修回日期: 2015-10-01
接受日期: 2015-10-19
在线出版日期: 2015-11-08
质子泵抑制剂(proton pump inhibitor, PPI)为苯并咪唑类衍生物, 其实质是H+-K+-ATP酶抑制剂, 常用于胃溃疡等酸相关性疾病的治疗.近年来, 探索PPI与肿瘤进程的相关研究成为热点. 本文综述了PPI与肿瘤微环境、改善耐药机制以及相关的信号通路的关系, 以期为肿瘤的治疗提供线索.
核心提示: 寻找有效的抗癌药物和有效改善抗癌药物耐药是目前癌相关性研究的核心和关键, 质子泵抑制改变肿瘤对抗癌药物的敏感性, 其机制与肿瘤的酸性微环境密切相关, 具有成为治疗肿瘤新策略的潜力.
引文著录: 但汉容, 金海, 文国容, 庹必光. 质子泵抑制剂与肿瘤关系的研究进展. 世界华人消化杂志 2015; 23(31): 4997-5003
Revised: October 1, 2015
Accepted: October 19, 2015
Published online: November 8, 2015
Proton pump inhibitors (PPIs) as benzene and imidazole derivatives are in essence H+-K+-ATPases inhibitors, and they are commonly used in the treatment of acid related diseases such as gastric ulcer. In recent years, exploring the relationship between PPIs and tumors has become a hot research topic. This paper summarizes the relationship of PPIs with tumor microenvironment, the improvement of drug resistance mechanisms, and related signaling pathways, with an aim to provide clues for the treatment of tumors.
- Citation: Dan HR, Jin H, Wen GR, Tuo BG. Relationship between proton pump inhibitors and tumors. Shijie Huaren Xiaohua Zazhi 2015; 23(31): 4997-5003
- URL: https://www.wjgnet.com/1009-3079/full/v23/i31/4997.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v23.i31.4997
目前, 肿瘤已经严重威胁着人类的健康, 据世界癌症报告估计, 2012年中国癌症发病人数为306.5万, 约占全球发病的1/5; 癌症死亡人数为220.5万, 约占全球癌症死亡人数的1/4. 我国癌症发病率接近世界水平, 但死亡率高于世界水平, 5年生存率低于美国等其他发达国家, 主要是因为我国癌症发现较多处于中晚期, 且治疗效果差; 另外, 恶性肿瘤对化疗药物耐药也是造成肿瘤患者治疗失败的主要原因. 所以, 探求肿瘤的早期诊断及其有效的治疗方法已经迫在眉睫. 自第一个质子泵抑制剂(proton pump inhibitor, PPI)奥美拉唑1987年在瑞典上市以来, 兰索拉唑、泮托拉唑等PPI陆续被研发出来. PPIs通过阻碍胃壁细胞H+-K+-ATP酶发挥抑制胃酸分泌的作用, 具有起效快、抑酸作用强、作用时间长、服用方便等特点, 并且能抑制基础胃酸的分泌及组胺、乙酰胆碱、胃泌素和食物刺激引起的酸分泌, 所以被临床广泛用于胃溃疡、十二指肠溃疡等酸相关性疾病的治疗. 近些年来, PPI在临床的应用中有了新的探索, 很多研究表明, PPI在肿瘤进展中发挥很重要的作用.
大量研究证实, 肿瘤酸性微环境在肿瘤的发生、发展进程和转移中的作用至关重要. 肿瘤组织酸性大于正常组织, 且肿瘤细胞具有胞内偏碱(pH约7.2)胞外偏酸(pH约6.8)、低氧浓度、高葡萄糖吸收率等特点[1]. 肿瘤微环境的细胞外低pH状态主要依赖肿瘤细胞的特殊生物学组分和质子泵活性[2]. 缺氧环境下, 低氧诱导因子-1(hypoxia inducible factor-1, HIF-1)被激活, 糖酵解代谢增加, 并且肿瘤细胞具有War-burg效应[3], 即在有氧环境下肿瘤细胞仍然进行糖酵解, 这是肿瘤酸性微环境形成的原因之一. 肿瘤细胞代谢旺盛, 高葡萄糖吸收率仍不能满足其代谢所需, 导致糖酵解增加, 肿瘤血管属于异常增生的功能不全的血管, 无法及时清除大量堆积的乳酸, 此为肿瘤酸性微环境形成的另一原因[4]. 有研究[5]认为组织缺氧和酸性环境会使良性肿瘤转变为恶性, 而肿瘤的酸性微环境使这个恶化过程形成一个恶性循环. 还有研究证实肿瘤的生长[6]、微血管形成[1]、侵袭和转移[7]也受肿瘤酸性微环境的影响, 其机制可能是因为蛋白水解酶在酸性环境中可能被激活, 促进细胞外基质的降解和重构, 从而促进肿瘤的侵袭和转移[8]. 另外肿瘤微环境对放化疗的敏感性[9]也有一定的影响.
特殊的质子泵V-ATPases, 他的一个重要作用是维持相对中性的细胞内pH值、酸性腔的pH值以及细胞外的pH值, 他在许多类型的转移性肿瘤中过表达并与肿瘤的侵袭性和转移潜能呈正相关[10-14], 因此, 阻断V-ATPases的表达可以抑制肿瘤的生长和转移. 有研究[15,16]发现PPIs能抑制V-ATPases的表达, 并能逆转细胞内外的pH梯度, 还能抑制V-ATPases活性且改变其亚细胞定位[17,18], 从而改变肿瘤微环境. 有研究[19]发现泮托拉唑(pantoprazole, PPZ)抑制增殖、诱导凋亡, 削弱细胞转移, 这也许是PPIs抑制V-ATPases的结果. 用兰索拉唑作用于乳腺癌细胞后能剂量依赖性的诱导细胞凋亡, 动物模型试验也证实兰索拉唑能显著抑制肿瘤发生并引发大规模的肿瘤细胞凋亡[20]. 还有研究[21]发现PPZ抑制小鼠肿瘤细胞V-ATPase的表达并抑制了另一个pH调节剂单羧酸转运(monocarboxylate transporter-1, MCT-1)表达, 与此同时, 腹水中乳酸的水平也降低. 所以, 近年来V-ATPases被提出作为抗癌治疗的靶点[22,23], 并有研究[18,24,25]表明, PPIs如奥美拉唑、埃索美拉唑、泮托拉唑具抗癌活性.
肿瘤细胞对化疗药物不敏感和耐药是肿瘤治疗失败的主要原因, 而药物分布局限也许是药物抵抗的重要机制[26-32]. 对于化疗的肿瘤而言, 药物必须从血管有效的分布在整个肿瘤组织甚至每个癌细胞达到一定的浓度才能引起细胞毒性[33,34]. 肿瘤细胞特殊的外酸内碱pH梯度和胞内的溶酶体、核内体等酸性细胞器影响了药物的摄取及活性, 因为很多化疗药物如蒽环类、长春新碱等呈弱碱性且亲脂性弱, 部分细胞外的药物在酸性环境中易发生质子化而不能透过胞膜, 从而不能进入肿瘤细胞内; 部分药物虽然能进入细胞内, 但他们容易积聚在质子化和游离的酸性细胞器中[35], 从而阻碍药物吸收入核作用于靶DNA. 药物在细胞内的作用是pH值依赖的, 细胞内轻微的pH改变都会对药物作用产生影响[36], 但药物敏感株V-ATPases活性较低, 调节pH能力差, 而耐药株对细胞pH稳定有较强的调节力[37], 这也许就是抗癌药物效果不佳的原因. 有研究表明, V-ATPases高表达[22]和活化增强[38]为肿瘤细胞耐药的机制之一. 另外, 通过增加酸性囊泡循环, 将药物排出细胞外可能是耐药产生的又一因素[37,39]. 归结起来, 肿瘤耐药的根本原因是其特殊的酸性环境, 碱化其细胞外环境也许会改善耐药现状. Taylor等[40]研究指出, 改变酸性肿瘤微环境是一种有效的, 耐受性良好, 成本较低的, 能克服抗癌药物耐药的新策略. 也有研究[41,42]发现, 碳酸氢盐碱化肿瘤细胞移植瘤小鼠能改善化疗药物敏感性, 碱化肿瘤细胞外环境可逆转溶酶体的化疗药物积聚[43]. 有研究[18]证实, PPI预处理的细胞株对铂类化合物、5-氟尿嘧啶、长春新碱等药物的化疗更敏感, 能显著增加胞质和核内细胞毒性药物; 同时进行动物体内实验, 口服PPI预处理可诱导顺铂对人实体肿瘤的敏感性. 陈敏等[44]研究发现, PPZ预处理能剂量依赖性的降低胃癌细胞株SGC7901和SGC7901耐药株的生存能力, 使化疗药物达到最大的细胞毒性, 并提高耐药株移植瘤裸鼠的抗肿瘤效果, 增加肿瘤组织中的凋亡指数. Patel等[45]的研究也发现, PPZ(>200 μmol/L)增加胞内pH值和阿霉素核摄取, PPZ预处理增加阿霉素的组织渗透力、实体肿瘤的血液分布和细胞毒性, 并且能增加人乳腺癌细胞MCF-7移植瘤小鼠生长延迟. You等[46]发现, 将人乳腺癌细胞耐药株MCF-7/ADR的V-ATPase敲除后, 能增加化学治疗药物敏感性. 最近又发现, 无论在体内还是体外, 质子泵抑制剂兰索拉唑与紫杉醇联合运用对转移性黑色素瘤的疗效较单纯运用紫杉醇有效[47]; 而且兰索拉唑与其他PPI相比具有更高的抗肿瘤效果, 并且在低剂量最有效[48]. PPI增敏原理是通过调控V-ATPases的表达和活性, 从而改变肿瘤细胞内外以及细胞内各区室间的pH梯度, 进而促进化疗药物进入细胞和核内发挥功能[18].
有研究[49]发现PPIs可浓度依赖性地抑制耐药胃癌细胞内的磷脂酰肌醇-3-激酶(phosphoinositide-3-kinase, PI3K)、Akt及其下游分子哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)、HIF-1α表达, 同时抑制Akt底物的磷酸化, 表明PPIs可抑制耐药胃癌细胞内的PI3K/Akt/mTOR/HIF-1α信号通路. Chen等[50]也研究证实泮托拉唑能明显抑制V-ATPase、mTOR、HIF-1α、P-糖蛋白(P-glyco-protein, P-gp)和多药耐药相关蛋白1(multidrug resistanec-associated protein 1, MRP1)在耐药株的表达, 可能是通过下调V-ATPases/mTOR/HIF-1α/P-gp和MRP1信号通路.
受翻译调控的肿瘤蛋白(translationally controlled tumor protein, TCTP)在许多肿瘤细胞中高度表达, 在肿瘤的进展中发挥重要的作用. Ma等[51]发现, TCTP水平下降抑制结肠癌细胞增殖和迁移. 有研究[52]认为TCTP通过其N端和Bcl-xL的BH3结构域相互作用, 阻止Bcl-xl磷酸化而起到抗凋亡作用; 也有研究者[53]认为, TCTP通过嵌入线粒体膜抑制Bax的二聚体化, 降低线粒体损伤, 抑制细胞凋亡, 这两者间的关系和具体的作用靶点还需进一步的深入研究. 质子泵抑制剂奥美拉唑和泮托拉唑浓度依耐性地减少HEK293和U937细胞中TCTP分泌[54], 这可能是PPI作用于其他非消化系肿瘤的新突破点.
PPZ诱导细胞凋亡, 减少胃癌细胞分泌IL-6, 抑制STAT3的激活, 且下调其下游靶点c-Myc、cyclinD1和Bcl-2, 其作用机制部分是通过抑制IL-6/STAT3信号通路[55]. 还有研究[20]发现PPZ治疗引起磷酸化的肺耐药蛋白(lung resistance protein-6, LRP6)减少, 而不是LRP6. β-catenin及其Wnt/β-catenin信号通路的靶基因c-Myc和cyclinD1都随着V-ATPases的抑制而减少. 因此, PPZ可作为V-ATPases的特异性抑制剂, 通过抑制Wnt/β-catenin信号通路中LRP6的磷酸化治疗胃癌. PPZ治疗后, 肿瘤细胞凋亡并伴随细胞外信号调节激酶失活, 相比之下, 正常胃黏膜细胞通过过表达抗凋亡调节分子热休克蛋白70(heat shock protein 70, HSP70)和HSP27阻止泮托拉唑诱导凋亡, 在裸鼠移植瘤模型中, 泮托拉唑显著抑制肿瘤发生并引起大范围的细胞凋亡, 可见PPI有选择性的抗肿瘤效应[24].
HIF-1已被证明是调节肿瘤细胞生存中具有重要作用的一个转录因子, 在低氧条件下和细胞外pH值低时被激活并维持稳定[56]. HIF-1α基因在给予PPZ的肿瘤中表达下降[21]. HIF-1α可以调节葡萄糖转运蛋白(glucose transporter-1, GLUT-1)的表达[56,57], GLUT-1表达减少会减少肿瘤细胞对葡萄糖的摄取, 最终诱导细胞死亡增强. HIF-1是HSP70和转化生长因子β(transforming growth factor-β, TGF-β)的调节分子, 这些分子又可以稳定HIF-1蛋白[16,56,58]. HSP70和TGF-β被证实在肿瘤细胞中抗凋亡和利于细胞存活, 给予PPZ体外处理细胞导致HSP70和TGF-β的表达减少可能是HIF-1α表达减少的直接后果. IL-10、IL-4和血管内皮生长因子(vascular endothelial growth factor, VEGF)下调与增强肿瘤细胞凋亡相关[59-61], 而且IL-10可以调节细胞凋亡蛋白Bcl-2. Sulkowska等[56]研究发现, Bcl-2蛋白在PPZ作用的肿瘤小鼠中表达减少可能是增强凋亡的原因之一; 另外, 在予以PPZ作用的肿瘤小鼠中CAD、p53和PUMA的表达增加, 可以得出PPZ诱导肿瘤细胞凋亡是通过依赖Caspase和p53通路的激活. 总之, 肿瘤细胞的增殖、迁移和凋亡等生物学行为受复杂的信号通路网络调节, 而在不同的肿瘤中也可能存在不同的机制, 质子泵抑制剂在其中的作用靶点和机制等, 这些都有待进一步的研究.
肿瘤在医学领域一直是需要攻克的难题, 也一直是科学研究的热点, 虽然在这方面的研究近年来取得了很大进展, 但肿瘤的发病率和死亡率仍居高不下. PPI作为一类最常用最有效的抑酸药, 近来发现与肿瘤的进程关系密切. 总之, PPI在肿瘤微环境和改善肿瘤耐药方面具有很重要的地位,其相关的机制虽已有一些探索, 但其确切的机制、靶向治疗的证据还有待进一步深入的研究. 另外, 目前这方面的研究大多还在体外和动物实验阶段, 还需要更多大量的临床实验来证实相关的药物配伍、疗效以及不良反应.
肿瘤酸性微环境作为肿瘤化学微环境的重要组成部分, 对其认识早期主要停留在实体肿瘤糖酵解代谢, 近来越来越多的证据显示肿瘤酸性微环境参与肿瘤的生长、微血管形成、侵袭和转移等过程调控. 而质子泵抑制剂对肿瘤酸性微环境的影响具有举足轻重的地位.
崔杰峰, 副研究员, 复旦大学附属中山医院肝癌研究所
质子泵抑制剂近年来作为有效的抑制肿瘤进展的药物已经进行了大量的研究, 并取得了很多突破性的成果, 但其在很多肿瘤中的研究还在功能现象层面, 其具体的抑癌机制还有待进一步的深入研究.
特殊的质子泵V-ATPases是质子泵抑制剂(proton pump inhibitor, PPI)作用的重要靶点, 通过Wnt/β-catenin信号通路抑制其在肿瘤中的表达, 改变肿瘤微环境, 与PPI改善肿瘤耐药密切相关.
本文从控制细胞内外PH的质子泵入手, 总结了质子泵抑制剂对肿瘤微环境以及肿瘤耐药机制的影响, 为质子泵抑制剂作为肿瘤治疗新策略提供理论依据.
综述了质子泵抑制剂与肿瘤耐药、肿瘤微环境的关系, 为肿瘤的治疗提供了新的理论依据和线索.
受翻译调控的肿瘤蛋白: 是一种普遍存在并大量表达的蛋白, 其合成受钙、真核翻译起始因子和双链RNA依赖的蛋白激酶调节, 具有与钙和微管蛋白结合、抗细胞凋亡、抑制翻译、促进组胺释放等生物学活性.
本文较好地综述了质子泵抑制剂与肿瘤耐药、肿瘤凋亡、增殖等机制的影响, 为认识肿瘤酸性微环境的生物学作用提供了参考.
编辑: 郭鹏 电编: 都珍珍
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