辣椒素预防及抗肿瘤作用机制研究进展

左明， 胡丽贞

610041成都，四川省肿瘤医院·研究所，四川省癌症防治中心，电子科技大学医学院 临床营养中心

恶性肿瘤是危害人类健康及生命的重要疾病，已成为我国人群死亡的首要原因[1]。肿瘤的化学预防与靶向治疗是临床科研工作者的重点课题，应用天然果蔬中的活性化合物进行预防和治疗癌症是目前研究的热点之一。辣椒是全球广泛食用的果蔬及香料，在辣椒皮质部分存在一种生物碱，即辣椒素(capsaicin)，其具有止痛、抗氧化、抗炎及减肥作用[2]。辣椒素通过靶向激活辣椒素受体(transient receptor potential vanilloid，TRPV)或其他信号通路，对多种肿瘤细胞，如神经胶质瘤[3-4]、结直肠癌[5]、前列腺癌[6]、胃癌[7]、肝癌[8]、胆管癌[9]、非小细胞肺癌[10]、乳腺癌[11]、纤维肉瘤[12]等产生抗肿瘤活性，还可激发T细胞介导的抗肿瘤免疫[13]，进而预防和抗肿瘤生长。本文就辣椒素预防及抗肿瘤作用机制相关研究进展进行综述。

1 辣椒素化学结构图和基本特性

辣椒素化学名为反式-8-甲基-N-香草基-6-壬烯酰胺(C18H27NO3)，具有辛辣味、刺激性[14]。天然辣椒素包含辣椒素、二氢辣椒素、去氢辣椒素、高辣椒素、高二氢辣椒素等，辣椒素体内代谢有4条途径[15]：(1)通过氧化形成苯氧基，二聚体化或者与P450 2El 共价结合失去活性；(2)侧烷基链羟基化；(3)辣椒素苯环去甲基化后，氧化为半苯醌或苯醌类衍生物；(4)辣椒素经酰胺水解酶的作用生成香草基胺和脂肪酸。

图1 辣椒素化学结构图

2 辣椒素预防肿瘤作用

研究发现辣椒素通过调控致癌物质的代谢，以及致癌物与细胞DNA之间的相互作用[15-16]，还通过调节microRNA表达，调控癌症相关基因的表达[17]，阻断实验性致癌和致突变过程，发挥预防癌症的作用。

有学者发现TRPV1激动剂辣椒素与肠道上皮细胞表达的TRPV1相互作用，激活Ca2+/钙蛋白酶，并导致蛋白酪氨酸磷酸酶1B(PTP1B)的活化来抑制EGFR诱导的上皮细胞增殖，从而抑制肠肿瘤发生[18]。在大鼠的喂养实验中，Kim等[19]发现，食物中加入辣椒素，能抑制烷化剂诱导的胃肠道肿瘤发生。在相似的实验中，Yoshitani等[20]研究表明辣椒素能明显降低氧化偶氮甲烷诱导的结肠癌发生。Anandakumar等[21]研究证明辣椒素对苯并(a)芘诱导的实验性肺癌有化学保护作用。辣椒素还可通过抑制胰腺炎症和K-ras基因突变，从而预防胰腺癌[22]。Sirtuin 1是一类依赖于NAD+的组蛋白去乙酰化酶，近期研究发现胃癌组织中hMOF(human male absent on the first)蛋白活性降低，而辣椒素可上调hMOF蛋白的表达。通过hMOF蛋白介导，辣椒素可作用于癌细胞中沉默信息调节因子 2 ( silent information regulator 2 )相关酶(Sirtuin 1，SIRT1)，调节癌细胞的组蛋白乙酰化，抑制癌细胞生长[23]。肿瘤相关烟酰胺腺嘌呤二核苷酸氧化酶(tumor-associated nicotinamide adenine dinucleotide oxidase，tNOX)位于癌细胞表面，其对肿瘤细胞生长至关重要。在肿瘤临床症状发生之前几年，癌症患者的血清中已存在tNOX，辣椒素作为tNOX的拮抗剂，可抑制tNOX，预防肿瘤的发生[24]。还有研究者发现，辣椒素通过抑制炎症细胞因子的产生，调节免疫功能，从而预防结肠肿瘤[25]。

3 抗肿瘤作用

辣椒素的抗肿瘤作用主要通过辣椒素受体依赖和辣椒素受体非依赖两条途径来实现。大量研究表明，辣椒素通过多种机制，产生抗肿瘤作用，如引起肿瘤细胞周期停滞[11,26]、代谢抑制[27-29]、肿瘤坏死[10]、凋亡[3,8,26,30-31]，甚至辣椒素可诱导肿瘤干细胞(CSC)的凋亡[32]，和自噬[3,33]。凋亡是细胞主动性程序死亡，主要有死亡受体、线粒体和内质网途径；而辣椒素诱导癌细胞凋亡有两条始动途径，通过间接激活TRPV1，或直接激活与上述三条凋亡通路相关的直接通路[2]，最后激活caspase-3，导致癌细胞DNA损伤，从而诱导癌细胞的凋亡[34]。还有研究发现，辣椒素可以降低肿瘤细胞的侵袭和转移能力，同时在体内外均能抑制肿瘤组织的血管生成[35]。

3.1 辣椒素受体依赖的抗肿瘤机制

辣椒素激活辣椒素受体产生抗肿瘤作用，主要有诱导肿瘤细胞凋亡、抗血管生成和降低癌细胞的转移；其促凋亡途径有：(1)辣椒素激活TRPV1，诱导凋亡相关因子FAS / CD95表达上调，启动死亡受体途径[36-37]。(2)激活p38/ MAPK通路[4]。(3)由TRPV6介导，钙蛋白酶途径，导致Ca2+介导的线粒体损伤和细胞色素c释放[38]。(4)其他途径，上调Fas/ Fas相关因子1的表达，诱导癌细胞凋亡[2]。

辣椒素除依赖辣椒素受体促凋亡外，还有研究发现辣椒素与TRPV1相互作用，降低尿路上皮癌的侵袭性，减少转移的可能，还可以抗血管生成，从而发挥抗肿瘤作用[37]。

3.2 辣椒素受体非依赖的抗肿瘤机制

辣椒素还可通过其他非依赖辣椒素受体的途径产生抗肿瘤作用。主要有：(1)促进癌细胞凋亡。辣椒素能够通过线粒体途径诱导肿瘤细胞凋亡。Huang等[8]发现辣椒素显著降低肝癌细胞线粒体跨膜电位，增加细胞内Ca2+水平和产生活性氧ROS(reactive oxygen species，ROS)，使细胞内Bax蛋白水平升高，Bcl-2蛋白水平下降，激活caspase-3，而诱导癌细胞凋亡；或通过线粒体去极化和内质网应激，诱导人鼻咽癌NPC-TW 039细胞凋亡[31]。辣椒素作为抗氧化剂能够抑制tNOX，引起细胞凋亡，发挥抗肿瘤活性[24]。Shim用不同浓度(5μM，10μM和20μM)的辣椒素处理MCF-7细胞24小时，肿瘤干细胞(CSC)数下降，呈剂量依赖性，用辣椒素(10μM以上)处理时，能够通过抑制其notch通路，引起乳腺癌CSC凋亡[32]。辣椒素诱导自噬致胶质瘤细胞凋亡[3]。Zheng发现辣椒素可以通过阻断PI3K/Akt/mTOR途径，增加自噬标志物LC3-II和Atg5的水平，诱导自噬，增强p62和Fap-1降解，增加caspase-3的活性以诱导细胞凋亡[33]。(2)诱导细胞周期阻滞，抑制细胞增殖。结直肠癌的发生与β-连环蛋白(β-catenin)基因遗传改变相关，而Lee等[5]发现辣椒素抑制β-连环蛋白(β-catenin)的转录，激活β-catenin蛋白酶体的降解，以及破坏β-catenin/TCF-4的相互作用，发挥抗结肠癌细胞增殖的作用。Chen 等[39]研究表明，辣椒素能够通过抑制细胞周期相关蛋白依赖性激酶(cyclin dependent kinase,CDK))进而诱导细胞周期停滞，从而抑制癌细胞增殖。Zheng等[40]研究辣椒素对雄激素受体(AR)的调控，发现辣椒素通过上调AR阳性前列腺癌细胞中miR-449a的表达，诱导雄激素受体的失活和降解来阻止肿瘤增殖和细胞周期进程。miR-449a的表达增加可以促进前列腺癌对辣椒素治疗的敏感性。Brown等[41]研究表明，在四种人小细胞肺癌(SCLC)细胞系中显示出强大的抗增殖活性，并发现辣椒素的抗增殖活性与细胞周期蛋白E、胸苷酸合成酶、cdc25A和cdc6在mRNA和蛋白质水平上的表达下降有关。辣椒素引起E2F4和p130对E2F响应性增殖启动子的募集，诱导G1停滞，E2F信号通路在此过程中发挥了关键性的作用。

辣椒素抗肿瘤的通路不仅是单一的途径，而存在多条途径。Thoennissen等[42]研究发现辣椒素通过调节EGFR /HER-2途径引起ER阳性和阴性乳腺癌细胞的细胞周期阻滞，还可诱导细胞凋亡，Chang等[26]对乳腺癌细胞研究也有相似发现，伴随线粒体膜电位显著降低，聚腺苷酸二磷酸核糖转移酶-1[poly(ADP-ribose)polymerase-1，PARP-1]的裂解，半胱天冬酶原-7(procaspase-7)表达降低，导致细胞凋亡和细胞周期发生S期阻滞。另有学者在通过对前列腺癌细胞的研究也有相似的发现[43]。辣椒素作用于胃癌SNU-1细胞会产生氧化应激，诱导肿瘤相关NADH氧化酶(tNOX)mRNA转录和蛋白质表达下调相关，导致细胞凋亡，同时有显著的细胞毒性作用，促进癌细胞的坏死[44]。辣椒素是组成型和白介素-6诱导型STAT3激活的阻断剂，下调STAT3调节基因产物如细胞周期蛋白D1，Bcl-2，Bcl-xL，生存素(survivin)和血管内皮生长因子(VEGF)的表达，诱导细胞在G1期停滞和肿瘤细胞凋亡，还可抗肿瘤血管生成[45]。

辣椒素还可激活p53-SMAR1阳性反馈环，诱导p53介导的HIF-1α降解，抑制Cox-2的表达，下调非小细胞肺癌(NSCLC)细胞VEGF的表达，阻止内皮细胞迁移和血管网形成，改变肿瘤微环境，导致肿瘤坏死[10]，另有研究表明辣椒素下调AMPK-NF-kappaB信号通路中MMP-9表达，抑制胆管癌细胞的转移[9]。

4 辣椒素与其他抗癌药物的相互作用

辣椒素与其他抗癌药物联用，具有化学增敏的效果，能增强抗癌药物的抗癌活性。辣椒素联合5-Fu，抑制胃癌细胞效果优于5-Fu单独使用，可能与辣椒素促进细胞色素C的释放以及抑制IкBα的磷酸化，阻断NF-kB信号通路有关[46]。Huh等[47]应用辣椒素联合顺铂进行研究，也有的相似的结果，发现辣椒素能提高顺铂的抗癌活性。辣椒素通过激活TRPV1和抑制肿瘤细胞中PCNA核移位，增强吡柔比星的抗肿瘤增殖效果[48]，还显著增强硼替佐米(Bortezomib/Velcade)和沙利度胺对多发性骨髓瘤细胞中的促凋亡作用[45]。

辣椒素和十字花科蔬菜中生物活性成分二聚吲哚(3,3'-Diindolylmethane，DIM)联合应用，可通过调节NF-kB、p53以及与凋亡相关靶基因的转录活性，协同抑制细胞增殖并诱导细胞凋亡[49]。

5 存在的问题及展望

辣椒素具有抗肿瘤作用，可作为癌症预防和治疗的潜在药物[7,33,40]，特别是与其他抗癌药物联合应用，具有广泛的应用前景[45-49]。辣椒素抗肿瘤作用机制复杂，目前具体机制尚不清楚，还应深入研究。但某些情况下辣椒素具有潜在的致癌作用[50]及促肿瘤转移作用[51]，需引起研究者的重视。

虽然动物体内研究表明辣椒素能够显著抑制癌组织的生长[2]，明显延长荷瘤小鼠的无进展生存期和总生存期[21],近期还有学者应用辣椒素贴剂治疗奥沙利铂化疗后诱发的神经病变相关的疼痛，并取得良好的效果[52]，但目前仍然缺乏辣椒素治疗肿瘤的临床资料。由于辣椒素受体广泛分布于人体的多种器官和组织，而且具有复杂的生理和病理功能，在肿瘤治疗的同时可能会带来严重的毒副反应[2,53]，此外，辣椒素具有一定刺激性，因此对辣椒素临床应用的安全性还需进一步深入研究，降低甚至去除其刺激性，将是未来的研究方向之一。

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