Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Invest New Drugs. 2011 Feb;29(1):33-40. doi: 10.1007/s10637-009-9330-9. Epub 2009 Oct 1.
MT477 is a novel thiopyrano[2,3-c]quinoline with anti-cancer activity. The purpose of the present study was to evaluate different doses and treatment schedules of MT477 in an in vivo xenograft model of non-Ras-mutated cancer, as well as determine its biological effects and mechanism of action via the four conventional PKC isoforms: α, βI, βII, and γ. Here, we show that MT477 inhibits the activity of PKC-α and its downstream targets, ERK1/2 and Akt, before it has an effect on Ras activity. MT477 treatment of cultured H226 cells induced apoptosis and increased focal cell adhesion and formation of actin stress fibers. H226 tumor size in mice continuously treated with intraperitoneal MT477 (1 mg/kg) was 62.1 ± 15.3% smaller than the average tumor size in control mice. Blood serum chemistry revealed minimal toxicity in mice. Taken together, these results support the conclusion that MT477 acts as a direct PKC-α inhibitor in non-Ras mutated cancer, with maximum effectiveness when given in a continuous treatment schedule.
MT477 是一种新型的噻吩并[2,3-c]喹啉类化合物，具有抗癌活性。本研究旨在评估 MT477 在非 Ras 突变型癌症的体内异种移植模型中的不同剂量和治疗方案，以及通过四种常规 PKC 同工型：α、βI、βII 和 γ 来确定其生物学效应和作用机制。在这里，我们表明 MT477 在对 Ras 活性产生影响之前，抑制 PKC-α 及其下游靶标 ERK1/2 和 Akt 的活性。MT477 处理培养的 H226 细胞诱导细胞凋亡，并增加焦点细胞黏附和肌动蛋白应力纤维的形成。持续腹腔内给予 MT477（1mg/kg）的 H226 肿瘤小鼠的肿瘤大小比对照组小鼠的平均肿瘤大小小 62.1±15.3%。血清化学分析显示小鼠的毒性最小。综上所述，这些结果支持 MT477 在非 Ras 突变型癌症中作为直接 PKC-α 抑制剂的结论，连续治疗方案时效果最佳。
