曾炫皓 章強(qiáng)強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院皮膚科，上海 200040)

·綜述·

真菌提取物抗腫瘤研究進(jìn)展

曾炫皓 章強(qiáng)強(qiáng)

(復(fù)旦大學(xué)附屬華山醫(yī)院皮膚科，上海 200040)

本文總結(jié)了近幾年真菌提取物的抗癌作用相關(guān)的研究成果。一方面包括了最近幾年關(guān)于真菌提取物誘導(dǎo)癌細(xì)胞凋亡、抑制癌細(xì)胞增生、減少癌細(xì)胞血管生成的各種機(jī)制研究，另一方面歸納了多種真菌提取物對(duì)癌細(xì)胞抑制作用的研究結(jié)果。近幾年的研究結(jié)果顯示，真菌提取物能夠抑制多種腫瘤細(xì)胞的增殖，并誘導(dǎo)其凋亡，其機(jī)制與Wnt、NK-κB、MAPK、線粒體凋亡等多種信號(hào)通路相關(guān)，靶點(diǎn)包括了p38、bcl-2、c-jun、IκB、β-catenin、Akt等多種與細(xì)胞生物活動(dòng)密切相關(guān)的蛋白。

真菌；腫瘤；機(jī)制；進(jìn)展

[Chin J Mycol，2017，12(3):184-192]

隨著世界人口老齡化，各種類型腫瘤的發(fā)病率不斷升高，嚴(yán)重威脅著人類的健康。真菌是大自然賦予人類的一座寶庫，從中我們提取出了大量的活性物質(zhì)用于治療各種不同類型的腫瘤。隨著對(duì)各種真菌研究的深入，一方面大量新的真菌活性物質(zhì)被發(fā)現(xiàn)，另一方面真菌活性物質(zhì)抗腫瘤的作用機(jī)制不斷被發(fā)現(xiàn)和完善。本文就近5 a發(fā)表的與抗癌真菌提取物相關(guān)的研究進(jìn)行總結(jié)和歸納。

1 真菌抗腫瘤活性物質(zhì)研究新進(jìn)展

1.1 真菌多糖

真菌多糖是一類10個(gè)以上的單糖以糖苷鍵連接而成的天然高分子多聚物，具有螺旋狀的立體構(gòu)型。近年來有多篇與真菌多糖研究進(jìn)展相關(guān)文章發(fā)表。其中Li等[1]報(bào)道了傳統(tǒng)中藥槐耳 (Huaier)的一種多糖類提取物TP-1對(duì)HCC SMMC-7721肝癌細(xì)胞的作用，其研究發(fā)現(xiàn)0.5、1和2 mg/kg劑量的TP-1能夠顯著抑制HCC SMMC-7721細(xì)胞的生長(zhǎng)和轉(zhuǎn)移，并且對(duì)普通的細(xì)胞毒作用較弱。由于在試驗(yàn)中發(fā)現(xiàn)TP-1能增加E-cadherin蛋白的表達(dá)，抑制N-cadherin蛋白的表達(dá)，他們認(rèn)為TP-1的抗腫瘤作用與其對(duì)AUF-1信號(hào)通路的調(diào)節(jié)作用相關(guān)。此外，TP-1還被發(fā)現(xiàn)可以通過抑制HIF-1α、VEGF、AUF-1以及AEG-1的表達(dá)，阻止腫瘤的血管生長(zhǎng)。Zhang等[2]報(bào)道了一種從草莖點(diǎn)霉 (Phomaherbarum)YS4108的菌絲中提取出的真菌多糖YCP，YCP在實(shí)驗(yàn)中能夠YCP能夠通過TLR2與TLR4相關(guān)機(jī)制來調(diào)節(jié)細(xì)胞內(nèi)p38、ERK、JNK、NF-κβ的表達(dá)，從而刺激B細(xì)胞產(chǎn)生更多的IgG抗體，并能在小鼠移植瘤模型上抑制Heps (肝癌細(xì)胞)、S180 (小鼠肉瘤細(xì)胞)、Lewis (肺癌細(xì)胞)腫瘤細(xì)胞的增殖。Li等[3]的研究發(fā)現(xiàn)姬松茸多糖 (A.blazeipolysaccharides)能夠影響HL-60 (人早幼粒白血病細(xì)胞)細(xì)胞線粒體膜電位，使線粒體釋放cytochrome c (細(xì)胞色素C)，從而誘導(dǎo)腫瘤細(xì)胞凋亡。

1.2 凝集素類

凝集素是普遍存在于自然界動(dòng)植物和微生物中的一類非免疫來源的蛋白質(zhì)或糖蛋白，一般由2或4個(gè)相同亞基組成。Nagre等[4]從絲核菌 (Rhizoctoniabataticola)中分離出一種命名為RBL的凝集素，它的N端終點(diǎn)有獨(dú)特的氨基酸序列KKKAYSSRII，這與其他凝集素不同。RBL對(duì)人類卵巢癌細(xì)胞具有很強(qiáng)的細(xì)胞毒性作用，并且能與卵巢癌細(xì)胞標(biāo)記蛋白CA125結(jié)合，其具體的作用機(jī)制尚不明確。Barkeer等[5]報(bào)道了分離自齊整小核菌 (Sclerotiumrolfsii)的一種凝集素Sclerotiumrolfsiilectin (SRL)能夠通過調(diào)節(jié)c-JUN與SOCS，抑制MAPK信號(hào)通路與JAK/STAT信號(hào)系統(tǒng)，最終誘導(dǎo)HT-29細(xì)胞 (人結(jié)腸癌癌細(xì)胞)凋亡。此外，其作用還被發(fā)現(xiàn)與miRNA密切相關(guān)。

1.3 萜類

萜類是真菌中廣泛存在的一種化合物，具有多種生物活性。Cheng等[6]的研究發(fā)現(xiàn)茯苓酸 (Pachymic acid)的抗癌作用的機(jī)制與熱休克蛋白激活以及蛋白質(zhì)折疊相關(guān)基因的表達(dá)引起的內(nèi)質(zhì)網(wǎng)應(yīng)激有關(guān)，并且在應(yīng)用內(nèi)質(zhì)網(wǎng)應(yīng)激阻滯劑后，其抗癌作用顯著減弱。Yang等[7]最新的研究發(fā)現(xiàn)，從Chondrostereumsp.提取出的Hirsutanol A的作用機(jī)制與ROS和線粒體膜電位改變?cè)斐傻木€粒體損傷，并釋放細(xì)胞色素C，而導(dǎo)致的細(xì)胞凋亡相關(guān)。Deng等[8]從地花菌 (Albatrellusconfluens)分離出一種名為neoalbaconol (NA)的小分子萜類物質(zhì)。NA能夠通過PI3-K/HK2信號(hào)通路發(fā)揮抗癌活性，能有效抑制多種癌細(xì)胞的增生。Gill等[9]的研究闡述了靈芝 (Ganodermalucidum)中的萜類化合物靈芝酸 (Ganoderic Acid)通過Wnt信號(hào)通路殺傷腫瘤細(xì)胞的機(jī)制。

1.4 真菌次級(jí)代謝產(chǎn)物

Zhao等[10]分離出一種命名為alternariol (AOH)的化合物，并在研究中發(fā)現(xiàn)它能夠抑制NIH3T3 (小鼠胚胎成纖維細(xì)胞)細(xì)胞DNA pol-β的過度表達(dá)，通過p38激活MAPK信號(hào)通路，增加ATF2的表達(dá)量，進(jìn)而殺傷NIH3T3細(xì)胞。Koul等[11]報(bào)道了來自嗜松青霉 (Penicilliumpinophilum)的dicatenarin和skyrin誘導(dǎo)人類胰腺癌細(xì)胞凋亡的機(jī)制，其作用機(jī)制可能與線粒體膜滲透性改變引起的caspase-3蛋白的表達(dá)增加相關(guān)。Tao等[12]的研究描述了來自鐮刀菌No.DZ27 (Fusariumsp.No.DZ27)的beauvericin對(duì)KB (口腔癌細(xì)胞)和KBv200 (耐長(zhǎng)春新堿的口腔癌細(xì)胞)細(xì)胞的增殖的抑制作用，與線粒體凋亡通路的聯(lián)系。Chen等[13]的研究發(fā)現(xiàn)來自Neosartoryapseufofischeri的gliotoxin (GTX)對(duì)腫瘤細(xì)胞的殺傷機(jī)制與Wnt和Caspase信號(hào)通路相關(guān)蛋白的激活密切相關(guān)。Kim等[14]從海洋藻類共生微生物中分離出名為Toluhydroquinone的化合物。Toluhydroquinone在實(shí)驗(yàn)中能夠通過抑制β-catenin的激活，激活Ras/Raf/MEK/ERK信號(hào)通路相關(guān)蛋白質(zhì)，進(jìn)而誘導(dǎo)癌細(xì)胞凋亡。

1.5 近幾年新發(fā)現(xiàn)的真菌活性物質(zhì)

Ramos等[15]分別從N.laciniosaKUFC 7896以及soilfungusN.fischeriKUFC 6344提取出的乙酸乙酯混合物E2和E3對(duì)多種腫瘤細(xì)胞有細(xì)胞毒性作用。Kim等[16]從Cordyceps提取出的Cordyceps pruinosa butanol fraction (CPBF)能通過多個(gè)細(xì)胞信號(hào)通路誘導(dǎo)Hela細(xì)胞 (實(shí)驗(yàn)用增殖表皮癌細(xì)胞)的凋亡。Harms等[17]分離出化學(xué)式為C15H16N2O5S的化合物，這種化合物能夠抑制K562細(xì)胞的增殖，并且這種作用與TNF相關(guān)的NF-κB信號(hào)通路密切相關(guān)。Ai等[18]從裙帶菜內(nèi)生真菌KcF8 (Guignardiasp.KcF8)提取的幾種化合物顯示出了對(duì)多種腫瘤細(xì)胞增殖的抑制作用。

2 真菌抗癌相關(guān)作用機(jī)制研究進(jìn)展

近幾年真菌提取物抗癌機(jī)制研究的進(jìn)展總結(jié)見表1。

如表1所示，真菌提取物抗癌機(jī)制常常與多個(gè)信號(hào)通路相關(guān)，下文就真菌提取物對(duì)腫瘤細(xì)胞作用的幾個(gè)主要途徑進(jìn)行敘述。

2.1 調(diào)節(jié)Wnt信號(hào)通路

如圖1所示，Wnt/β-catenin信號(hào)由Wnt蛋白、跨膜受體胞質(zhì)蛋白、核內(nèi)轉(zhuǎn)錄因子、下游靶基因等組成，包括：①經(jīng)典Wnt/β-catenin信號(hào)通路。②Wnt/Ca2+信號(hào)通路。③c-Jun N端激酶介導(dǎo)的細(xì)胞集性信號(hào)通路。Wnt信號(hào)通路在細(xì)胞增殖、轉(zhuǎn)化、黏附、存活、和凋亡等都有重要作用。目前，較為明確的是經(jīng)典Wnt信號(hào)通路。通常情況下β-catenin與軸蛋白、APC、GSK-3β組成多蛋白復(fù)合體結(jié)合后被磷酸，進(jìn)而被泛素化降解，保持β-catenin處于較低水平。但當(dāng)Wnt信號(hào)激活的時(shí)候，會(huì)抑制下游蛋白復(fù)合體磷酸化，促進(jìn)β-catenin釋放。在腫瘤細(xì)胞中，Wnt異常持續(xù)激活導(dǎo)致大量β-catenin進(jìn)入細(xì)胞核，從而導(dǎo)致腫瘤細(xì)胞增殖異常[42]。近幾年的研究中發(fā)現(xiàn)Cordycepin可以通過增強(qiáng)GSK-3β介導(dǎo)的β-catenin磷酸化，抑制腫瘤細(xì)胞增殖[23]；真菌化合物Ganoderic acid、gliotoxin (GTX)、Toluhydroquinone、Antrodia camphorata (AC)能夠通過調(diào)節(jié)參與Wnt信號(hào)通路的蛋白質(zhì)，抑制β-catenin的激活，從而抑制腫瘤細(xì)胞的增殖[9,13-14,37]。

表1 真菌提取物抗癌作用相關(guān)作用機(jī)制和信號(hào)通路

圖1 Wnt信號(hào)通路示意以及真菌提取物作用位點(diǎn)

Fig.1 Wnt signal pathway and the targets of anti-cancer fungal extracts

2.2 調(diào)節(jié)NF-κB信號(hào)通路

NF-κB的激活機(jī)制主要依賴于IκB蛋白磷酸化所導(dǎo)致的泛素化蛋白的水解作用。通常，細(xì)胞質(zhì)中的NF-κB與其抑制蛋白IκB相結(jié)合而處于失活狀態(tài)，IκB激酶 (IκK)在接受到有效的刺激后激活，誘使IκB發(fā)生磷酸化，進(jìn)而IκB被泛素連接酶所識(shí)別而發(fā)生泛素化。IκB在泛素化后水解，解除了其對(duì)NF-κB的抑制作用，其NLS的重新暴露使其迅速與細(xì)胞核κB位點(diǎn)發(fā)生特異結(jié)合，實(shí)現(xiàn)對(duì)相關(guān)基因表達(dá)的調(diào)控作用。該通路的異常活化與腫瘤細(xì)胞的增生、侵襲和轉(zhuǎn)移都有密切的聯(lián)系[42]。近年發(fā)現(xiàn)的多種真菌提取物均能通過干擾該通路，達(dá)到抗癌效果。如表1所示，ascochlorin (ASC)能夠與NF-κB結(jié)合，而阻止其對(duì)DNA的調(diào)控作用[21]；Allantopyrone A通過調(diào)節(jié)TNF-α的表達(dá)對(duì)TNF-R1-TRADD-RIP通路進(jìn)行調(diào)節(jié)，最終通過RIP抑制NF-κB的激活[24]；6-acetylmonodethiogliotoxin除了調(diào)節(jié)TNF-α，還可以通過直接阻止NF-κB p65進(jìn)入DNA[17];isosclerone可以通過降低Iκk活性，減少IκB磷酸化，從而抑制NF-κB的激活[31]；isotetrahydro-auroglaucin與flavoglaucin能夠直接抑制IκB-α磷酸化，也可以抑制NF-κB p65與DNA的連接[30]；Trichothecin (TCN)能夠通過抑制IκK-β的磷酸化，阻止NF-κB的激活[34]。

2.3 調(diào)節(jié)caspase家族蛋白

含半胱氨酸的天冬氨酸蛋白水解酶 (Caspase)家族與哺乳動(dòng)物的細(xì)胞凋亡密切相關(guān)。其中caspase-8 (MACH)參與細(xì)胞凋亡的起始，它既可以自我活化也可以在顆粒酶B的剪切下活化。活化后的caspase-8可以剪切PARP，還參與caspase3或caspase8的活化過程。在Fas、DR4、DR5等介導(dǎo)的外源性細(xì)胞凋亡中，caspase-8能夠引發(fā)caspase蛋白酶的級(jí)聯(lián)反應(yīng)。同時(shí)caspase也可以裂解促細(xì)胞凋亡因子蛋白 (BH3 interacting domain death agonist protein，Bid)，其裂解產(chǎn)生的羧基端片段tBid能夠誘導(dǎo)線粒體釋放細(xì)胞色素c。caspase-3是細(xì)胞凋亡主要的終末剪切酶，是細(xì)胞凋亡的執(zhí)行者，其激活是細(xì)胞凋亡進(jìn)入不可逆階段的標(biāo)志。Caspase最主要的作用機(jī)制包括：①降解調(diào)節(jié)死亡蛋白bcl-2。②催化RARP的裂解。③活化核酸內(nèi)切酶DFF、CAD[43]。如表1所示，在實(shí)驗(yàn)中多種真菌提取物作用于癌細(xì)胞后都可以引起caspase3以及caspase8表達(dá)的增加，以及bcl-2和RARP的減少。

2.4 調(diào)節(jié)線粒體凋亡通路

線粒體凋亡通路包括內(nèi)源性線粒體凋亡通路以及外源性死亡受體通路。內(nèi)源性的線粒體死亡受體通路：各種刺激導(dǎo)致的線粒體損傷，引起線粒體細(xì)胞色素C釋放，從而激活caspase蛋白，誘導(dǎo)細(xì)胞凋亡。外源性死亡受體通路包括：①由系列級(jí)聯(lián)反應(yīng)導(dǎo)致的caspase-3激活，如Fas/FasL介導(dǎo)的死亡結(jié)構(gòu)域蛋白激活。②由于Bid、bcl-2等活性變化導(dǎo)致的線粒體外膜通透性改變所引起的caspase-3激活[44]。

近幾年的研究發(fā)現(xiàn)多種真菌提取物能夠通過上述兩種途徑介導(dǎo)細(xì)胞凋亡。如表1所示，dicatenarin、skyrin物質(zhì)等能夠改變線粒體膜，導(dǎo)致細(xì)胞色素C釋放，激活caspase3而引起細(xì)胞凋亡[11]；A.blazeipolysaccharides (ABP)能夠通過影響線粒體膜電位改變引起細(xì)胞色素C，而導(dǎo)致細(xì)胞凋亡[3]。Verrucarin A (VA)能夠通過影響ROS的濃度導(dǎo)致線粒體損傷[35]。Cordycepspruinosabutanol fraction (CPBF)通過調(diào)節(jié)bcl-2蛋白，引起線粒體膜通透性改變而導(dǎo)致caspase-3激活[16]。

2.5 調(diào)節(jié)MAPK信號(hào)通路

絲裂原活化蛋白激酶 (MAPK)信號(hào)通路是在真核細(xì)胞中廣泛存在的一類絲/蘇氨酸蛋白激酶，MAPKs家族包括了p38 MAPK、ERK、BML/ERK5、ERK27、NLK、ERK8,具體分為3種類型：①ERK通路。②p38 MAPK通路。③JNK/SAPK通路。其中ERK的激活與細(xì)胞增殖相關(guān)，JNK與細(xì)胞應(yīng)激與凋亡相關(guān)，p38與炎癥密切相關(guān)。在多種腫瘤的發(fā)生發(fā)展中均可以檢測(cè)到MAPK信號(hào)通路的異常激活[45]。此外，MAPK信號(hào)通路還與腫瘤新生血管的生成有密切聯(lián)系[46]。Lee等的研究發(fā)現(xiàn)ascochlorin能夠調(diào)節(jié)ERK1/2與p38的磷酸化水平，進(jìn)而抑制MAPK信號(hào)通路的激活。如表1所示，Zhao等[10]在實(shí)驗(yàn)中發(fā)現(xiàn)Alternariol能夠通過促進(jìn)p38 MAPK磷酸化，抑制腫瘤細(xì)胞中DNA-pol β的過度表達(dá)。Barkeer等[5]在實(shí)驗(yàn)中發(fā)現(xiàn)Sclerotiumrolfsiilectin (SRL)能夠顯著降低c-JUN在細(xì)胞中的濃度，并且引起多種MAPK通路相關(guān)蛋白濃度的變化。Kim等[14]的研究發(fā)現(xiàn)Toluhydroquinone能夠抑制MEK1/2和ERK1/2的磷酸化，并且可以抑制Rac1的表達(dá)。Xia等[38]在實(shí)驗(yàn)中發(fā)現(xiàn)Mycoepoxydiene可以抑制ERK、c-jun、JNK、p38等MAPK相關(guān)蛋白的磷酸化。此外，部分真菌提取物可以通過MAPK信號(hào)通路影響腫瘤的血管生成，如Ascochlorin、TP-1、Compound (3)[1,21,40]。

2.6 其他機(jī)制

Song等[27]的研究發(fā)現(xiàn)diaporine A能夠通過上調(diào)mTOR的靶向性作用因子miR-99a，影響腫瘤細(xì)胞的增殖。Cheng等[6]的研究發(fā)現(xiàn)Pachymic acid能夠通過增加XBP-1s、ATF4、Hsp70、CHOP和phospho-eIF2α的表達(dá)，引起內(nèi)質(zhì)網(wǎng)應(yīng)激，進(jìn)而抑制腫瘤細(xì)胞增殖。Deng等[8]的研究發(fā)現(xiàn)neoalbaconol (NA)通過調(diào)節(jié)磷脂酰肌醇-3-羥激酶 (phosphatidylinositol 3-hydroxy kinase，PI3K)與蛋白激酶B (protein kinase B，AKT)的磷酸化，引起己糖激酶2 (hexokinase 2，HK2)的活性的降低，抑制腫瘤細(xì)胞的增殖。

3 真菌提取物抗癌作用實(shí)驗(yàn)匯總

2012～2016年40篇文章報(bào)道的真菌提取物對(duì)各種不同癌細(xì)胞的抑制作用總結(jié)見表2。從表2可以看出，不同的真菌提取物對(duì)不同類型的腫瘤細(xì)胞有抑制作用，并且部分真菌提取物在抑制腫瘤細(xì)胞的同時(shí)，對(duì)正常細(xì)胞的毒性較小。除外少數(shù)幾種真菌提取物只在相對(duì)較高的劑量時(shí)才能顯著抑制腫瘤細(xì)胞生長(zhǎng)，大部分真菌提取物都能在較低濃度下顯著抑制腫瘤細(xì)胞生長(zhǎng)，表現(xiàn)出顯著的抗癌作用。

4 小 結(jié)

真菌是大自然賦予人類的一座寶庫，從真菌中篩選抗癌天然物質(zhì)的潛力巨大。一方面，真菌提取物的種類繁多，既能找到針對(duì)癌癥發(fā)生的共同機(jī)制和信號(hào)通路發(fā)揮作用的物質(zhì)，也能找到針對(duì)特殊類型的癌癥機(jī)制發(fā)揮作用的物質(zhì)。另一方面，從生物體中篩選天然藥物相比通過化學(xué)合成藥物更為方便和快捷，并且不會(huì)存在化學(xué)合成藥物的諸多限制[50]。隨著研究技術(shù)的不斷提高，越來越多的真菌提取物的作用機(jī)制被揭示。近幾年研究的真菌提取物的抗癌作用機(jī)制主要為通過調(diào)節(jié)MAPK、Wnt、NK-κB等信號(hào)通路抑制腫瘤細(xì)胞增殖，以及通過線粒體直接或間接激活caspase家族蛋白誘導(dǎo)癌細(xì)胞凋亡。真菌提取物抗癌的有效性與可靠性已經(jīng)在大量的細(xì)胞實(shí)驗(yàn)中被證實(shí)，但是大量真菌提取物在活體中的作用還有待進(jìn)一步的研究。真菌提取物用作抗癌藥物有巨大前景，對(duì)其進(jìn)一步研究有助我們發(fā)現(xiàn)新的抗腫瘤藥物。

表2 真菌提取物對(duì)各類腫瘤細(xì)胞的抑制作用

名稱來源菌種腫瘤細(xì)胞名稱效果參考文獻(xiàn)cephalochrominCosmosporaviliorYMJ89051501A549對(duì)Hep3B,Caco-2,HT1080,Huh7,SW1353,A549的24hIC50值分別是(14.31±0.14),(12.40±0.05),(4.98±1.49),(4.64±0.29),(3.54±0.36),(2.72±0.42)μmol/L[29]isoscleroneAspergillusfumigatusMCF-7對(duì)MCF-7的IC50值為63.92μmol/L附近[31]Compounds5-7Guignardiasp.KcF8K562;A549;Huh-7;H197;MCF-7;U937;BGC823;HL60;HeLa;MOLT-4對(duì)多種腫瘤細(xì)胞的LD50值波動(dòng)在0.05～39.2μmol/L[18]A.cinnamomeaAntrodiacinnamomeaSK-HEP-1對(duì)SK-HEP-1的24hIC50值在500μg/mL附近[32]FumigaclavineCAspergillusfumigatusMCF-7對(duì)MCF-7的24hIC50值在60μmol/L附近[33]neoalbaconol(NA)AlbatrellusconfluensC666-1;HK1NPC;ZR-75-1對(duì)C666-,HK1NPC,ZR-75-1的24hIC50值分別是10μmol/L,18μmol/L和7.5μmol/L[8]Trichothecin(TCN)endophyticfun-gusoftheherb-alplantMayte-nushookeriLoesHL-60;HepG2;A549;PANC-1對(duì)HL-60,HepG2,A549,PANC-1的24hIC50值分別是0.18μmol/L,0.82μmol/L,0.39μmol/L,0.28μmol/L[34]VerrucarinA(VA)MyrotheciumverrucariaMDA-MB-231;T47D對(duì)MDA-MB-231和T47D的24hIC50值在400ng/mL附近[35]Ganodermatsugae(GT)GanodermaSKOV-3;OVCAR-3對(duì)SKOV-3的24hIC50值在1mg/mL附近,而對(duì)OVCAR-3作用不明顯[36]Antrodiacamphorata(AC)AntrodiacamphorataSKOV-3對(duì)SKOV-3的24hIC50值在196μg/mL附近[37]HirsutanolAChondrostereumsp.SW620對(duì)SW620和MDA-MB-231的24hIC50值分別是13.43μmol/L和35.67μmol/L[7]

[1] Li C,Wu X,Zhang H,et al.A Huaier polysaccharide reduced metastasis of human hepatocellular carcinoma SMMC-7721 cells via modulating AUF-1 signaling pathway[J].Tumour Biol,2015,36(8):6285-6293.

[2] Zhang X,Ding R,Zhou Y,et al.Toll-like receptor 2 and Toll-like receptor 4-dependent activation of B cells by a polysaccharide from marine fungusPhomaherbarumYS4108[J].PLoS ONE,2013,8(3):e60781.

[3] Li X,Zhao X,Wang H,et al.A polysaccharide from the fruiting bodies of Agaricus blazei Murill induces caspase-dependent apoptosis in human leukemia HL-60 cells[J].Tumour Biol,2014,35(9):8963-8968.

[4] Nagre NN,Chachadi VB,Sundaram PM,et al.A potent mitogenic lectin from the mycelia of a phytopathogenic fungus,Rhizoctoniabataticola,with complex sugar specificity and cytotoxic effect on human ovarian cancer cells[J].Glycoconj J,2010,27(3):375-386.

[5] Barkeer S,Guha N,Hothpet V,et al.Molecular mechanism of anticancer effect ofSclerotiumrolfsiilectin in HT29 cells involves differential expression of genes associated with multiple signaling pathways:A microarray analysis[J].Glycobiology,2015,25(12):1375-1391.

[6] Cheng S,Swanson K,Eliaz I,et al.Pachymic acid inhibits growth and induces apoptosis of pancreatic cancerinvitroandinvivoby targeting ER stress[J].PLoS One,2015,10(4):e122270.

[7] Yang F,Chen WD,Deng R,et al.Hirsutanol A,a novel sesquiterpene compound from fungusChondrostereumsp.,induces apoptosis and inhibits tumor growth through mitochondrial-independent ROS production:hirsutanol A inhibits tumor growth through ROS production[J].J Transl Med,2013,11:32.

[8] Deng Q,Yu X,Xiao L,et al.Neoalbaconol induces energy depletion and multiple cell death in cancer cells by targeting PDK1-PI3-K/Akt signaling pathway[J].Cell Death Dis,2013,4:e804.

[9] Gill BS,Kumar S,Navgeet.Ganoderic acid A targeting beta-catenin in Wnt signaling pathway:in silico andinvitrostudy[J].Interdiscip Sci,2016.

[10] Zhao J,Ma J,Lu J,et al.Involvement of p38MAPK-ATF2 signaling pathway in alternariol induced DNA polymerase beta expression[J].Oncol Lett,2016,12(1):675-679.

[11] Koul M,Meena S,Kumar A,et al.Secondary metabolites from endophytic fungusPenicilliumpinophiluminduce ROS-mediated apoptosis through mitochondrial pathway in Pancreatic Cancer Cells[J].Planta Med,2016,82(4):344-355.

[12] Tao YW,Lin YC,She ZG,et al.Anticancer activity and mechanism investigation of beauvericin isolated from secondary metabolites of the mangrove endophytic fungi[J].Anticancer Agents Med Chem,2015,15(2):258-266.

[13] Chen J,Wang C,Lan W,et al.Gliotoxin inhibits proliferation and induces apoptosis in Colorectal Cancer Cells[J].Mar Drugs,2015,13(10):6259-6273.

[14] Kim NH,Jung HI,Choi WS,et al.Toluhydroquinone,the secondary metabolite of marine algae symbiotic microorganism,inhibits angiogenesis in HUVECs[J].Biomed Pharmacother,2015,70:129-139.

[15] Ramos AA,Castro-Carvalho B,Prata-Sena M,et al.Crude extracts of marine-derived and soil fungi of the genus neosartorya exhibit selective anticancer activity by inducing cell death in colon,breast and skin cancer cell lines[J].Pharmacognosy Res,2016,8(1):8-15.

[16] Kim HG,Song H,Yoon DH,et al.Cordycepspruinosaextracts induce apoptosis of HeLa cells by a caspase dependent pathway[J].J Ethnopharmacol,2010,128(2):342-351.

[17] Harms H,Orlikova B,Ji S,et al.Epipolythiodiketopiperazines from the marine derived fungusDichotomomycescejpiiwith NF-kappa B inhibitory potential[J].Mar Drugs,2015,13(8):4949-4966.

[18] Ai W,Wei XY,Lin XP,et al.Guignardins A-F,spirodioxynaphthalenes from the endophytic fungusGuignardiasp KcF8 as a new class of PTP1B and SIRT1 inhibitors[J].TETRAHEDRON,2014,70(35):5806-5814.

[19] Chang HT,Chou CT,Chen IS,et al.Mechanisms underlying effect of the mycotoxin cytochalasin B on induction of cytotoxicity,modulation of cell cycle,Ca2+homeostasis and ROS production in human breast cells[J].Toxicology,2016,370:1-19.

[20] Hu Z,Yang A,Fan H,et al.Huaier aqueous extract sensitizes cells to rapamycin and cisplatin through activating mTOR signaling[J].J Ethnopharmacol,2016,186:143-150.

[21] Lee SH,Kwak CH,Lee SK,et al.Anti-inflammatory effect of ascochlorin in LPS-stimulated RAW 264.7 macrophage cells is accompanied with the down-regulation of iNOS,COX-2 and proinflammatory cytokines through NF-kappaB,ERK1/2,and p38 signaling pathway[J].J Cell Biochem,2016,117(4):978-987.

[22] Bhatia DR,Dhar P,Mutalik V,et al.Anticancer activity of Ophiobolin A,isolated from the endophytic fungus bipolaris setariae[J].Nat Prod Res,2016,30(12):1455-1458.

[23] Tian X,Li Y,Shen Y,et al.Apoptosis and inhibition of proliferation of cancer cells induced by cordycepin[J].Oncol Lett,2015,10(2):595-599.

[24] Yokoigawa J,Morimoto K,Shiono Y,et al.Allantopyrone A,an alpha-pyrone metabolite from an endophytic fungus,inhibits the tumor necrosis factor alpha-induced nuclear factor kappa B signaling pathway[J].J Antibiot(Tokyo),2015,68(2):71-75.

[25] Wang Y,Qi X,Li D,et al.Anticancer efficacy and absorption,distribution,metabolism,and toxicity studies of aspergiolide A in early drug development[J].Drug Des Devel Ther,2014,8:1965-1977.

[26] Kundu S,Kim TH,Yoon JH,et al.Viriditoxin regulates apoptosis and autophagy via mitotic catastrophe and microtubule formation in human prostate cancer cells[J].Int J Oncol,2014,45(6):2331-2340.

[27] Song Y,Dou H,Wang P,et al.A novel small-molecule compound diaporine A inhibits non-small cell lung cancer growth by regulating miR-99a/mTOR signaling[J].Cancer Biol Ther,2014,15(10):1423-1430.

[28] Li YX,Kang KH,Kim HJ,et al.Invitroinduction of apoptosis by isosclerone from marine-derived fungusAspergillusfumigatus[J].Bioorg Med Chem Lett,2014,24(16):3923-3927.

[29] Hsiao CJ,Hsiao G,Chen WL,et al.Cephalochromin induces G0/G1 cell cycle arrest and apoptosis in A549 human non-small-cell lung cancer cells by inflicting mitochondrial disruption[J].J Nat Prod,2014,77(4):758-765.

[30] Kim KS,Cui X,Lee DS,et al.Inhibitory effects of benzaldehyde derivatives from the marine fungusEurotiumsp SF-5989 on inflammatory mediators via the induction of heme oxygenase-1 in lipopolysaccharide-stimulated RAW264.7 macrophages[J].Int J Mol Sci,2014,15(12):23749-23765.

[31] Li YX,Himaya S,Dewapriya P,et al.Anti-proliferative effects of isosclerone isolated from marine fungusAspergillusfumigatusin MCF-7 human breast cancer cells[J].Process Biochemistry,2014,49(12):2292-2298.

[32] Chen YJ,Thang MW,Chan YT,et al.Global assessment ofAntrodiacinnamomea-induced microRNA alterations in hepatocarcinoma cells[J].PLoS One,2013,8(12):e82751.

[33] Li YX,Himaya SW,Dewapriya P,et al.Fumigaclavine C from a marine-derived fungusAspergillusfumigatusinduces apoptosis in MCF-7 breast cancer cells[J].Mar Drugs,2013,11(12):5063-5086.

[34] Su J,Zhao P,Kong L,et al.Trichothecin induces cell death in NF-kappaB constitutively activated human cancer cells via inhibition of IKKbeta phosphorylation[J].PLoS One,2013,8(8):e71333.

[35] Palanivel K,Kanimozhi V,Kadalmani B,et al.Verrucarin A,a protein synthesis inhibitor,induces growth inhibition and apoptosis in breast cancer cell lines MDA-MB-231 and T47D[J].Biotechnol Lett,2013,35(9):1395-1403.

[36] Kuo HP,Hsu SC,Ou CC,et al.Ganoderma tsugae extract inhibits growth of HER2-Overexpressing cancer cells via Modulation of HER2/PI3K/Akt Signaling Pathway[J].Evid Based Complement Alternat Med,2013,2013:219472.

[37] Yang HL,Lin KY,Juan YC,et al.The anti-cancer activity ofAntrodiacamphorata against human ovarian carcinoma (SKOV-3) cells via modulation of HER-2/neu signaling pathway[J].J Ethnopharmacol,2013,148(1):254-265.

[38] Xia XC,Chen Q,Liu K,et al.Mycoepoxydiene inhibits antigen-stimulated activation of mast cells and suppresses IgE-mediated anaphylaxis in mice[J].Int Immunopharmacol,2013,17(2):336-341.

[39] Chen Q,Chen T,Li W,et al.Mycoepoxydiene inhibits lipopolysaccharide-induced inflammatory responses through the suppression of TRAF6 polyubiquitination[corrected][J].PLoS One,2012,7(9):e44890.

[40] Cao S,Cryan L,Habeshian KA,et al.Phenolic compounds as antiangiogenic CMG2 inhibitors fromCostaricanendophytic fungi[J].Bioorg Med Chem Lett,2012,22(18):5885-5888.

[41] Jeong JH,Jeong YJ,Cho HJ,et al.Ascochlorin inhibits growth factor-induced HIF-1alpha activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells[J].J Cell Biochem,2012,113(4):1302-1313.

[42] Ma B,Hottiger MO.Crosstalk between Wnt/beta-Catenin and NF-kappaB signaling pathway during inflammation[J].Front Immunol,2016,7:378.

[43] Chen H,Yang X,Feng Z,et al.Prognostic value of Caspase-3 expression in cancers of digestive tract:a meta-analysis and systematic review[J].Int J Clin Exp Med,2015,8(7):10225-10234.

[44] Chen Y,Zhang H,Zhou HJ,et al.Mitochondrial redox signaling and tumor progression[J].Cancers (Basel),2016,8(4).

[45] Rauch N,Rukhlenko OS,Kolch W,et al.MAPK kinase signalling dynamics regulate cell fate decisions and drug resistance[J].Curr Opin Struct Biol,2016,41:151-158.

[46] Varinska L,Gal P,Mojzisova G,et al.Soy and breast cancer:focus on angiogenesis[J].Int J Mol Sci,2015,16(5):11728-11749.

[47] Lee HH,Kim SO,Kim GY,et al.Involvement of autophagy in cordycepin-induced apoptosis in human prostate carcinoma LNCaP cells[J].Environ Toxicol Pharmacol,2014,38(1):239-250.

[48] Darsih C,Prachyawarakorn V,Wiyakrutta S,et al.Cytotoxic metabolites from the endophytic fungusPenicilliumchermesinum:discovery of a cysteine-targeted Michael acceptor as a pharmacophore for fragment-based drug discovery,bioconjugation and click reactions[J].Rsc Advances,2015,5(86):70595-70603.

[49] Ramos AA,Prata-Sena M,Castro-Carvalho B,et al.Potential of four marine-derived fungi extracts as anti-proliferative and cell death-inducing agents in seven human cancer cell lines[J].Asian Pac J Trop Med,2015,8(10):782-790.

[50] Gill BS,Kumar S,Navgeet.Triterpenes in cancer:significance and their influence[J].Mol Biol Rep,2016,43(9):881-896.

[本文編輯] 王 飛

·消息·

The recent progresses of anti-cancer fungal extracts

ZENG Xuan-hao,ZHANG Qiang-qiang

(DepartmentofDermatology，HuaShanHospital，F(xiàn)udanUniversity，Shanghai200040，China)

This review summaries theadvance in anti-cancer fungal extracts in recent years.On the one hand,related multiple mechanisms might include the anti-cancer fungal extracts inducing apoptosis,inhibiting proliferation and angiogenesis.On the other hand,the anti-cancer effects of various anti-cancer fungal extracts in cancer cells are also reviewed.These study show that anti-cancer fungal extracts can inhibit the proliferation of cancer cells and induce apoptosis in cancer cells.The mechanisms of those functions involved various signal pathways,including Wnt,NK-κB,MAPK and Mitochondria related apoptosis signal pathways,and related to various proteins related to biological activity such as p38,bcl-2,c-jun,IκB,β-catenin,Akt.

fungus;cancer;mechanisms;progresses

國(guó)家自然科學(xué)基金 (81573056)

曾炫皓，男 (漢族)，碩士研究生在讀.E-mail:969358560@qq.com

章強(qiáng)強(qiáng),E-mail:zhangqq8@163.com

R 979.1

A

1673-3827(2017)12-0184-09

2016-10-24