绿茶多酚EGCG与舒尼替尼的联合抗肿瘤作用研究

Molecular targeted drugs have recently developed rapidly and have brought innovations to cancer treatment. Sunitinib, a novel oral multitargeted tyrosine kinase inhibitor, has a good prospect for clinical application. From the phenomenon that drinking tea interfered with symptom control in a patient treated with sunitinib, we completed a study which firstly showed epigallocatechin-3-gallate (EGCG), the major constituent of green tea, interacted with sunitinib and reduced the bioavailability of sunitinib. The results were published in JOURNAL OF MOLECULAR MEDICINE. Accidentally, our further study preliminarily showed the combination of EGCG with sunitinib might lead synergetic antitumor effect if there were an enough interval time or different administration pathway between these two agents. Previously, many studies had shown remarkable cancer chemo-preventive and chemotherapeutic effects of EGCG against many types of cancers, and some important proangiogenitors could also be reduced by EGCG, which may support the possible synergetic antitumor effect of EGCG and sunitinib. In this project, we try to explore: the interval time that EGCG has no negative impact on the antitumor effect of sunitinib; the optimal way that EGCG enhance the antitumor efficacy of sunitinib; the underlying mechanisms by investigating the anti-angiogenesis, signal pathway blockage and the abolition of immunosuppression. This is a rational next step beyond our prior research, and no similar study has been published till now. The results from this project will have significant practical implications for tea-drinking during sunitinib administration, especially for Chinese patients, and may provide information for combined strategies of targeted therapies with other antitumor modalities.

分子靶向新药给恶性肿瘤的治疗带来了重要进展，舒尼替尼（SU）是一种有很好应用前景的小分子多靶点激酶抑制剂。我们由临床现象出发，在国际上首次发现茶的主要成份EGCG与SU可直接发生相互作用，并降低SU的生物利用度，结果已发表在JMM杂志。我们进一步的动物实验意外发现，避开二者的直接作用，采取合适的间隔时间或不同给药方式，二者联合可在体内起到更强的抗肿瘤效果。EGCG已被报道有显著的防癌抗癌作用，并可降低促血管生成因子的表达，因此可能与SU产生协同的抗肿瘤作用。本课题拟重点探讨：确定饮茶与服用SU的最短间隔时间以避免相互不良作用，给患者提供指导；确定最佳的EGCG增效SU抗肿瘤作用的联合方式；从抗肿瘤血管生成、信号途径阻断、取消免疫抑制等方面研究增效机制。本实验有前期研究基础，目前国际上无二者联合应用的报道。结果对指导有饮茶习惯的中国患者人群有重要意义，也能为其它靶向药物的联合治疗策略提供参考

舒尼替尼是靶向血管内皮生长因子受体1-3，血小板衍生生长因子受体，干细胞因子受体的一种口服小分子多激酶抑制剂，靶点包括肿瘤血管内皮细胞和肿瘤细胞本身，是一个很有临床应用前景的药物。但舒尼替尼使用一段时间后会出现因细胞因子上调、替代信号通路激活、肿瘤细胞侵袭性升高等而出现的一系列反馈调节及耐药机制，寻找联合或增效的药物是延长肿瘤控制时间的重要手段。EGCG是绿茶中含量最高、最主要的活性成份，有显著的防癌抗癌作用。我们前期发现EGCG与舒尼替尼在体外能相互作用而妨碍舒尼替尼的吸收。饮茶是种方便易行的行为，且理论上讲，EGCG在抗癌机制上与舒尼替尼有可能有协同的作用，因此如果能找到一种合理的给药策略避免二者直接作用的同时增加舒尼替尼抗肿瘤疗效，将很具有实际临床意义。我们选择了PIK3CA 突变的人非小细胞肺癌细胞株H460、H1975和人乳腺癌细胞株MCF-7细胞株作为研究对象，探索了EGCG增效舒尼替尼的合理时间间隔给药策略，研究了EGCG协同舒尼替尼增效的分子机制。通过采用先舒尼替尼后EGCG序贯给药策略，EGCG不仅可避免因为与舒尼替尼的直接作用导致的舒尼替尼血液浓度下降，还可增效舒尼替尼抑制肿瘤细胞生长及VEGF合成分泌。EGCG增效舒尼替尼协同抗肿瘤机制主要依赖于EGCG能够抑制由舒尼替尼暴露引起的IRS/MAPK信号通路反馈性强化。舒尼替尼暴露后加用EGCG可以增强舒尼替尼的疗效。我们的研究为合理应用舒尼替尼，指导饮茶和服用舒尼替尼的关系提供了一定的指导意义。