Deregulation of PI3K signalling pathway is strongly involved in pathology of cancer and development of resistance in tumour cells. Here, we report that pharmacologically active vasicinone analogue, RLX (7, 8, 9, 10-Tetrahydroazepino [2, 1-b] quinazolin-12-(6H)-on), exhibited potent anticancer activities both in vitro and in vivo. In this study, RLX treatment displayed strong inhibition of proliferation against various cancer cell lines. However, colon cancer cells were found to be the most sensitive towards RLX mediated inhibition of proliferation. The result showed that RLX treatment followed strong concentration dependent inhibition of HCT-116 cell proliferation and colony formation. RLX treatment to HCT-116 was observed to be associated with down-regulation of p110α and p85 subunits of PI3K thereby decreasing the expression of subsequent downstream effector proteins. Interestingly, silencing of PI3K gene by siRNA in combination with RLX confirmed the anti-proliferation effect of RLX against HCT-116 cells and is mediated by the PI3K pathway. We also found that RLX induced sub-G1 arrest and mitochondrial potential loss followed by pFoxO3a(Thr32) nuclear-cytoplasmic translocation inhibition. Moreover, RLX treatment in in vivo models substantially resulted in a tumour growth inhibition. Overall, our findings reveal the functional role of the PI3K/Akt/FoxO3a pathway that gets deregulated in cancer and suggests its simultaneous targeting by RLX thereby further identifying the compound as a potent inhibitor of the PI3K/Akt/FoxO3a pathway under in vitro and tumour regression in vivo.

中文翻译：

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基于喹唑啉的小分子通过抑制实验性结肠癌中的PI3K / Akt / FoxO3a信号传导发挥有效的肿瘤抑制特性。

PI3K信号通路的失调与癌症的病理过程和肿瘤细胞耐药性的发展密切相关。在这里，我们报告的药理活性vasicinone类似物，RLX（7，8，9，10-Tetrahydroazepino [2，1-b] quinazolin-12-（6H）-on），在体外和体内均显示出有效的抗癌活性。在这项研究中，RLX治疗对多种癌细胞系显示出强烈的增殖抑制作用。但是，发现结肠癌细胞对RLX介导的增殖抑制最敏感。结果表明，RLX处理对HCT-116细胞增殖和集落形成具有强烈的浓度依赖性抑制作用。观察到针对HCT-116的RLX处理与PI3K的p110α和p85亚基的下调相关，从而降低了后续下游效应子蛋白的表达。有趣的是，siRNA与RLX结合使PI3K基因沉默证实了RLX对HCT-116细胞的抗增殖作用，并由PI3K途径介导。我们还发现RLX诱导亚G1逮捕和线粒体电位损失，继之以pFoxO3a（Thr32）核细胞质易位抑制。而且，在体内模型中的RLX治疗实质上导致了肿瘤生长的抑制。全面的，