荔枝果实的抗癌活性成分及其抗癌机制研究进展

严召颖,孙心雨,杨 娜,唐盛梅,邵金华,何福林,蒋黎艳*

(湖南科技学院化学与生物工程学院,湖南永州 425199)

摘 要:目前,全球癌症负担持续加重,现有干预手段面临耐药性和毒副作用等瓶颈,科学家们正致力于从天然产物中挖掘能够有效预防以及改善癌症相关疾病进程的资源。荔枝果实作为兼具营养与药用价值的天然资源,富含多酚类(原花青素、酚酸、黄酮)、维生素C、膳食纤维及多糖等多种抗癌活性成分。在癌症防治中通过调控细胞周期、诱导细胞凋亡和自噬、抑制EMT 及相关信号通路等途径展现出多维度抗癌潜力。本文基于现有研究成果,归纳总结了荔枝果实中的抗癌活性成分及其在癌症增殖、转移等阶段中的作用机制,旨在为开发基于荔枝果实的新型抗癌药物体系和临床应用提供理论参考。

关键词:荔枝果实;抗癌;生物活性成分;抗癌机制

癌症是细胞在基因水平上失去对其生长的正常调控,使细胞异常增生与分化而导致的一种疾病[1]。癌症由细胞恶性增生引发,具有侵袭性和转移性[2],是世界上死亡率最高的常见疾病,对人类健康造成极大威胁。癌变是组织发育失败的结果[3],其产生可能与细胞周期停滞、细胞功能凋亡、细胞侵袭和迁移等有关,以预防为主的抗癌药物研发一直是科研人员研究的课题。植物是抗癌药物的来源。目前,用于癌症化疗的药物中,天然产物或其结构类似物仍占50%左右[4]。荔枝果实作为一种药食同源的水果,被誉为“果中之皇后”,富含多酚、黄酮、维生素C 和多糖等多种活性成分[5]。这些活性成分可通过不同机制如调控细胞周期、抑制癌细胞迁移、增强免疫能力等来发挥抗癌作用,降低癌症发生的风险。研究表明荔枝果实所含活性成分对乳腺癌[6]、肝癌[7]、前列腺癌[8]、结肠癌[9]等的发生具有一定的预防和抑制作用。

荔枝果实丰富的抗癌活性成分在多种癌症相关疾病的预防和改善方面展现出了一定的潜力,为开发多靶点、协同作用的抗癌药物开辟了新维度。现有研究不仅系统鉴定了荔枝含有的多种抗癌活性成分,更深入阐明了这些成分通过多途径作用机制发挥抗癌功效。但是研究一般多集中于单一活性成分,并且荔枝果实抗癌活性成分的具体作用机制研究较为分散。基于此,本文归纳总结了荔枝果实中的抗癌活性成分,详细阐述了其抗癌机制,旨在为后续荔枝果实的药物开发及综合利用提供参考。

1 抗癌活性成分

1.1 多酚类化合物

荔枝多酚是以邻二酚结构为特征,通过提供电子给自由基,使其电子配对而变得稳定,中和自由基,降低氧化应激水平,保护细胞免受DNA损伤,从而降低癌变风险[10]。荔枝果实中多酚类化合物主要有原花青素类、酚酸类、黄酮类等,不同部位(果肉、鲜干果核、鲜干果壳)和不同品种的荔枝中的总酚含量不同:张汉辉等[11]通过对荔枝果实的总酚含量进行测定,发现荔枝果肉多酚、鲜核多酚、鲜壳多酚、干核多酚及干壳多酚样品的总酚含量(w,后同)分别为872.51、840.58、865.07、721.31及446.47 mg·g-1。Li等[12]测定了妃子笑、黑叶和糯米糍等9个荔枝品种的总酚含量,结果表明其含量范围在9.39~30.16 mg·g-1,平均为16.27 mg·g-1,而且酚类物质含量最高的品种和最低的品种之间相差将近3.2倍。

原花青素类化合物是由不同数量的儿茶素(catechin)或表儿茶素(epicatechin,EC)缩合而成的一大类酚类化合物。荔枝果实的原花青素类主要是B型原花青素、原花青素A2、原花青素A4、A 型三聚体及四聚体等[13],其分子结构中有富电子的羟基部分[14],抗氧化性强,具有显著的抗癌生物活性。原花青素可通过抑制肿瘤细胞血管生成、调控细胞周期和抑制细胞增殖/分化、调控Wnt/β-catenin 细胞信号通路、促进癌细胞凋亡、以癌症干细胞为靶向标、抑制癌细胞侵袭和转移等多种途径起抗癌作用[15-16]。Yao 等[9]通过尾静脉注射CT26 细胞建立了肺转移小鼠模型,发现荔枝原花青素通过触发肠肺轴,影响T 细胞的免疫反应,对结肠癌肺转移具有很强的抑制作用。荔枝果皮含有高水平的表儿茶素,而且不同时期和不同品种的荔枝其含量也不同。在果实发育中期,妃子笑荔枝果皮的表儿茶素含量为2.5~3.5 mg·g-1,而糯米糍中的表儿茶素含量高于妃子笑,为6.5~12.0 mg·g-1[17]。表儿茶素是儿茶素类化合物中的一种,属于非酯型儿茶素,其分子结构有多个反应活性基团和活性部位,可通过影响肿瘤细胞的周期进程而抑制肿瘤细胞的周期生长[18],Gong等[19]经Sephadex LH-20 层析得到的酚类组分,初步证实对人肺腺癌细胞(A549)具有抑制作用和较高的抗氧化活性,然后进一步纯化经LC-MS 鉴定,表明EC具有抗癌活性。

酚酸类化合物是一类含有酚环的有机酸化合物,分子中含有一个或多个酚基(-OH)。根据其骨架结构不同可分为两类:苯甲酸类和肉桂酸类[20]。酚酸类化合物有游离态和结合态两种存在形式[21],水果中的酚酸以游离态和结合态共存,游离态酚酸通常具有较高的生物活性,可以直接被生物体吸收利用。荔枝果实中的酚酸类化合物主要分布在果肉和果核中,主要包括没食子酸、绿原酸、原儿茶酸、槲皮素和咖啡酸等,这些天然酚酸化合物的抗癌作用可以通过抑制肿瘤细胞增殖和迁移等过程实现。哈卿[22]研究发现,没食子酸对正常细胞(成纤维细胞)和肿瘤细胞(人肝癌SMMC-7721 细胞)的增殖均有一定程度的抑制作用,且抑制肿瘤细胞增殖的作用更为敏感。没食子酸可以下调成纤维细胞中可促进肿瘤细胞增殖、迁移、转移和血管生成相关因子的表达来发挥抗肿瘤作用。Yang 等[23]研究发现,原儿茶酸能够通过逆转上皮-间质转化过程(epithelial-mesenchymal transition,EMT),抑制肿瘤细胞的迁移和侵袭,达到抗癌作用。

黄酮类化合物是指具有两个酚羟基的苯环通过中央三碳原子相互连接而成的一类化合物[24],以C6-C3-C6 为骨架结构,是荔枝在长期自然选择过程中产生的一类次生代谢产物,广泛存在于荔枝果皮和核中。荔枝果实中鉴定出的黄酮类化合物主要有花青素、黄酮、黄酮醇、黄烷醇、查尔酮、二氢查尔酮、二氢黄酮醇和异黄酮等[25],可以通过干预不同信号通路来抑制肿瘤的增殖和转移。Zhang 等[8]研究发现,荔枝核总黄酮(total flavonoids from litchi semen,TFLS)可以通过抑制HGFR/NF-κB 信号通路调节骨内微环境,从而抑制前列腺癌在骨内的生长。黎敏航等[26]研究发现,TFLS 可以抑制HepG2 的增殖,促进其凋亡,还可以通过逆转HepG2细胞EMT的过程以减弱其迁移与侵袭的能力,这些作用可能与TFLS激活SHP-1 阻断JAK/STAT3 信号通路相关。荔枝果实中的花青素含量较为丰富,可以通过调节不同基因的表达来发挥抗肿瘤作用。Emanuele等[27]研究发现,荔枝花青素在人乳腺癌细胞中具有明显的抗肿瘤作用,上调了主要参与细胞周期调节、凋亡和信号转导的基因,下调了主要与癌细胞侵袭和恶性相关的基因。刘亮等[28]采用柱层析法对荔枝果皮中的主要花色苷进行了分离纯化与结构鉴定,发现该花色苷的糖基由葡萄糖和鼠李糖组成。此外,还有研究发现,荔枝果皮(litchi fruit pericarp,LFP)提取物在人乳腺癌细胞中也表现出潜在的抗肿瘤活性,主要是通过上调和下调参与细胞周期调节和细胞增殖、凋亡、信号转导和转录调节的多个基因,使癌细胞的DNA损伤、增殖抑制和诱导其凋亡[29]

1.2 维生素C

维生素C 又名抗坏血酸,由两个共轭双键组成。人类自身不能合成,必须从食物中获取。荔枝在生长发育过程中逐步合成和积累各种维生素,维生素C 是荔枝果实的重要营养成分之一,主要存在于荔枝果肉中,不同品种荔枝果实中维生素C 含量不同。如黑叶每100 g 含有约32 mg 维生素C,而妃子笑每100 g 含有约56 mg 的维生素C[30]。维生素C的抗肿瘤效果与其含量密切相关,但在贮藏期间,荔枝果实的维生素C 会被氧化,导致维生素C 含量越来越少。因此,需要采用适宜的保鲜技术维持其在荔枝果实中的稳定性。例如,可以利用银杏叶粗提物对荔枝进行防腐保鲜,抑制膜脂质过氧化反应,有利于荔枝维生素C 的保存[31]。维生素C 能产生活性氧类自由基,如过氧化氢、羟自由基等,并能在肿瘤细胞中与关键的细胞分子和细胞器发生相互作用,产生氧化降解反应,形成氧化降解复合物,抑制肿瘤细胞的活性[32]。维生素C 还可以通过影响肿瘤凋亡的相关基因p53Bcl-2 等的表达,诱导肿瘤细胞凋亡,即通过上调p53基因表达或激活其活性,促进其凋亡过程,达到抗肿瘤效果[33]

1.3 膳食纤维

膳食纤维是指天然存在于食物中的可食用碳水化合物或人造碳水化合物的聚合物,在人体肠道中不能被内在的消化酶分解[34],被称为人体“第七类营养素”。荔枝果实的果渣中富含膳食纤维,龚小洁[35]采用酶-重量法测定了不同荔枝果肉中的膳食纤维含量,白蜡、妃子笑和怀枝果肉中膳食纤维的含量分别为0.77、0.75、1.16 g·100 g-1。荔枝果实中的膳食纤维可以通过调节肠道功能和强化抗氧化功能双重途径在润肠通便和预防结肠癌中发挥作用。徐灼辉[36]通过对结肠组织基因进行qt-PCR 分析得出,荔枝干果肉膳食纤维-结合酚能够增加水通道蛋白的表达量,发挥润肠通便的功能,与结肠癌的预防密切相关。此外,研究发现膳食纤维的摄入量与结肠癌的发病率呈负相关[37]。另外,荔枝果渣可溶性膳食纤维(soluble dietary fiber,SDF)中结合酚含量为4.53 mg·g-1,对DPPH 和ABTS 自由基的清除效果极为显著,可以减少对细胞生物分子的攻击,降低患癌风险[38-39]。罗非君等[40]指出膳食纤维还可通过阻滞细胞周期、抑制癌变信号通路的活化等机制抑制和预防癌症。

1.4 多糖

荔枝多糖是从荔枝果实中提取的一种天然多糖化合物,其糖残基上可连接特定的官能团如乙酰基团和甲基化基团,且具有致密的网状结构和典型的碳水化合带[41]。除了抗氧化、增强免疫力的生物功效外,荔枝多糖还具有抗肿瘤的作用[42]。Huang等[43]发现鲜荔枝果肉和干荔枝果肉(fresh and dried litchi pulp,LPF and LPD)中的多糖均以浓度依赖的方式抑制人肝癌细胞HepG2、人宫颈癌细胞Hela、人肺癌细胞A549 三种肿瘤细胞系的增殖。与LPF 相比,LPD 在50~750 μg·mL-1 范围内对HepG2、Hela 和A549细胞的增殖表现出更高的抑制作用,同时LPD在浓度范围为50~400 μg·mL-1时是促进脾淋巴细胞增殖、增强NK 细胞的细胞毒性和巨噬细胞的吞噬作用的刺激剂。此外,研究还表明多糖作用于肿瘤细胞的两个关键机制是抑制癌细胞生长并诱导其程序性死亡(直接作用)和通过引发宿主的各种免疫反应来清除自由基、促使癌细胞分化、增强人类和动物的抗肿瘤能力(间接作用)[44]

1.5 皂苷

荔枝果实中还有其他具有抗癌活性的物质如皂苷。天然存在的皂苷可以作用于癌细胞中的多种靶标,从而在癌症中发挥潜在的抗增殖作用[45]。荔枝皂苷主要存在于荔枝核中,属于三萜皂苷类化合物。李关宁等[46]开展的临床试验表明,在乳腺癌术后辅助内分泌治疗中应用荔枝核皂苷,能够有效降低患者的性激素水平;同时,治疗后患者的TT细胞、Th 细胞、NK 细胞等免疫细胞的活性显著升高(P<0.05),而Ts 细胞的活性则显著降低(P<0.05),导致Th/Ts 比值升高。这些变化表明机体的免疫功能得到了显著提升,从而有助于延缓肿瘤的进展或复发。

2 抗癌机制

荔枝果实富含的多种生物活性物质为其发挥抗癌作用提供了物质基础。这些次生代谢产物通过多途径协同作用发挥抗癌作用,如通过停滞细胞周期、诱导细胞凋亡等来抑制癌细胞增殖,通过抑制EMT 过程等抑制细胞的迁移与侵袭,增强免疫能力以及与化学药物协同增效等,从而达到抗癌效果。

2.1 抑制癌细胞增殖

癌症的病理学特征表现为细胞的异常增殖行为,抑制癌细胞增殖是癌症治疗的核心目标。荔枝果实的抗癌活性成分能够通过停滞癌细胞周期、诱导细胞程序性死亡和激活自噬相关通路等多重机制,有效抑制癌细胞的异常增殖活性,从而发挥抗癌作用。

2.1.1 停滞细胞周期 细胞周期是指细胞从一次分裂完成开始到下一次分裂结束所经历的全过程,分为间期(G1、S、G2 期)与分裂期(M 期)两个阶段[47]。癌症的发生与细胞周期异常密切相关。荔枝果实不同部位的活性成分可以通过调控细胞周期关键蛋白,抑制多种癌细胞增殖。TFLS 可以降低A549 细胞中Cyclin B1 蛋白的表达,增加p21 蛋白的表达,导致细胞停滞在G2/M 期,抑制人源性非小细胞肺癌A549 细胞的增殖[48]。王修杰[49]首次发现荔枝果皮提取物可以通过影响细胞周期进程,抑制人乳腺癌、肝癌细胞增殖,这与荔枝酚酸、原花青素、黄酮等活性成分有关。此外,原花青素B2对人乳腺癌细胞的MCF-7 细胞周期有阻滞作用,将周期阻滞在G0/G1期,从而达到抑制MCF-7细胞生长的效果[50]

2.1.2 诱导细胞凋亡 细胞凋亡是由基因控制的细胞自主的有序死亡,又称细胞程序性死亡,由级联反应中起作用的特定的半胱天冬酶组介导,在哺乳动物系统中有内源性和外源性两条细胞凋亡途径[51]。在抗癌机制中,细胞凋亡是抑制癌细胞的重要途径之一。Wang等[7]研究了LFP提取物对人肝癌细胞的体外抗肿瘤活性,发现LFP 提取物对肿瘤生长具有明显的抑制作用,其作用机制可能与诱导肝癌细胞凋亡有关。LFP 提取物还可通过上调细胞周期调控、凋亡和信号转导相关基因,下调与癌细胞侵袭和恶性程度相关基因,诱导细胞凋亡;并且在乳腺癌小鼠异种移植瘤模型中,LFP提取物处理后,肿瘤质量显著减少,具体表现为肿瘤体积的显著减小,同时伴随着caspase-3蛋白表达的显著增加[29]。槲皮素可以通过抑制Pl3K/Akt 信号通路诱导线粒体依赖性凋亡,从而抑制胃癌干细胞的增殖[52]

2.1.3 诱导细胞自噬 自噬是细胞通过降解并回收蛋白质和细胞器以维持细胞内稳态的过程,在细胞中发挥保护作用[53]。在癌症中,自噬可以促进肿瘤细胞自身、宿主和局部肿瘤微环境(tumor microenvironment,TME)系统的肿瘤发生。由于需要代谢支持和免疫逃避,肿瘤细胞比大多数正常组织更依赖自噬。同时,自噬也具有抑制肿瘤的作用,因为它无法通过细胞分裂来扩散异常成分[54]。荔枝果实的多酚类化合物可通过激活上述自噬相关通路,发挥其潜在的抗癌效应。Emanuele 等[55]研究发现,荔枝多酚类化合物可以引发早熟的自噬反应(16~24 h),并伴随着自噬相关1/自噬激活激酶1(ATG1/ULK1)、beclin-1、微管相关蛋白1 轻链3(LC3)-Ⅱ和p62 蛋白表达水平的升高,从而降低HT29 细胞的存活率和克隆形成,起到抗癌作用。

2.2 抑制细胞的迁移与侵袭

癌细胞的迁移和侵袭是癌症恶化的核心病理特征,癌细胞不仅表现出异常增殖特性,还可以通过上皮-间质转化(epithelial-mesenchymal transition,EMT)获得迁移能力破坏周围细胞组织,以及通过直接侵袭的方式扩散至邻近器官或借助循环系统转移到远处的器官。

2.2.1 抑制上皮-间质转化过程 上皮-间质转化过程是早期肿瘤向侵袭性肿瘤转化的第一步,通过诱导肿瘤细胞发生一系列改变,赋予肿瘤细胞运动和迁移能力从而促进肿瘤的进展和转移[56-58]。荔枝果实的活性成分可通过不同机制抑制EMT,从而降低肿瘤侵袭转移能力。如原儿茶酸可以作为肺肿瘤细胞上皮-间质转化的新型阻断剂,抑制间质标志物(纤连蛋白、Vimentin 和N-cadherin)、MMP-9、MMP-2、twist 和snail 的表达,促进上皮标志物(E-cadherin和Occludin)的表达,通过逆转EMT 过程,消除肿瘤细胞的迁移和侵袭潜力[23]。TFLS 可以通过调控Skp2-p21/p53 信号轴来抑制非小细胞肺癌(nonsmall cell lung cancer,NSCLC)的增殖和转移。TFLS 中的槲皮素、表儿茶素可以与Skp2 结合,降低Skp2的蛋白表达,从而抑制EMT过程[48]

2.2.2 抗血管生成 血管生成,即新血管的形成,是一个复杂的动态过程,受各种促血管生成和抗血管生成分子的调控。在肿瘤的生长、侵袭和转移中起着至关重要的作用[59]。在癌症相关疾病的干预中,施用靶向并抑制促血管生成因子活性的抗血管生成药物是抗血管生成的主要策略。

血管生成的机制主要受化学刺激调节,如血管内皮生长因子(vascular endothelial growth factor,VEGF)、成纤维细胞生长因子(fibroblast growth factor,FGF)、血小板衍生生长因子(platelet-derived growth factor,PDGF)、血管生成素(angiopoietin,Ang)、肝细胞生长因子(hepatocyte growth factor,HGF)、胰岛素样生长因子(insulin-like growth factor,IGF)、肿瘤坏死因子(tumor necrosis factor,TNF)等[60-62]。Xiang 等[63]研究荔枝籽多酚的抗血管生成活性,结果表明,荔枝籽多酚抑制了VEGF蛋白的表达。而VEGF 作为血管生成诱导剂之一,可作为血管生成的标志物,在癌症相关疾病的预防中有着潜在的作用。

2.2.3 抑制相关信号通路 (1)AKT/mTOR/NF-κB信号通路。Akt 是细胞中一个关键的信号转导网络,涉及多种细胞刺激或毒性损伤的激活过程,对各类细胞的细胞迁移、生长和凋亡有着关键作用[64]。Akt 能激活IKK 蛋白,包括IKK-α 和IKK-β,导致IκBα的磷酸化和随后的降解,从而导致I-κBα/NF-κB复合物的解离、NF-κB 的核易位和NF-κB 信号通路的激活,而TFLS 可以通过抑制IκBα 的磷酸化和NF-κB 的核表达,从而抑制NF-κB 信号通路的激活[65]。此外,Akt 能够激活一种自噬抑制剂——mTOR。mTOR 可形成两种不同的功能复合物mTORC1 和mTORC2,它们与细胞生长、增殖、运动、存活、侵袭和迁移的转移级联相关[66]。研究表明,TFLS 可以抑制Akt的激活,靶向mTOR 通路,进而抑制前列腺癌细胞的体外生长和转移[67]

(2)Skp2-p21/p53 信号通路。Skp2 作为SCF(Skp1-Cullin1-F-box)E3 连接酶复合体的重要组成部分,发挥着特异性识别底物的关键作用,并介导底物的泛素化降解过程[68]。p21 是Skp2 的底物之一,通过阻滞细胞周期抑制肿瘤生长,可被Skp2泛素化降解。P53 是细胞周期和肿瘤抑制的关键基因,通过诱导细胞周期阻滞、DNA 修复或凋亡维持基因组稳定,在细胞周期调控和肿瘤抑制中发挥关键作用。Skp2 介导p21/p53 的降解会削弱这些保护机制,导致癌细胞失控增殖。TFLS 可明显上调p53 的表达,下调Skp2 的表达,通过调控Skp2-p21/p53 信号通路,抑制非小细胞肺癌的增殖和转移,发挥抗肿瘤作用。研究发现,TFLS 中的槲皮素、表儿茶素与Skp2 有较强的结合能力,可能是TFLS 靶向Skp2 发挥作用的效应物质[48]

(3)JAK2/STAT3 信号通路。JAK2/STAT3 通路是JAK/STAT 信号转导通路中的一个重要分支,该通路与细胞周期调控、免疫调节以及生长因子响应等多种关键生物学过程密切相关。在细胞增殖、凋亡和血管新生的调控中发挥关键作用,其异常的细胞信号和调控与肿瘤的发生、发展密切相关[69]。TFLS 可激活SHP-1 的表达,阻断JAK2/STAT3 信号通路,降低磷酸化JAK2 与磷酸化STAT3 的表达水平[26],进而抑制HepG2的增殖来起到抗癌作用。

2.3 增强免疫能力

免疫系统是机体执行免疫应答及免疫功能的重要系统,B 淋巴细胞、T 淋巴细胞以及巨噬细胞是负责免疫功能的主要细胞。而肿瘤免疫治疗可以通过激活、增强或改造免疫系统中的关键成分,使其能够更好地识别并攻击癌细胞[70]。Huang 等[43]构建了化学诱导的免疫抑制小鼠模型,研究发现荔枝果肉多糖能够显著增强免疫调节能力,包括促进脾淋巴细胞的增殖和增强NK 细胞的细胞毒性;荔枝果肉中的杂多糖LP1-3 能够刺激肠系膜淋巴结细胞增殖和细胞因子分泌,从而起到增强机体体液免疫的作用[71]。这些研究结果表明,荔枝果肉中的多糖可能作为一种潜在的天然抗癌和免疫调节剂,值得进一步研究和开发。此外,荔枝果实的原花青素可以触发肠-肺轴,影响T细胞免疫应答,即通过增加CD8+细胞毒性、T 淋巴细胞浸润和减少巨噬细胞数量来抑制结肠癌肺转移[9]

2.4 与化疗药物产生协同增效作用

化疗作为癌症治疗的手段之一,在临床上发挥着关键作用。然而,化疗药物往往伴随着严重的副作用,且长期使用易导致肿瘤细胞耐药性产生。因此,寻找能够与化疗药物产生协同增效作用的植物化学成分成为当前癌症研究的重要方向。荔枝果实的活性成分在与化疗药物联合使用时展现出显著的协同增效作用。

紫杉醇是从太平洋紫杉树的树皮中分离出来的一种四环二萜类化合物。作为一种低毒、高效和广谱的天然抗癌药,紫杉醇对多种类型的癌症均有抵抗作用[72],主要是通过抑制细胞有丝分裂发挥抗癌作用[73]。荔枝核总黄酮与紫杉醇联合对前列腺癌耐药细胞的增殖具有抑制作用[74],紫杉醇通过抑制PI3K/AKT 信号通路、激活MAPK 信号通路和诱导细胞凋亡来抑制肿瘤细胞的增殖[75],而TFLS通过抑制NF-κB 和Akt/mTOR 等信号通路发挥抗肿瘤作用[67]。因此,TFLS 与紫杉醇联用存在协同增效作用。来曲唑属于芳香酶抑制剂,是抗肿瘤药物中的内分泌治疗药物,通过抑制雌激素合成发挥抗癌作用,通常用于乳腺癌的治疗。然而,来曲唑的不良反应发生率高达33%。李关宁等[46]立足于临床观察,发现来曲唑与荔枝核皂苷均能降低雌激素水平,二者起协同作用。荔枝核皂苷可以减轻来曲唑药物带给患者的呕吐、骨痛、头疼等不良反应,起到增效减毒作用。

3 结 语

荔枝果实作为天然植物资源,具有多种抗癌活性成分,可通过调控细胞周期、诱导细胞凋亡和自噬、抑制EMT及相关信号通路等途径展现出多维度抗癌潜力,为天然抗癌药物的研发提供了重要资源。现有研究不仅揭示了荔枝果实单一成分的作用机制,还初步揭示了其与化疗药物的协同增效作用,尤其是在逆转耐药性和降低毒副作用方面具有独特优势。然而,目前荔枝果实的抗癌研究多集中在体外机制方面,缺乏体内试验验证;同时,关于其活性成分的生物利用度、剂量效应及毒理学评价尚未完善,临床转化研究匮乏,实际应用潜力亟待挖掘。未来关于荔枝果实的抗癌研究应聚焦以下方向:(1)多成分协同抗癌效应及分子机制解析;(2)活性成分的靶向递送及稳定性优化;(3)基于人工智能的活性成分筛选与结构修饰;(4)临床前及临床试验推进,验证其安全性与有效性。此外,还可以结合现代生物技术开发高附加值抗癌产品,推动荔枝资源从“食”到“药”的转化,为癌症相关疾病的预防和改善提供绿色、经济的新方法。

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Advances in the research on anticancer active ingredients and their anti‐cancer mechanisms in litchi fruits

YAN Zhaoying, SUN Xinyu, YANG Na, TANG Shengmei, SHAO Jinhua, HE Fulin, JIANG Liyan*
(College of Chemistry and Bio-engineering, Hunan University of Science and Engineering, Yongzhou 425199, Hunan, China)

Abstract:Currently, the global cancer burden continues to increase. Existing cancer treatments face bottlenecks such as drug resistance and toxic side effects, and scientists are looking for natural products that can effectively prevent and treat cancer. litchi fruit as a kind of food with medicine effect is rich in polyphenols (proanthocyanidins, phenolic acid, flavonoids), vitamin C, dietary fiber, polysaccharides and saponins and other active ingredients. Research has shown that litchi fruit has a certain preventive and inhibitory effect on the occurrence of breast cancer, colon cancer, prostate cancer and liver cancer,etc. due to the active ingredients. The total phenolic content of nine Litchi varieties, including Feizixiao,Heiye and Nuomici, ranged from 9.39 to 30.16 mg·g-1, with an average of 16.27 mg·g-1, which showed potent antioxidant properties and reduced the risk of cancerous lesions. The Litchi proanthocyanidins could inhibit the metastasis of colon cancer by triggering the intestinal-lung axis to influence the immune response of T-cells, and the total flavonoids from Litchi kernel could inhibit the development of breast cancer, prostate cancer and liver cancer. The total flavonoids from Litchi Semen (TFLS) could inhibit the growth of prostate cancer in bone by inhibiting the HGFR/NF-κB signaling pathway, and TFLS could reduce the expression level of phosphorylated JAK2 and STAT3 by activating SHP-1 to block the JAK2/STAT3 signaling pathway. The TFLS could inhibit the proliferation of HepG2 cells by activating SHP-1 to block the JAK2/STAT3 signaling pathway, and also inhibit the migration and invasion ability of HepG2 cells by reversing the EMT process of the cells, thus exerting anti-tumor effects.In addition, the TFLS could inhibit the proliferation and metastasis of non-small cell lung cancer(NSCLC) through regulating the Skp2-p21/p53 signaling axis. The vitamin and dietary fiber contents of litchi also differed from each other. The Vitamin C content ranked in the forefront of common fruits, the black leaves contained about 32 mg of vitamin per 100 g, while toffee contained about 56 mg of vitamin C per 100 g; the content of dietary fiber in the pulp of white wax, toffee and wyche wass 0.77 g·100 g-1,0.75 g·100 g-1 and 1.16 g·100 g-1, respectively, which built an intestinal defense barrier for the organism. The litchi dietary fiber could play a role in preventing colon cancer through regulating intestinal function and strong antioxidant function dual pathway. Studies showed that the intake of dietary fiber was negatively correlated with the incidence of colon cancer; litchi polysaccharides could also inhibit the proliferation of human hepatocellular carcinoma cells HepG2, human cervical cancer cells Hela, human lung cancer cells A549 three kinds of tumor cell lines in a concentration-dependent manner, and the degree of inhibition and litchi fresh and dried also had a certain relationship; the use of litchi kernels and nuclei of litchi could help to build a defense barrier for the body. The use of litchi nuclear saponin for endocrine treatment of breast cancer could also delay the progression and recurrence of breast cancer. In addition to these anti-cancer mechanisms, the anti-cancer active ingredients in litchi could also produce synergistic effects with drugs, reducing the adverse effects of anti-tumor drugs. The litchi nuclear flavonoids and paclitaxel combined with the proliferation of drug-resistant cells of prostate cancer inhibition, so that the two could be used in conjunction with synergistic inhibitory effects. The rich anticancer active ingredients of litchi fruit and its potential shown in the prevention and treatment of many kinds of cancers have opened up a new dimension for the development of multi-targeted and synergistic anticancer drugs. Existing studies have not only systematically identified a variety of anticancer active ingredients, but also elucidated the anticancer efficacy of these ingredients through multiple pathways,but the studies are generally conducted on a single active ingredient, and the studies on the specific mechanism of action of the anticancer active ingredients in litchi fruits are relatively dispersed. Therefore, this paper summarized the anticancer active ingredients in Litchi chinensis fruit and their mechanisms of action in the stages of cancer proliferation and metastasis, with the aim of providing reference for the subsequent drug development and comprehensive utilization of L. chinensis fruit.

Key words:Litchi fruits; Anticancer; Bioactive components; Anticancer mechanism

中图分类号:S667.1

文献标志码:A

文章编号:1009-9980(2026)01-0176-10

DOI:10.13925/j.cnki.gsxb.20250184

收稿日期:2025-04-03

接受日期:2025-07-02

基金项目:湖南省自然科学基金项目(2024JJ7192);湖南省教育厅科学研究项目(24C0472);永州市指导性科技计划项目(2023YZ022)

作者简介:严召颖,女,学士,研究方向为食品质量与安全控制。Tel:0746-6381164,E-mail:3442152811@qq.com

*通信作者 Author for correspondence. E-mail:lyj5423@163.com