Abstract：
AKT is one of the overexpressed targets in nonsmall cell lung cancer (NSCLC) and plays an important role in its progression and offers an attractive target for the therapy. The PI3K/AKT/mTOR pathway is upregulated in NSCLC. Acridone is an important heterocycle compound which treats cancer through various mechanisms including AKT as a target. In the present work, the study was designed to evaluate the safety profile of three acridone derivatives (AC-2, AC-7, and AC-26) by acute and repeated dose oral toxicity. In addition to this, we also checked the pAKT overexpression and its control by these derivatives in tumor xenograft model. The results from acute and repeated dose toxicity showed these compounds to be highly safe and free from any toxicity, mortality, or significant alteration in body weight, food, and water intake in the rats. In the repeated dose toxicity, compounds showed negligible variations in a few hematological parameters at 400 mg/kg. The histopathology, biochemical, and urine parameters remained unchanged. The xenograft model study demonstrated AC-2 to be inhibiting HOP-62 induced tumor via reduction in p-AKT1 (Ser473) expression significantly. In immunofluorescence staining AC-2 treated tissue section showed 2.5 fold reduction in the expression of p-AKT1 (Ser473). Histopathology studies showed the destruction of tumor cells with increased necrosis after treatment. The study concluded that AC-2 causes cell necrosis in tumor cells via blocking the p-AKT1 expression. The findings may provide a strong basis for further clinical applications of acridone derivatives in NSCLC.
摘要：
AKT是非小细胞肺癌（NSCLC）的过表达靶标之一，在其进展中起着重要作用，并为其治疗提供了有吸引力的靶标。在NSCLC中PI3K/AKT/mTOR通路上调。吖啶酮是一种重要的杂环化合物，通过多种机制治疗癌症，包括以AKT为靶点。在目前的工作中,本研究旨在通过急性和重复剂量口服毒性评估3种吖啶酮衍生物(AC-2,AC-7和AC-26)的安全性.除此之外,我们还检查了这些衍生物在肿瘤异种移植模型中的pAKT过表达及其控制。从急性和重复剂量毒性的结果表明，这些化合物是高度安全的，没有任何毒性，死亡率,或者体重的显著改变，食物,和老鼠的水摄入量。在重复剂量毒性中，化合物在400mg/kg时的一些血液学参数变化可忽略不计。组织病理学,生物化学，和尿液参数保持不变。异种移植模型研究表明AC-2通过显著降低p-AKT1(Ser473)表达来抑制HOP-62诱导的肿瘤。在免疫荧光染色中,AC-2处理的组织切片显示p-AKT1(Ser473)的表达减少2.5倍。组织病理学研究表明，治疗后肿瘤细胞的破坏伴随着坏死的增加。该研究得出结论，AC-2通过阻断p-AKT1表达导致肿瘤细胞坏死。这些发现可能为吖啶酮衍生物在NSCLC中的进一步临床应用提供了坚实的基础。
