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首页> 外文期刊>Cell death & disease. >Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway
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Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway

机译：双PI3K / MTOR抑制剂BEZ235作为对紫杉醇抗性胃癌的有前途的治疗策略，通过靶向PI3K / AKT / MTOR途径

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Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G2/M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.
机译：Paclitaxel（PTX）广泛用于胃癌（GC）的前线化疗，但抗性限制了其使用。由于缺乏适当的模型，GC中PTX抗性潜力的机制尚未得到很好的研究。使用已建立的PTX抗性GC细胞载有HGC-27R，我们首次进行了GC中PTX抗性的第一时间的综合生物学性质和分子机制。数据显示，PTX抗性GC细胞的特征是通过微管障碍，EMT表型，对抗杀菌药物的反应减少，以及对凋亡的抗性（由上调的β-小管蛋白III，Vimentin，G2 / M分子的减毒变化或促凋亡）响应抗胺类药物或凋亡诱导剂的因素分别为响应）。还观察到磷酸阳性3-激酶，乳头/苏氨酸激酶Akt和哺乳动物靶标的催乳素（PI3K / AKT / mTOR）和丝裂原毒性蛋白激酶（MAPK）途径，这可能是上述表型交替的原因。体外数据表明，靶向这些途径足以引发PTX抗性GC中的抗肿瘤反应，其中双PI3K / MTOR抑制剂BEZ235比MTOR抑制剂血管司或MEK抑制剂AZD6244显示出更高的治疗效率。在携带HGC-27R肿瘤的小鼠中也证实了BEZ235的抗肿瘤效应。因此，这些数据表明PI3K / AKT / MTOR和MAPK途径抑制，尤其是PI3K / MTOR双阻滞，这可能是对PTX抗性GC的有前途的治疗策略。

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