薯蓣皂苷在恶性肿瘤中的作用及分子机制研究进展
Research Progress on the Role and Molecular Mechanisms of Dioscin in Malignant Tumors
DOI: 10.12677/acm.2025.1572133, PDF, HTML, XML,    科研立项经费支持
作者: 俞 红:丽水市中心医院麻醉科复苏室,浙江 丽水;黄旭华:浙江大学医学院附属第一医院普胸外科,浙江 杭州;曾庆辉, 郑春辉, 章方彪, 赵 纯*:丽水市中心医院心胸外科,浙江 丽水;李淑玲:丽水市中心医院手术室,浙江 丽水
关键词: 薯蓣皂苷恶性肿瘤抗肿瘤机制信号通路联合治疗Dioscin Malignant Tumor Antitumor Mechanism Signaling Pathways Combination Therapy
摘要: 薯蓣皂苷作为一种天然活性成分,近年来在恶性肿瘤治疗领域展现出重要的研究价值和应用潜力。恶性肿瘤是全球范围内威胁人类健康的主要疾病之一,而传统治疗手段如化疗和放疗往往伴随严重的副作用,因此开发高效低毒的新型抗肿瘤药物成为研究热点。薯蓣皂苷通过多种机制发挥抗肿瘤作用,包括抑制肿瘤细胞增殖、诱导凋亡、抑制侵袭转移以及调节免疫微环境等。研究表明,薯蓣皂苷能够靶向调控多条信号通路,从而影响肿瘤的发生发展。然而,目前关于薯蓣皂苷的具体作用靶点和分子机制仍存在许多未解之谜,其在临床转化中的应用也面临挑战。本文系统综述了薯蓣皂苷在多种恶性肿瘤中的抗肿瘤效应及其分子机制,并探讨了其在临床前研究中的应用前景及可能的联合治疗策略,以期为薯蓣皂苷的进一步研究和临床开发提供理论支持。
Abstract: Dioscin, a natural bioactive compound, has recently attracted increasing attention for its potential therapeutic value and application prospects in the treatment of malignant tumors. Malignant tumors remain one of the leading global threats to human health, and conventional therapies such as chemotherapy and radiotherapy are often associated with severe adverse effects. Thus, the development of novel anticancer agents with high efficacy and low toxicity has become a research focus. Dioscin exhibits antitumor effects through multiple mechanisms, including inhibition of tumor cell proliferation, induction of apoptosis, suppression of invasion and metastasis, and modulation of the tumor immune microenvironment. Studies have demonstrated that dioscin can target and regulate various signaling pathways involved in tumorigenesis and cancer progression. However, the specific molecular targets and detailed mechanisms of action of dioscin remain incompletely understood, and its clinical translation still faces several challenges. This review systematically summarizes the antitumor activities and underlying molecular mechanisms of dioscin across various types of malignancies. Furthermore, it discusses the potential of dioscin in preclinical studies and explores possible strategies for combination therapy, aiming to provide theoretical support for further investigation and clinical development of dioscin.
文章引用:俞红, 黄旭华, 曾庆辉, 郑春辉, 李淑玲, 章方彪, 赵纯. 薯蓣皂苷在恶性肿瘤中的作用及分子机制研究进展[J]. 临床医学进展, 2025, 15(7): 1341-1349. https://doi.org/10.12677/acm.2025.1572133

1. 引言

恶性肿瘤是全球公共卫生领域的重大挑战,其高发病率与死亡率促使研究者不断探索更安全有效的治疗策略。传统治疗手段如化疗、放疗及靶向治疗虽取得一定进展,但耐药性、毒副作用及肿瘤异质性等问题仍制约临床疗效。近年来,天然产物因其多靶点、低毒性的特点成为抗肿瘤药物研发的重要方向。薯蓣皂苷(Dioscin)作为从薯蓣科植物中提取的甾体皂苷类化合物[1],在多种恶性肿瘤模型中展现出显著的抗增殖、促凋亡及抑制转移等活性[2],其作用机制涉及调控PI3K/AKT、MAPK、NF-κB等关键信号通路。例如,在肺癌中,薯蓣皂苷通过靶向AKT1激酶抑制PI3K/AKT通路,下调MMP2和PCNA表达,从而减少肿瘤侵袭与转移[3];在结直肠癌中,其通过促进c-myc泛素化降解,抑制糖酵解关键酶HK-2的活性,进而诱导肿瘤细胞凋亡[4]。此外,薯蓣皂苷还能通过激活自噬减轻氧化应激,或通过TLR4/NF-κB轴缓解炎症反应[5],这些机制为其在口腔鳞癌[6]、胃癌[7]及骨关节炎[8]等疾病中[9] [10]的治疗潜力提供了理论依据。本文系统综述薯蓣皂苷的抗肿瘤效应及其分子机制,旨在为开发新型抗肿瘤药物提供科学参考。

本研究严格遵循系统综述(PRISMA)规范制定检索策略。为全面收集薯蓣皂苷在恶性肿瘤中作用及分子机制的相关研究,本研究系统检索了多个中英文数据库,包括中文数据库中国知网(CNKI)、万方数据和维普资讯(VIP),以及英文数据库PubMed、Web of Science、Embase和Cochrane Library。检索时间范围设定为各数据库建库起始至2025年4月30日。检索采用的主题关键词包括中文关键词“薯蓣皂苷”、“恶性肿瘤”、“抗肿瘤机制”、“信号通路”、“联合治疗”以及对应的英文关键词“Dioscin”、“Malignant Tumor”、“Antitumor Mechanism”、“Signaling Pathways”、“Combination Therapy”,并根据不同数据库的具体要求对检索词进行逻辑组合(AND/OR)调整以优化检索式。文献筛选标准明确为:纳入研究对象聚焦于薯蓣皂苷在各类恶性肿瘤中的作用及分子机制的基础研究(体外细胞实验、动物模型实验)、临床前研究及相关综述文献,语种限定为中英文;排除标准则包括研究对象为非恶性肿瘤(如良性肿瘤或其他疾病)的文献、无法获取全文或数据不完整的文献以及重复发表的文献。文献筛选流程依次包括初步检索、去除重复记录、基于标题和摘要的初步筛选、对潜在相关文献进行全文精读评估,最终确定符合纳入标准的文献。

2. 薯蓣皂苷的化学结构与来源

2.1. 薯蓣皂苷的化学结构特征

薯蓣皂苷是一种甾体皂苷类化合物,其化学结构由疏水性的甾体骨架和亲水性的糖链组成。其甾体骨架为螺甾烷型,由27个碳原子构成,包含六个环(A-F环),其中F环通过螺缩酮结构与E环相连。糖链部分通常由1~3个糖基(如葡萄糖、鼠李糖或半乳糖)通过β-糖苷键与甾体骨架的C-3位羟基连接[11]。这种独特的结构赋予薯蓣皂苷两亲性,使其能够与细胞膜相互作用,并通过调节膜受体或信号通路发挥生物活性。研究表明,薯蓣皂苷的糖基化程度和糖链类型直接影响其溶解性、稳定性和药理活性[12],例如糖链的去除(如生成薯蓣皂苷元Diosgenin)会显著改变其抗肿瘤和抗炎效应[13]。此外,薯蓣皂苷的C-5和C-6位双键、C-25位甲基构型(R/S)等结构细节也与其靶向AKT1、NF-κB等关键蛋白的能力密切相关。

2.2. 薯蓣皂苷的天然来源与提取方法

薯蓣皂苷广泛分布于薯蓣科(Dioscoreaceae)植物中,如穿龙薯蓣(Dioscorea nipponica Makino)、黄精(Polygonatum sibiricum)等传统药用植物[14]。这些植物在中医中常用于治疗慢性支气管炎、咳嗽和哮喘,其药理活性部分归因于薯蓣皂苷的存在,其提取方法通常采用有机溶剂(如甲醇、乙醇)回流或超声辅助提取,结合大孔吸附树脂或硅胶柱层析进行纯化[15]。例如,穿龙薯蓣的干燥根茎经乙醇提取后,通过AB-8树脂富集,再经高效液相色谱(HPLC)分离可获得高纯度薯蓣皂苷。近年来,绿色提取技术(如超临界CO2萃取)因能减少有机溶剂残留而受到关注。值得注意的是,不同植物来源的薯蓣皂苷可能存在结构微异(如糖基取代差异),这可能导致其药理活性的多样性,例如黄精来源的薯蓣皂苷在抑制子宫内膜癌细胞迁移中表现出对MAPK信号通路的特异性调控[16]

3. 薯蓣皂苷的抗肿瘤作用

3.1. 抑制肿瘤细胞增殖

薯蓣皂苷在多种肿瘤模型中表现出显著的抗增殖活性。研究表明,薯蓣皂苷通过调节ATM/p53信号通路抑制皮肤癌A431细胞的增殖,显著降低细胞存活率并抑制集落形成能力[17]。在结直肠癌中,薯蓣皂苷通过促进c-myc的泛素化降解,进而抑制糖酵解关键酶HK2的表达,从而阻断肿瘤细胞的能量供应并抑制其增殖[18]。此外,在非小细胞肺癌(NSCLC)中,薯蓣皂苷通过下调Survivin蛋白的表达,显著抑制肿瘤细胞的存活[19]。这些发现表明,薯蓣皂苷通过多靶点作用机制干扰肿瘤细胞的增殖过程,为其抗肿瘤应用提供了理论依据[20]

3.2. 诱导肿瘤细胞凋亡

薯蓣皂苷可通过多种途径诱导肿瘤细胞凋亡。在骨肉瘤细胞中,薯蓣皂苷通过上调ROS依赖的p38 MAPK信号通路,激活线粒体凋亡途径,表现为BAX表达上调、BCL-2表达下调,并激活caspase-3/9的剪切[21]。在口腔鳞状细胞癌(OSCC)中,薯蓣皂苷通过促进BMI1蛋白的泛素化降解,解除其对促凋亡蛋白Noxa的抑制,从而诱导细胞凋亡。此外,在皮肤癌A431细胞中,薯蓣皂苷通过激活p53依赖的凋亡通路,显著增加DNA损伤标志物和凋亡相关蛋白的表达[17]。这些研究揭示了薯蓣皂苷通过调控凋亡相关蛋白和信号通路,发挥其促凋亡作用。

3.3. 抑制肿瘤侵袭与转移

薯蓣皂苷对肿瘤的侵袭和转移具有显著的抑制作用。在皮肤癌A431细胞中,薯蓣皂苷显著下调MMP2、MMP9、RHO和cdc42等侵袭相关蛋白的表达[17],从而抑制肿瘤细胞的迁移和侵袭能力。在非小细胞肺癌(NSCLC)中,薯蓣皂苷与柔红霉素联合使用时,通过下调MMP-2、VE-Cad、TGF-β1和HIF-1α等蛋白的表达,进一步抑制肿瘤血管生成拟态通道的形成和转移[22]。此外,薯蓣皂苷还可通过抑制糖酵解途径,减少肿瘤细胞的能量供应,从而间接抑制其侵袭能力。这些研究为薯蓣皂苷在抗肿瘤转移中的应用提供了实验依据[16]

4. 薯蓣皂苷抗肿瘤的分子机制

4.1. 调控细胞周期相关蛋白

薯蓣皂苷通过调控细胞周期相关蛋白的表达,抑制肿瘤细胞的异常增殖。研究表明,薯蓣皂苷能够下调细胞周期蛋白(如Cyclin D1和Cyclin E)的表达[23],同时上调细胞周期依赖性激酶抑制剂(如p21和p27)的水平[24],从而阻滞肿瘤细胞从G1期向S期的过渡[24]。这种作用在多种肿瘤细胞系中均得到验证,包括乳腺癌、肝癌和肺癌等。此外,薯蓣皂苷还能通过抑制CDK2和CDK4的活性[25],进一步阻断细胞周期的进程,最终导致肿瘤细胞增殖受阻。

4.2. 激活凋亡信号通路

薯蓣皂苷通过激活凋亡信号通路,诱导肿瘤细胞的程序性死亡。在线粒体途径中,薯蓣皂苷能够增加促凋亡蛋白(如Bax和Bak)的表达,同时抑制抗凋亡蛋白(如Bcl-2和Bcl-xL)的功能[26],导致线粒体膜电位下降和细胞色素C的释放,进而激活caspase级联反应。在死亡受体途径中,薯蓣皂苷可通过上调Fas和TRAIL受体的表达,激活caspase-8,最终引发凋亡[27]。这些机制在骨肉瘤[28]等多种肿瘤模型中均得到证实。

4.3. 抑制肿瘤微环境中的炎症反应

薯蓣皂苷通过抑制肿瘤微环境中的炎症反应,间接发挥抗肿瘤作用[29]。炎症反应在肿瘤的发生、发展和转移中起关键作用,而薯蓣皂苷能够下调促炎细胞因子(如TNF-α、IL-6和IL-1β)的表达,同时抑制NF-κB和STAT3等炎症相关信号通路的激活[30]。此外,薯蓣皂苷还能减少肿瘤相关巨噬细胞(TAMs)的浸润和活化,从而降低肿瘤微环境的免疫抑制性,增强机体的抗肿瘤免疫应答[31]。这些作用在胶质瘤等炎症相关性肿瘤中尤为显著。

5. 薯蓣皂苷在恶性肿瘤中的研究进展

5.1. 乳腺癌

目前关于薯蓣皂苷在乳腺癌中的研究相对较少,但已有初步证据表明其可能通过调控关键信号通路发挥抗肿瘤作用。薯蓣皂苷能够显著抑制肿瘤细胞的增殖和迁移[32],这一作用可能通过下调MEK/ERK和JNK信号通路实现,即通过抑制MAPK信号通路的关键蛋白(如p-MEK、p-ERK和p-JNK)的表达,从而减少肿瘤细胞的侵袭和转移能力。此外,薯蓣皂苷还可能通过下调基质金属蛋白酶(MMP2和MMP9)的表达,进一步抑制乳腺癌细胞的迁移和侵袭[33]。这些发现为薯蓣皂苷在乳腺癌治疗中的潜在应用提供了理论基础,但仍需更多实验验证[34]

5.2. 肺癌

薯蓣皂苷在肺癌中的研究较为深入[3] [35],其抗肿瘤作用主要通过靶向PI3K/AKT信号通路实现。研究表明,薯蓣皂苷能够与AKT1激酶结合,抑制其磷酸化,从而阻断下游信号传导。在体外实验中,薯蓣皂苷显著抑制了肺癌细胞(如A549和PC-9)的增殖、侵袭和迁移能力,同时降低了p-AKT、MMP2和PCNA的表达水平[36]。在体内实验中,薯蓣皂苷减少了肺癌小鼠模型中的肺结节数量和肺损伤,并降低了死亡率。此外,薯蓣皂苷还能通过激活caspase-3诱导肿瘤细胞凋亡[37]。这些结果表明,薯蓣皂苷通过双重机制(抑制AKT信号通路和诱导凋亡)发挥抗肺癌作用,为其在肺癌治疗中的潜在应用提供了有力支持[38]

5.3. 结直肠癌

薯蓣皂苷在结直肠癌中的抗肿瘤作用主要通过调控肿瘤糖代谢和诱导细胞凋亡实现[39]。研究发现,薯蓣皂苷能够显著抑制结直肠癌细胞的糖酵解过程[4],表现为葡萄糖吸收和乳酸生成的减少。这一作用与薯蓣皂苷对己糖激酶-2 (HK2)的抑制密切相关。薯蓣皂苷通过促进E3泛素连接酶FBW7与c-myc的结合,加速c-myc的泛素化降解,从而下调HK2的表达。此外,薯蓣皂苷还能破坏HK2与VDAC-1的相互作用,进一步抑制糖酵解并诱导细胞凋亡[40]。在体内实验中,薯蓣皂苷显著抑制了结直肠癌异种移植瘤的生长[41]。这些结果表明,薯蓣皂苷通过靶向c-myc/HK2轴调控肿瘤代谢,为结直肠癌的治疗提供了新的策略[42]

5.4. 肝癌

目前关于薯蓣皂苷在肝癌中的直接研究较少,但其在其他肿瘤中的抗炎和抗纤维化作用可能为肝癌治疗提供启示[43]。薯蓣皂苷在矽肺模型中的研究表明,它能够通过促进肺泡巨噬细胞的自噬,减少线粒体活性氧(mtROS)的产生,从而抑制炎症和纤维化。肝癌的发生发展与慢性炎症和纤维化密切相关,因此薯蓣皂苷可能通过类似机制在肝癌中发挥作用。此外,薯蓣皂苷在其他肿瘤中表现出的调控MAPK和PI3K/AKT信号通路的能力,也可能在肝癌中抑制肿瘤细胞的增殖和转移。然而,这些推测仍需进一步的实验验证,以明确薯蓣皂苷在肝癌中的具体作用机制和疗效。

6. 薯蓣皂苷的联合治疗与临床应用前景

6.1. 与化疗药物的协同作用

薯蓣皂苷作为一种天然甾体皂苷,近年来在抗炎和抗肿瘤领域展现出潜在的应用价值。研究表明,薯蓣皂苷通过调控Sirt1/FoxO1信号轴,能够抑制机械应力诱导的软骨细胞凋亡和代谢紊乱,从而保护软骨组织免受损伤。这一机制提示薯蓣皂苷可能通过类似的途径增强化疗药物的疗效[44]。例如,薯蓣皂苷通过激活Sirt1表达,抑制FoxO1的磷酸化和核质转移,从而逆转细胞生长抑制和凋亡。此外,薯蓣皂苷还能通过抑制NF-κB信号通路,减少炎症因子的释放,这可能有助于减轻化疗药物引起的炎症副作用。尽管目前关于薯蓣皂苷与化疗药物协同作用的研究较少[45] [46],但其在软骨保护和抗炎中的作用机制为未来联合治疗提供了理论基础。

6.2. 与免疫治疗的潜在联合应用

薯蓣皂苷在免疫调节方面的作用逐渐受到关注。研究发现,薯蓣皂苷能够通过激活LXRα,抑制IL-1β诱导的炎症反应,减少PGE2和NO的生成,并下调COX-2和iNOS的表达[47]。此外,薯蓣皂苷还能抑制MMPs (如MMP1、MMP3和MMP13)和ADAMTS-5的过度表达,从而保护软骨基质稳态[48]。这些抗炎和免疫调节作用表明,薯蓣皂苷可能与免疫治疗药物(如PD-1/PD-L1抑制剂)产生协同效应,增强抗肿瘤免疫反应。特别是在类风湿性关节炎(RA)模型中,薯蓣皂苷通过抑制SIRT1的脱乙酰化活性,减少eNAMPT的释放[49],从而缓解炎症反应。这一发现为薯蓣皂苷在免疫治疗中的潜在应用提供了新的研究方向[50]

6.3. 临床前研究的挑战与展望

尽管薯蓣皂苷在体外和动物模型中表现出显著的抗炎[51]和软骨保护作用,但其临床应用仍面临诸多挑战[52]。首先,薯蓣皂苷的药代动力学特性尚不明确,其在人体内的吸收、分布、代谢和排泄需要进一步研究[53]。其次,薯蓣皂苷的作用机制涉及多条信号通路(如Sirt1/FoxO1、NF-κB和MAPK),其在不同疾病模型中的特异性仍需验证。此外,薯蓣皂苷与其他药物的相互作用及其长期安全性也需要评估[54]。未来研究应重点关注薯蓣皂苷的剂型优化和靶向递送系统,以提高其生物利用度和治疗效果[55]。同时,开展更多临床前和临床试验,探索薯蓣皂苷在骨关节炎、类风湿性关节炎和肿瘤等疾病中的联合治疗潜力,将是推动其临床应用的关键。

7. 结论

薯蓣皂苷作为一种具有多靶点抗肿瘤活性的天然化合物,其分子机制研究已取得显著进展,为恶性肿瘤治疗提供了新的潜在策略。现有证据表明,薯蓣皂苷可通过调控细胞周期、诱导凋亡、抑制血管生成及调节免疫微环境等多种途径发挥抗肿瘤作用,展现出良好的临床应用前景。然而,目前的研究仍以体外实验和动物模型为主,其临床转化面临诸多挑战,包括药代动力学特性不明确、潜在毒性评估不足以及与其他治疗手段的协同效应尚需验证。

从研究现状来看,薯蓣皂苷的抗肿瘤机制虽已部分阐明,但不同研究之间存在一定差异,例如其对不同肿瘤细胞系的敏感性及作用靶点可能有所不同。因此,未来研究需进一步整合现有数据,明确其核心作用通路,并通过多中心临床试验验证其安全性和有效性。此外,薯蓣皂苷与其他抗肿瘤药物(如化疗药或免疫检查点抑制剂)的联合应用值得深入探索,以优化其治疗潜力并减少耐药性风险。

总体而言,薯蓣皂苷的研究仍处于从基础向临床过渡的关键阶段。未来需加强跨学科合作,结合药理学、毒理学及临床医学,推动其从实验室走向临床实践。在平衡不同研究的观点时,应注重机制研究的严谨性,同时兼顾临床转化的可行性,以确保薯蓣皂苷最终能够成为恶性肿瘤综合治疗中的有效补充手段。

基金项目

丽水市科技计划项目(2022GYX27)。

NOTES

*通讯作者。

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