60細(xì)胞增殖的影響, 結(jié)果表明, SFPS誘導(dǎo)HL-60細(xì)胞凋亡并呈濃度和時(shí)間依賴性, 24 h的IC50為390 mg/L; 同時(shí)G2/M期細(xì)胞比例增多。王建光等[30]研究SFPS對(duì)乳腺癌MCF-7細(xì)胞凋亡的誘導(dǎo)作用, 發(fā)現(xiàn)SFPS可阻滯MCF-7由G0/G1期進(jìn)入S期, 升高細(xì)胞凋亡指數(shù)(APO)。陳金星等[31]研究SFPS對(duì)人大腸癌Lovo細(xì)胞和RKO細(xì)胞增殖的作用, 實(shí)驗(yàn)發(fā)現(xiàn)SFPS對(duì)Lovo 細(xì)胞和RKO細(xì)胞作用24 h的IC50分別為149和123 mg/L。RKO細(xì)胞G0/G1期的細(xì)胞比例隨著濃度的增加而增高, 相應(yīng)的S期細(xì)胞比例顯著下降, 而Lovo細(xì)胞的細(xì)胞周期時(shí)相比無(wú)明顯改變。將腫瘤細(xì)胞阻滯于G0/G1和G2/M期, 降低S期的細(xì)胞比例被認(rèn)為是由于細(xì)胞周期蛋白依賴性激酶受到抑制和細(xì)胞周期檢查點(diǎn)激活導(dǎo)致凋亡小體的產(chǎn)生, 隨后導(dǎo)致細(xì)胞死亡。

2.2 增強(qiáng)免疫機(jī)制

目前常用的一些抗癌藥物具有免疫抑制作用, 如環(huán)孢素, 有報(bào)道稱用該藥后, 患者腫瘤發(fā)生率高達(dá)一般人的30倍。Yoon等[32]研究SFPS對(duì)小鼠巨噬細(xì)胞RAW 264.7和整個(gè)脾臟細(xì)胞的作用, 研究發(fā)現(xiàn)SFPS可以激活RAW 264.7細(xì)胞產(chǎn)生細(xì)胞因子, 如腫瘤壞死因子-α(TNF-α)、白細(xì)胞介素-1β(IL-1β)和白細(xì)胞介素-6(IL-6), 并且刺激了全脾細(xì)胞的有絲分裂。陳柳君等[33]體內(nèi)實(shí)驗(yàn)表明, SFPS能顯著影響小鼠脾指數(shù)和胸腺指數(shù); 體外實(shí)驗(yàn)表明, SFPS對(duì)RAW 264.7細(xì)胞的增值能力和吞噬能力影響不一, 但都能明顯促進(jìn)TNF-α。王揚(yáng)等[34]通過(guò)腹腔注射得率最高的羊棲菜多糖F1和f1組分, 發(fā)現(xiàn)對(duì)小鼠抗SRBC抗體生成有促進(jìn)作用, 同時(shí)明顯提高小鼠脾指數(shù)。況煒等[35]研究SFPS對(duì)離體小鼠脾細(xì)胞免疫調(diào)節(jié)活性發(fā)現(xiàn)SFPS能顯著升高小鼠脾細(xì)胞IL-2、TNF-α和IFN-γ。嚴(yán)全能等[36]通過(guò)腹腔注射SFP2發(fā)現(xiàn)其能顯著提高小鼠胸腺指數(shù), 提高小鼠NK細(xì)胞殺傷活性及腹腔巨噬細(xì)胞的吞噬活性。Chen等[21]利用環(huán)磷酰胺治療腫瘤小鼠使其產(chǎn)生免疫抑制, 實(shí)驗(yàn)結(jié)果表明, 經(jīng)SFPS刺激后小鼠的脾淋巴細(xì)胞開(kāi)始增殖, 顯著增加了腹膜巨噬細(xì)胞的吞噬率和細(xì)胞因子(IL-2、IL-6和TNF-α)的分泌。同年, Chen等[37]對(duì)接種A549細(xì)胞的小鼠口服使用SFPS 28d, 實(shí)驗(yàn)結(jié)果表明, SFPS不僅顯著抑制小鼠肺腺癌A549的生長(zhǎng), 而且能顯著提高血清中TNF-α含量, 促進(jìn)A549荷瘤小鼠腹腔巨噬細(xì)胞產(chǎn)生IL-1和TNF-α以及脾細(xì)胞的增殖。Toll樣受體(TLRs)是一種膜結(jié)合受體, 對(duì)病原體的識(shí)別通過(guò)誘導(dǎo)促炎細(xì)胞因子的產(chǎn)生和共刺激分子的上調(diào)來(lái)快速激活先天免疫。TLR信號(hào)通路被分為兩組: MyD88依賴途徑導(dǎo)致促炎細(xì)胞因子的生產(chǎn)快速激活NF-κB和MAPK通路, IFN-β與緩慢成熟的樹(shù)突細(xì)胞激活NF-κB和MAPK通路。當(dāng)使用Toll 樣受體特異性抗體和NF-κB特異性抑制劑預(yù)處理腹膜巨噬細(xì)胞發(fā)現(xiàn)SFPS誘導(dǎo)的細(xì)胞因子TNF-α和IL-1減少, 表明SFPS誘導(dǎo)巨噬細(xì)胞分泌細(xì)胞因子至少部分是由TLRs/NF-κB信號(hào)傳導(dǎo)途徑所介導(dǎo)的[38]。但是SFPS通過(guò)NF-κB信號(hào)途徑調(diào)節(jié)免疫應(yīng)答的確切機(jī)制尚未闡明, Chen[39]通過(guò)PDTC、BAY11-7082、IKK16和SB203580等特異性抑制劑研究, 發(fā)現(xiàn)SFPS通過(guò)CD14/IKK和P38激活NF-κB信號(hào)傳導(dǎo)途徑。Fan等[40]通過(guò)研究SFPS對(duì)HepG2細(xì)胞的作用, 也發(fā)現(xiàn)SFPS可以在HepG2荷瘤小鼠中促進(jìn)腹膜巨噬細(xì)胞分泌細(xì)胞因子TNF-α和IL-1。Fan等[41]進(jìn)一步通過(guò)SFPS對(duì)鼻咽癌進(jìn)行抗腫瘤研究, 發(fā)現(xiàn)SFPS能增加脾臟中IgM水平, 用抗TLR4和TLR2的特異性抗體預(yù)處理脾淋巴細(xì)胞, 能顯著抑制脾淋巴細(xì)胞的增殖并阻斷SFPS誘導(dǎo)IgM產(chǎn)生。絲裂原活化蛋白激酶(MAPK)級(jí)聯(lián)是一個(gè)高度保守的模塊, 參與細(xì)胞的各種功能, 包括細(xì)胞遷移, 增殖以及對(duì)環(huán)境的應(yīng)激適應(yīng)和炎癥反應(yīng), MAPK可分為4個(gè)亞族: ERK、p38、JNK和ERK5。SB203580是p38 MAPK的特異性抑制劑, 處理脾淋巴細(xì)胞后有效抑制SFPS誘導(dǎo)的IgM分泌, 因此SFPS的免疫活性至少部分由TLR2/TLR4受體和p38 MAPK信號(hào)通路介導(dǎo)。因此增強(qiáng)腫瘤患者的宿主免疫可以恢復(fù)腫瘤細(xì)胞和免疫反應(yīng)之間的動(dòng)態(tài)平衡, 從而發(fā)揮潛在的抗腫瘤作用。

2.3 抑制腫瘤微血管的形成

血管生成是腫瘤發(fā)生的重要過(guò)程, 持續(xù)血管生成是惡性腫瘤的特征之一。VEGF也稱為VEGF-A, 與VEGF受體-2接合導(dǎo)致不同信號(hào)通路的級(jí)聯(lián), 介導(dǎo)內(nèi)皮細(xì)胞增殖和遷移、促進(jìn)其存活和血管通透性的基因上調(diào), 是血管形成的關(guān)鍵因子。VEGFR-2被認(rèn)為是生理性和病理性血管生成的一個(gè)重要對(duì)的信號(hào)轉(zhuǎn)換器, Chen等[25]通過(guò)研究SFPS對(duì)腫瘤血管生長(zhǎng)的影響, 進(jìn)而探索SFPS對(duì)肺癌的抑制作用, 結(jié)果發(fā)現(xiàn), 40 mg/kg SFPS能顯著減少腫瘤塊的質(zhì)量, 具有誘導(dǎo)人臍靜脈內(nèi)皮細(xì)胞凋亡(HUVECs)的能力, 顯著降低了CD31、VEGF-A的表達(dá)及其受體VEGFR-2在HUVECs中的表達(dá), SFPS在體外實(shí)驗(yàn)中對(duì)SPC-A-1細(xì)胞的增殖和體內(nèi)腫瘤生長(zhǎng)均有抑制性, 降低了腫瘤微血管密度(MVD)。Chen 等[42]發(fā)現(xiàn)羊棲菜多糖FP08S2在16.84 μmol/L 時(shí)能顯著損害HMEC-1細(xì)胞形成毛細(xì)血管的能力, 還可以抑制人類微血管內(nèi)皮細(xì)胞(HMEC-1)癌細(xì)胞的遷移和侵襲; 進(jìn)一步的研究表明, FP08S2可以結(jié)合VEGF和VEGFR-2以干擾VEGF-EGFR-2相互作用阻礙了裸鼠A549和轉(zhuǎn)移、生長(zhǎng), 并呈現(xiàn)出顯著的抗腫瘤微血管生成活性。況煒等[20]研究發(fā)現(xiàn), 300及1000 mg/L 的SFPS可通過(guò)抑制腫瘤血管內(nèi)皮細(xì)胞的增殖而抑制腫瘤的生長(zhǎng)。陳慧玲等[43]研究發(fā)現(xiàn), 30～100 mg/L SFPS能顯著降低人胃癌MGC-803細(xì)胞培養(yǎng)基上清VEGF的含量, 具有抑制腫瘤血管內(nèi)皮細(xì)胞增殖的作用, 其作用機(jī)制與下調(diào)腫瘤細(xì)胞VEGF-A和腫瘤血管內(nèi)皮細(xì)胞VEGFR-2的表達(dá)有關(guān)。這些發(fā)現(xiàn)表明, SFPS除了直接抑制腫瘤細(xì)胞生長(zhǎng)外, 還能通過(guò)阻斷VEGF信號(hào)來(lái)抑制微血管生成, 可以在細(xì)胞和血管兩個(gè)方面控制腫瘤生長(zhǎng), 提升腫瘤治愈機(jī)率, 為藥物治療腫瘤開(kāi)辟新路徑。

2.4 改變細(xì)胞膜流動(dòng)性和鈣通道

腫瘤的發(fā)生不僅是因?yàn)榧?xì)胞分裂失控所導(dǎo)致細(xì)胞過(guò)度增生, 還可能與細(xì)胞凋亡通路受阻所致, 凋亡的誘導(dǎo)和抑制與信號(hào)轉(zhuǎn)導(dǎo)通路有關(guān), 而Ca2+作為第二信使使其功能與細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)密切相關(guān), 因此, Ca2+與細(xì)胞凋亡密切相關(guān)。季宇彬[44]通過(guò)建立S180腫瘤動(dòng)物模型, 分低、中、高劑量空腹給予SFPS 7d, 采集制備紅細(xì)胞懸液發(fā)現(xiàn)中劑量組(20 mg/(kg·d))SFPS能降低荷瘤小鼠紅細(xì)胞內(nèi)[Ca2+]i, 升高膜表面唾液酸含量, 增強(qiáng)膜表面Na+、K+-ATPase及Ca2+, Mg2+- ATPase的活性, 排除離子跨膜轉(zhuǎn)運(yùn)障礙, 提高紅細(xì)胞的電泳合淌度增加紅細(xì)胞在血循環(huán)中黏附腫瘤細(xì)胞的可能性[45]。季宇彬等[46]發(fā)現(xiàn)SFPS可以通過(guò)升高SGC-7901腫瘤細(xì)胞內(nèi)[Ca2+]i啟動(dòng)腫瘤細(xì)胞凋亡機(jī)制而達(dá)到抗腫瘤作用。高世勇等[47]進(jìn)一步觀察SFPS對(duì)SGC-7901細(xì)胞內(nèi)Ca2+含量的變化, 發(fā)現(xiàn)50 mg/L 的SFPS誘導(dǎo)腫瘤細(xì)胞凋亡可以通過(guò)升高人胃癌細(xì)胞內(nèi)的[Ca2+]i而達(dá)到的, [Ca2+]i升高時(shí)Ca2+來(lái)源于細(xì)胞內(nèi)的鈣庫(kù)釋放。李杰女等[48]分離純化獲得羊棲菜多糖SFPS-B1, 測(cè)得SFPS-B1對(duì)SGC-7901細(xì)胞的IC50為189.30 mg/L, 并發(fā)現(xiàn)SFPS-B1作用腫瘤細(xì)胞后, SGC-7901細(xì)胞內(nèi)[Ca2+]i明顯上升, pH值明顯降低, 使得與細(xì)胞凋亡相關(guān)的酶和蛋白活性發(fā)生改變, 最終引起了細(xì)胞凋亡。

2.5 改變凋亡相關(guān)基因表達(dá)

腫瘤細(xì)胞發(fā)生凋亡時(shí), 凋亡相關(guān)的基因及蛋白也會(huì)發(fā)生明顯的變化。嚴(yán)璘璘等[49]發(fā)現(xiàn)SFPS作用Lovo細(xì)胞24 h的IC50為375 mg/L, Lovo細(xì)胞中Caspase-3酶原蛋白表達(dá)降低, Caspase-3的mRNA高表達(dá), 提示Caspase-3的活化參與了SFPS誘導(dǎo)Lovo細(xì)胞凋亡的調(diào)控。其進(jìn)一步研究SFPS誘導(dǎo)Lovo細(xì)胞凋亡過(guò)程中Caspase-3、Caspase-8、Caspase-9的活性變化, 實(shí)驗(yàn)發(fā)現(xiàn)Caspase-3、Caspase-8、Caspase-9活性均有時(shí)間依賴性增高的趨勢(shì), 但Caspase-8活性變化不明顯, 這提示SFPS作用Lovo細(xì)胞后, 通過(guò)激活啟動(dòng)Caspase-9, 進(jìn)而激活下游效應(yīng)Caspase-3的級(jí)聯(lián)反應(yīng)來(lái)實(shí)現(xiàn)的[50]。王建光等[29]研究SFPS對(duì)MCF-7細(xì)胞凋亡相關(guān)基因的影響中發(fā)現(xiàn)50 mg/L的SFPS能夠上調(diào)凋亡相關(guān)蛋白Fas和FasL的表達(dá), 促進(jìn)腫瘤細(xì)胞凋亡。胡晨熙等[24]以300 μg/mL羊棲菜褐藻糖膠(CSFP-1)處理48 h Bcl-2蛋白表達(dá)顯著減少, Beclin-1蛋白表達(dá)顯著增加, 且存在時(shí)間和劑量相關(guān)性。季宇彬等[51]通過(guò)對(duì)SFPS對(duì)腫瘤細(xì)胞P53基因表達(dá)研究發(fā)現(xiàn)給藥組400 μg/mL SFPS組P53基因的表達(dá)率明顯高于陰性對(duì)照組, 表明SFPS可顯著誘導(dǎo)腫瘤細(xì)胞P53水平的增加從而達(dá)到抗腫瘤的作用。Ji[52]在體外培養(yǎng)的人胃癌細(xì)胞系SGC-7901中加入同濃度的SFPS-B2進(jìn)行藥物刺激, SFPS-B2可以抑制SGC-7901細(xì)胞的生長(zhǎng), 相關(guān)凋亡酶 Caspase-3、Caspase-9的活性增強(qiáng), 對(duì)增殖基因Bcl-2的表達(dá)起抑制作用, 并對(duì)凋亡基因Bax、細(xì)胞色素C基因的表達(dá)起促進(jìn)作用。

2.6 其他作用機(jī)制

季宇彬等[44]分析SFPS對(duì)S180荷瘤小鼠紅細(xì)胞相關(guān)生化功能影響, 通過(guò)流式細(xì)胞儀發(fā)現(xiàn)SFPS能提高紅細(xì)胞膜電位水平, 可調(diào)節(jié)或恢復(fù)S180荷瘤小鼠紅細(xì)胞多種生理生化功能。陳慧玲[53]等通過(guò)將不同濃度的SFPS作用于離體小鼠NK細(xì)胞和小鼠腹腔巨噬細(xì)胞, 研究發(fā)現(xiàn)30 mg/L 的SFPS能明顯增強(qiáng)離體小鼠NK細(xì)胞活性, 促進(jìn)巨噬細(xì)胞釋放NO。Yoon等[32]發(fā)現(xiàn)羊棲菜多糖能調(diào)節(jié)小鼠巨噬細(xì)胞RAW 264.7中的NO。Fan等[40]研究發(fā)現(xiàn)1 000 μg/mL 的SFPS能極顯著增加HepG2荷瘤小鼠血清中NO水平, 同時(shí)通過(guò)增加Bax基因表達(dá), 抑制Bcl-2基因表達(dá)來(lái)誘導(dǎo)HepG2細(xì)胞凋亡。Ji[52]在體外培養(yǎng)的人胃癌細(xì)胞系SGC-7901中加入不同濃度的SFPS-B2進(jìn)行藥物刺激72 h, 其IC50為189.30 g/L, 且細(xì)胞內(nèi)線粒體通透性轉(zhuǎn)換孔(MPTP)被激活且線粒體膜電位(MMP)含量下降。

3 討論

目前治療惡性腫瘤的主要方法是手術(shù)切除, 放射治療, 激素治療, 抗激素治療和化療。腫瘤化療的兩大障礙是藥物的毒性和耐藥性, 細(xì)胞毒類抗腫瘤藥物由于對(duì)腫瘤細(xì)胞的選擇性低, 在殺傷腫瘤細(xì)胞的同時(shí)對(duì)正常的組織細(xì)胞產(chǎn)生不同程度的毒性, 導(dǎo)致脫發(fā), 貧血, 免疫缺陷, 疲勞, 生育及神經(jīng)等問(wèn)題, 毒性反應(yīng)成為腫瘤化療時(shí)藥物用量受限的關(guān)鍵因素。此外, 化療過(guò)程中腫瘤細(xì)胞對(duì)藥物耐藥性是腫瘤化療失敗的重要原因, 也是腫瘤化療急需要解決的問(wèn)題。因此, 尋找新化合物作為潛在抗癌藥物的探索有助于研究各種來(lái)源多糖的抗癌活性。在過(guò)去的十年里, 超過(guò)100多種來(lái)源的多糖被證實(shí)在一系列的癌細(xì)胞系中表現(xiàn)出良好的抗癌活性, 同時(shí)證明了大多數(shù)多糖克服了常規(guī)化療中的主要缺點(diǎn), 比如甲殼質(zhì)類多糖對(duì)腫瘤細(xì)胞具有選擇性細(xì)胞毒性, 其他幾種多糖能夠起到免疫調(diào)節(jié)劑的作用, 不僅可以增強(qiáng)人體對(duì)癌細(xì)胞的防御作用還可以與常規(guī)化療藥物聯(lián)合使用, 降低化療藥物引起的免疫機(jī)制。

近十年來(lái), 對(duì)羊棲菜多糖的研究已經(jīng)顯示出作為抗癌藥物的一線希望。羊棲菜多糖具有良好的藥用前景, 因其對(duì)腫瘤細(xì)胞的增殖凋亡起控制作用, 針對(duì)正常人胃黏膜上皮細(xì)胞進(jìn)行細(xì)胞毒性實(shí)驗(yàn)[50], 發(fā)現(xiàn)SFPS在5~5 000 mg/L濃度范圍內(nèi)無(wú)明顯殺傷力, 表明SFPS具有選擇細(xì)胞毒性能力, 而且SFPS具有提升免疫應(yīng)答水平的功能; SFPS已經(jīng)對(duì)許多腫瘤細(xì)胞進(jìn)行了體外實(shí)驗(yàn), 但有必要使用不同癌癥的動(dòng)物模型對(duì)其體內(nèi)研究進(jìn)行評(píng)估。劉雪等[54]用CaCl2溶液提取羊棲菜多糖, 分離純化后的SFP-2主要由巖藻糖和半乳糖構(gòu)成, 紅外圖譜顯示具有硫酸基團(tuán)吸收峰。具有良好的抗氧化活性。李媛等[55]利用核磁共振波譜儀對(duì)從羊棲菜中分離純化的褐藻膠結(jié)構(gòu)進(jìn)行分析, 發(fā)現(xiàn)β-D-甘露糖醛酸與α-L-古羅糖醛酸的比值為0.98, G嵌段的平均長(zhǎng)度為16.2。肖保衡等[56]從羊棲菜中獲得褐藻糖膠, 純化發(fā)現(xiàn)CSFP2的硫酸基含量最高, 儀器分析表明其結(jié)構(gòu)可能以Gal為主鏈, 以1→6糖苷鍵連接, 在C3、C4和C6位置上連接甘露糖, 在C3位上含有硫酸根基團(tuán)。目前對(duì)羊棲菜多糖的結(jié)構(gòu)均有一定報(bào)道, 但是羊棲菜多糖的構(gòu)效關(guān)系較少, 尤其是抗腫瘤方面的構(gòu)效鮮有報(bào)道。Jin等[57]研究羊棲菜來(lái)源的巖藻聚糖硫酸酯抗補(bǔ)體活性, 發(fā)現(xiàn)高分子質(zhì)量及高硫酸化巖藻聚糖硫酸酯具有更好的抗補(bǔ)體活性。Wei等[58]研究海帶中提取的巖藻聚糖硫酸酯及脫硫酸鹽衍生物的抗血管生成活性及抗腫瘤活性, 發(fā)現(xiàn)巖藻聚糖硫酸酯比脫硫酸基衍生物具有較強(qiáng)的抗血管生成作用。研究膀胱癌細(xì)胞系時(shí), Chen等[59]從半葉馬尾藻中分離出的低分子質(zhì)量的巖藻聚糖硫酸酯能顯著抑制血管生成。Matsubara等[60]研究表明, 低分子質(zhì)量的巖藻聚糖硫酸酯可以促進(jìn)人臍靜脈內(nèi)皮細(xì)胞新生血管, 高分子巖藻聚糖硫酸酯對(duì)人臍靜脈內(nèi)皮細(xì)胞新生血管有抑制作用。王雪妹[61]等研究表明來(lái)源于海帶中低分子質(zhì)量多糖硫酸酯抗炎效果明顯高于高分子質(zhì)量多糖硫酸酯。多糖的結(jié)構(gòu)-活性關(guān)系全面研究有助于開(kāi)發(fā)具有抗癌活性的多糖及其合成類似物, 通過(guò)靶抑制實(shí)驗(yàn)可以研制其作用途徑。此外, 不同種屬來(lái)源的巖藻聚糖硫酸酯結(jié)構(gòu)差異巨大, 羊棲菜多糖的結(jié)構(gòu)與抗腫瘤活性之間的構(gòu)效關(guān)系尚未研究透徹, 因此探尋羊棲菜多糖的抑制功效及其抑制機(jī)制, 增強(qiáng)藥用活性和專一性, 不僅深入了羊棲菜多糖藥理性的研究, 而且將提升羊棲菜綜合利用價(jià)值帶動(dòng)養(yǎng)殖戶經(jīng)濟(jì)效益。

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Progress in research on the antitumor activities ofpolysaccharides and their underlying mechanisms

DING Hao-miao, HONG Jia-yao, CHEN Xue-jia, LI Qin-qing, LI Gui-feng, WANG Cai-sheng, QIAN Guo-ying

(College of Biological and Environmental Sciences, Zhejiang Wanli University, Ningbo 315100, China)

Apolysaccharide isolated fromis a succedaneum being developed for chemotherapeutic medicine. It displays antitumor activity in various tumor cell lines, exhibits good anticancer activity in several cancer cell lines, and possesses selective activity against tumor cells with minimal toxic side effects. Polysaccharides isolated fromhave been reported to act on malignant cells mainly via induction of apoptosis. They kill cancer cells, prevent metastasis via cell cycle arrest, enhance immunity, effect changes in calcium channels, alter cell membrane fluidity, disrupt mitochondrial membrane, and produce nitric oxide. The present study aimed to review previous research conducted on the antitumor activities ofpolysaccharides and the mechanisms underlying these antitumor activities to provide a theoretical and evidential basis for in-depth exploration and understanding of these polysaccharides.

; polysaccharides; antitumor mechanism

Sep. 16, 2019

R285

A

1000-3096(2020)03-0129-09

10.11759/hykx20190916001

2019-09-16;

2019-12-02

寧波“十三五”海洋經(jīng)濟(jì)創(chuàng)新發(fā)展示范項(xiàng)目資助 (NBHY-2017-S5, NBHY-2017(1)); 海藻化妝品開(kāi)放研究及產(chǎn)業(yè)化示范 (1740004099)

[Ningbo “13th Five-Year Plan” Demonstration Project of Marine Economy Innovation and Development, No. NBHY-2017-S5, NBHY-2017(1); Open Research and Industrialization Demonstration of Seaweed Cosmetic , No. 1740004099]

丁浩淼(1991-), 男, 浙江寧波人, 博士, 主要從事天然產(chǎn)物功能研究, Email: 1601091039@nbu.edu.cn; 汪財(cái)生, 男,通信作者, 高級(jí)實(shí)驗(yàn)師, 電話: 0574-88222232; E-mail: wangcaisheng@zwu.edu.cn;錢國(guó)英, 女, 通信作者, 教授, 電話: 0574-88225850; E-mail: qiangy@ zwu.edu.cn

(本文編輯: 康亦兼)