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肿瘤多药耐药（MDR）是导致化疗与靶向治疗失败的重要原因。近年来，中药活性成分由于其“多成分-多靶点-低毒性”的特点，在逆转MDR和增强化疗疗效方面展现出独特优势。本文系统综述了MDR的关键分子机制，重点探讨了黄芩素、姜黄素、丹参酮等典型活性成分在抑制药物外排泵、重建凋亡稳态、干扰DNA修复通路及改善肿瘤免疫微环境等方面的作用。研究表明，这些成分不仅能够独立发挥逆转耐药的作用，还可与常用化疗药物协同增效，显著提升抗肿瘤综合疗效。本综述为中药改善肿瘤耐药研究提供了理论支持，并为多靶点联合干预策略的构建与优化提供了新思路。
肿瘤多药耐药（multidrug resistance，MDR）是导致癌症治疗失败的主要因素之一，其主要表现为癌细胞对多种结构和作用机制不同的抗肿瘤药物产生交叉耐药性[1]。MDR的形成是一个多因素、多机制协同作用的过程，核心机制主要包括三磷酸腺苷（adenosine triphosphate，ATP）结合盒转运蛋白（ATP-binding cassette transporters，ABC）如P-糖蛋白（P-glycoprotein，P-gp）、乳腺癌耐药蛋白等的过度表达，导致药物外排增强；细胞凋亡程序的抑制，使癌细胞逃避免疫清除；DNA损伤修复机制的异常激活，提高细胞对药物诱导损伤的耐受能力；以及肿瘤微环境（tumor microenvironment，TME）中免疫抑制、低氧、酸性、促炎状态等因素的综合干扰[2]。此外，DNA甲基化、组蛋白修饰、非编码RNA等表观遗传异常亦在MDR发生中起到重要调控作用[3]。这些改变相互交织，构建出一个高度复杂、动态可塑的耐药网络，严重削弱了化疗及靶向治疗的疗效。
目前临床主要通过加大药物剂量、调整用药方案或联合逆转剂（如P-gp抑制剂、凋亡诱导剂、信号通路抑制剂等）方式尝试逆转MDR表型[4]。尽管上述策略在一定程度上改善了部分患者的治疗反应，但普遍存在疗效不稳定、不良反应大、作用靶点局限等问题，难以有效覆盖MDR网络的复杂调控机制。因此，亟需开发具有多靶点、低毒性、协同增效的新型耐药逆转干预策略。
传统中医药在肿瘤治疗中已有长期应用基础，具有扶正祛邪、抗肿瘤、缓解毒副反应、延缓耐药进展等综合作用。近年来，越来越多研究集中于中药活性成分在MDR逆转中的潜力。大量证据表明，中药来源的天然产物凭借“多成分-多靶点-多通路”的药理特性，能够同时干预多个耐药相关通路，重塑肿瘤细胞的药物敏感性[5]。其中，黄酮类、生物碱类、萜类、多酚类及香豆素类等活性成分在调控药物外排泵表达、促进凋亡、抑制DNA修复、改善肿瘤免疫微环境等方面展现出显著效果[6]。此外，部分活性成分如姜黄素、白藜芦醇等已进入临床前或临床研究阶段，并在与化疗药物联合应用中展现出良好的协同疗效和安全性[7]。相比传统化学抑制剂，中药活性成分具有低毒性、良好耐受性等优势，成为当前逆转耐药研究的重要方向之一。
1 直接靶向耐药相关蛋白
1.1 抑制ABC转运泵
药物转运蛋白是MDR发展的关键分子驱动因素，其通过ATP依赖的主动外排机制显著降低细胞内化疗药物浓度。常见的ABC家族成员包括P-gp、乳腺癌耐药蛋白（breast cancer resistance protein，BCRP/ABCG2）、多药耐药相关蛋白1（multidrug resistance-associated protein 1，MRP1/ABCC1）以及肺耐药相关蛋白（lung resistance-related protein，LRP）等[8]。尤其是P-gp，作为ABC转运蛋白的代表，是多种肿瘤中MDR的核心介导因素之一。该蛋白能够识别多种结构类型的抗癌药物，并将其主动泵出细胞外，从而显著降低药物在癌细胞内的有效浓度[9-11]。
目前，P-gp的过表达已在多种耐药性恶性肿瘤中被证实。传统中药在逆转P-gp介导的耐药中展现出独特优势。一方面，中药活性成分可作为底物类似物与化疗药物竞争结合P-gp的药物结合位点，阻断药物外排；另一方面，可通过抑制ATP酶活性，剥夺泵功能所需的能量来源或者在转录、翻译、蛋白稳定性层面下调P-gp的表达水平，改变P-gp构象，从而间接抑制其泵出功能 [12]。Alopecurone B（ALOB）是一种从苦参中分离得到的黄酮类化合物，苦参具有清热燥湿、杀虫止痒等传统功效。Xia等[13]研究表明，ALOB可下调P-gp的表达水平，促进阿霉素（doxorubicin，DOX）在骨肉瘤耐药株MG-63/DOX细胞核内的积聚，从而增强DOX诱导的细胞凋亡。丹参素可以降低多药耐药基因1和B淋巴细胞瘤-2（B-cell lymphoma-2，Bcl-2）的表达诱导凋亡，在体外有效杀伤多药耐药肿瘤细胞 [14]。甾体皂苷类薯蓣皂苷通过双重调控P-gp蛋白转录合成与泛素化降解途径逆转耐药，即靶向蛋白激酶B（protein kinase B，Akt）/磷酸化p38丝裂原活化蛋白激酶（mitogen-activated protein kinases，MAPK）/糖原合成酶激酶3β（glycogen synthase kinase 3 beta，GSK3β）信号网络，抑制Akt、c-Jun氨基端激酶（c-Jun N-terminal kinase，JNK）、细胞外信号调节激酶（extracellular signal-regulated kinase，ERK）及GSK3β位点磷酸化，阻断P-gp基因转录激活。通过增强E3泛素连接酶与P-gp的结合，促进P-gp Lys48位点多聚泛素化修饰[15]。
1.2 调控药物代谢酶
药物代谢是药物的生物转化过程，通常由药物代谢酶介导，在肿瘤耐药中通过多种机制发挥作用，包括I相酶如细胞色素P450酶（cytochrome P450，CYP）对药物的氧化、还原或水解代谢，降低药物活性；II相酶如谷胱甘肽转移酶（glutathione S-transferase，GST）、葡萄糖醛酸转移酶（UDP-glycosyltransferase，UGT）通过结合反应促进药物解毒和排出；III相酶通过外排泵减少细胞内药物蓄积。这些酶的异常表达或活性改变导致化疗药物代谢加速或清除增强，从而削弱药效，是肿瘤耐药的重要机制之一[16]。中药天然成分可通过选择性调节CYP450酶家族及非P450酶系等的活性，重塑TME中的药物代谢平衡，进而逆转耐药。雷公藤可以选择性抑制CYP3A4及CYP2C19/CYP2D6，减少化疗药物代谢失活[17]。黄芩素通过激活芳烃受体 ，诱导CYP1A1/1A2活性以增强部分前药的激活效率，同时抑制CYP3A降低药物降解，增加环磷酰胺活化[18]。丹参酮通过上调CYP1A2的蛋白和mRNA表达，促进依托泊苷等依赖该酶活化的前药转化为活性形式，弥补耐药细胞中代谢激活不足的缺陷[19]。
2 间接调控耐药信号通路
2.1 表观遗传调控
表观遗传调控通过改变组蛋白修饰（如组蛋白去乙酰化酶4抑制剂恢复乙酰化水平）和DNA甲基化状态（如逆转耐药基因的低甲基化），重新激活抑癌基因并抑制促耐药基因的表达，从而增强肿瘤细胞对化疗药物的敏感性[20]。中药活性成分可以通过调控表观遗传，联合传统化疗有效逆转多药耐药。
盐酸小檗碱是一种天然异喹啉生物碱，虽然单独抗菌活性较弱，但能显著增强多重耐药菌对抗生素的敏感性，甚至逆转其对替加环素、舒巴坦钠、美罗培南和环丙沙星等药物的耐药性。其机制涉及adeB基因的表达与AdeB转运蛋白结合，减少AdeABC泵对抗生素的排出，从而减少药物外排[21]。小檗碱还能通过下调RAD51蛋白表达和磷酸化水平，破坏DNA损伤修复机制，削弱肿瘤基因组稳定性[22]。盐酸小檗胺可以靶向结合磷脂酰肌醇3-激酶（phosphatidylinositol-3 kinase，PI3K）催化亚基，阻断下游Akt/哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）磷酸化，以此增强肝癌细胞对索拉非尼敏感性[23]。白藜芦醇直接结合XPA蛋白，阻断其与损伤DNA的结合能力，导致顺铂诱导的DNA交联修复失败[24]。
2.2 TME重塑
TME是由癌细胞、癌症相关成纤维细胞（cancer-associated fibroblasts，CAFs）、免疫细胞（如骨髓来源的抑制性细胞和肿瘤相关巨噬细胞）、细胞外基质及缺氧-酸性-氧化应激网络组成的动态生态系统。TME通过炎症微环境、缺氧等物理屏障，以及代谢重编程和免疫逃逸协同驱动上皮-间充质转化和多药耐药[25-26]。而中药活性成分的多靶点干预策略可以通过抑制或激活自噬，改变TME的缺氧、酸性和氧化应激状态，增强药物敏感性。丹参酮IIA可以抑制CAFs的血小板衍生生长因子受体β/ERK1/2通路，减少血小板源性生长因子-BB和趋化因子2的分泌，削弱CAFs对癌细胞耐药性的支持作用[27]。抑制下游Janus激酶1和2，促进血管完整性和原位灌注来抑制肿瘤生长，改善免疫抑制性微环境，与PD-1单克隆抗体联合治疗时，表现出更强的免疫激活表型[28]。人参皂苷Rg3可以通过逆转免疫抑制状态,将促肿瘤的M2型巨噬细胞重新极化为抗肿瘤的M1型，抑制髓源性抑制细胞和白细胞介素-6/信号传导及转录激活蛋白（signal transducer and activator of transcription，STAT3）/p-STAT3信号通路，减少M2巨噬细胞的浸润及其介导的耐药性，从而改善免疫抑制性TME。同时减少肿瘤相关成纤维细胞和胶原纤维，破坏肿瘤的纤维化结构，降低细胞外基质的屏障作用，增强药物渗透性[29]。
图1和表1中汇总了不同种类的中药在肿瘤耐药上的作用机制及应用。其中黄酮类和多酚类成分是抑制ABC转运泵的主要代表，而黄酮类和皂苷类则在药物代谢酶调控中作用突出；不同类别成分的作用机制相互补充，为构建“多成分—多靶点”的联合逆转策略提供了坚实的分子基础。
3 协同增效的配伍策略
3.1 中药-化疗药协同
中药活性成分与化疗药物的协同配伍不仅可通过直接抑制耐药蛋白表达及调控凋亡通路以增强化疗敏感性，还涉及铁死亡诱导、免疫微环境调控等新兴机制，从而在多维度克服多药耐药并减轻毒副作用[52]。例如，低剂量表没食子儿茶素与DOX联用可抑制Nrf2介导的抗氧化通路，增强氧化应激并促进药物内化，显著提升对A549耐药肺癌细胞的杀伤效果[53]。黄芩苷则通过扰乱细胞内铁稳态，激活p53/SLC7A11/GPX4信号轴并促进脂质过氧化，从而诱发铁死亡，增强5-FU对乳腺癌细胞的化疗敏感性[54-55]。葛根素能够抑制上皮-间质转化进程并下调ABCB1外排泵功能，有效逆转乳腺癌对奥沙利铂的耐药表型，联合应用显著抑制肿瘤转移并提升体内抗肿瘤效果[56]。综上，中药活性成分通过多靶点、多机制协同化疗药物，不仅显著提高肿瘤细胞对药物的响应能力，还有助于降低系统毒性，为逆转MDR提供了有效的联合策略。
3.2 中药-靶向药协同
靶向药物虽在肿瘤治疗中展现出高特异性，但长期使用易引发耐药和毒副作用。中药活性成分可通过多靶点调控与靶向药物形成协同效应[57]。人参皂苷Rg3联合厄洛替尼可以通过抑制表皮生长因子受体/PI3K/Akt通路，增强厄洛替尼的治疗效果[58]。熊果酸可以促进髓样细胞白血病1蛋白的蛋白酶体降解、抑制SLC7A11诱导铁死亡增加索拉菲尼的化疗敏感性,表现出协同效应[59]。黄腐酚与奥希替尼联合治疗破坏USP9X与Ets-1之间的相互作用，抑制Ets-1在Thr38位点的磷酸化并促进其降解，从而靶向Ets-1/c-Met信号通路，诱导耐药细胞发生内源性凋亡，在体内外均显著恢复了奥希替尼耐药非小细胞肺癌细胞对奥希替尼的敏感性[59]。
3.3 纳米载药协同增效
随着纳米技术在药物传递领域的深入研究，纳米共递送系统为联合抗肿瘤治疗提供了新策略。纳米载体通过调控粒径、优化结构及表面功能化修饰，可实现高效载药、延长体内循环时间，并借助增强渗透与滞留效应或主动靶向机制，显著提升药物在肿瘤组织中的富集与滞留。该类系统不仅可改善药物的溶解性、稳定性和生物利用度，还能通过协同增效、逆转多药耐药和减轻系统毒性，显著增强抗肿瘤疗效[60]。
研究显示，纳米葛根素可通过调控Akt/基质金属蛋白酶9（matrix metallopeptidase 9，MMP- 9）信号通路、抑制NSUN2介导的RNA甲基化、阻断Akt/血管内皮生长因子A/MMP-9轴，进而重塑免疫抑制性TME，增强HepG2细胞对DOX的敏感性，逆转化疗耐药[61]。Baek等[62]开发了一种共载姜黄素与紫杉醇的多功能脂质纳米粒，通过在表面修饰叶酸配体实现针对肿瘤细胞上叶酸受体的主动靶向，该策略显著增强细胞内药物积累并有效逆转MDR。此外，共载白藜芦醇与紫杉醇的纳米系统可显著抑制P-gp的表达，增加药物在耐药细胞内的蓄积，减少外排，从而有效逆转MDR[63]。综上所述，纳米共递送系统不仅显著提升了天然活性成分与化疗药物的协同抗肿瘤效果，还在一定程度上克服了传统化疗中常见的耐药性和毒副作用问题，展现出广阔的临床转化前景，是未来抗肿瘤药物研发的重要方向之一。
4 结语
MDR 治疗选择包括联合治疗、靶向治疗、药物递送系统、耐药机制抑制和免疫治疗。当耐药机制受到抑制时，癌细胞通过适应替代耐药机制或途径获得耐药性[64]。为了有效对抗耐药性，需要全面了解与MDR相关的多种机制。中药活性成分在逆转MDR方面展现出显著的协同增效潜力，通过多靶点逆转耐药，优于单一靶点的化学抑制剂。配伍策略需结合“直接抑制外排 + 信号通路调控+递药技术优化”。未来需加强基于患者的个性化用药验证，推动中药增敏剂纳入联合治疗方案。这些多途径、多靶点的协同作用，不仅为逆转MDR提供了新策略，还减轻了化疗的毒副作用，展现了中药在肿瘤综合治疗中的独特优势。未来研究需进一步结合临床验证，以推动其转化应用。
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