胰腺癌靶向药物研究进展

胰腺癌靶向药物研究进展
胰腺癌是一种恶性胰腺肿瘤，根据以往的研究知道，原癌基因KRAS在肿瘤生长和扩散的代谢途径中起重要作用，突变的KRAS基因可以诱发胰腺癌的遗传突变。

一项发表于Journal of Clinical Investigation杂志的研究表明，小鼠中突变的KRAS能保持肿瘤的生长及帮助癌前肿瘤转变成浸润性肿瘤，且当KRAS 被关闭时，肿瘤消失了且没有复发的迹象。

而KRAS基因突变在胰腺癌中的比例高达80—90%，由此可知，特异性靶向KRAS药物的研发将对胰腺癌的治疗产生深远影响。

发表在JNB（The Journal of Nutritional Biochemistry）的一篇名为《Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells》的研究显示一种从植物中萃取的ubiquininone-like的小分子Antroquinonol（安卓健）可抑制胰腺癌PANC-1和ASPC-1细胞增殖和降低其细胞浓度。

该小分子为一非多醣体、三菇类的全新成分小分子结构，萃取自牛樟芝，研究表明其对恶性肿瘤体外和体内具有广谱活性。

碘化丙啶染色DNA的流式细胞仪分析表明，Antroquinonol可诱导细胞周期的G1期阻滞和随后的细胞凋亡。

在丝氨酸的磷酸化位点（473），Antroquinonol 抑制Akt的磷酸化，这是Akt的激酶活性的关键。

同时，其可在丝氨酸的磷酸化位点（2448）抑制哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化，mTOR的活性依赖这个氨酰基部分。

该研究同时表明，Antroquinonol影响mTOR/p70S6K/4E-BP1信号传导通路中的若干个信号途径。

（Antroquinonol可抑制mTOR（Ser2448），p70S6K （Thr421/Ser424 和Thr389）和4E-BP1（Thr37/Thr46and Thr70）等蛋白磷酸化）。

此外，该小分子结构还可诱导多种细胞周期调控因子与线粒体抗凋亡蛋白的下降。

在此过程中，K-RAS和其磷酸化的表达却显著增加。

免疫共沉淀试验结果显示，其K-RAS基因和Bcl-xL显著增强，这表明细胞凋亡。

与此同时，研究还表明Antroquinono通过向上调节的p21（WAF1/CIP1）和K-RAS基因之间的串扰，能够诱导癌细胞凋亡，癌细胞自噬性死亡和加速癌细胞衰老。

总结来看，小分子Antroquinonol可通过抑制PI3K/ Akt / mTOR信号通路，抑制胰腺癌细胞活性，引发癌细胞的自噬性死亡同时加速癌细胞衰老。

此前已有研究证明了PI3K-Akt信号通路对于细胞增殖、分化和凋亡的调节的必要性，其组成性活化与肿瘤发生及肿瘤侵袭转移密切相关。

该小分子结构Antroquinonol对该通
路高活性的抑制作用，可能为胰腺癌临床治疗带来新的契机。

（编者注：《Antroquinonol, a natural ubiquinone derivative, induces a cross talk between apoptosis, autophagy and senescence in human pancreatic carcinoma cells》原文摘录：Pancreatic cancer is a malignant neoplasm of the pancreas. A mutation and constitutive activation of K-ras occurs in more than 90% of pancreatic adenocarcinomas. A successful approach for the treatment of pancreatic cancers is urgent. Antroquinonol, a ubiquinone derivative isolated from a camphor tree mushroom, Antrodiacamphorata, induced a concentration-dependent inhibition of cell proliferation in pancreatic cancer PANC-1 and AsPC-1 cells. Flow cytometric analysis of DNA content by propidium iodide staining showed that antroquinonol induced G1 arrest of the cell cycle and a subsequent apoptosis. Antroquinonol inhibited Akt phosphorylation at Ser473, the phosphorylation site critical for Akt kinase activity, and blocked the mammalian target of rapamycin (mTOR) phosphorylation at Ser2448, a site dependent on mTOR activity. Several signals responsible for mTOR/p70S6K/4E-BP1 signaling cascades have also been examined to validate the pathway. Moreover, antroquinonol induced the down-regulation of several cell cycle regulators and mitochondrial antiapoptotic proteins. In contrast, the expressions of K-ras and its phosphorylation were significantly increased. The coimmunoprecipitation assay showed that the association of K-ras and Bcl-xL was dramatically augmented, which was indicative of apoptotic cell death. Antroquinonol also induced the cross talk between apoptosis, autophagic cell death and accelerated senescence, which was, at least partly, explained by the up-regulation of p21Waf1/Cip1 and K-ras. In summary, the data suggest that antroquinonol induces anticancer activity in human pancreatic cancers through an inhibitory effect on PI3-kinase/Akt/mTOR pathways that in turn down-regulates cell cycle regulators. The translational inhibition causes G1 arrest of the cell cycle and an ultimate mitochondria-dependent apoptosis. Moreover, autophagic cell death and accelerated senescence also explain antroquinonol-mediated anticancer effect.）。