Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, São Paulo, Brazil.
Life Sci. 2022 Nov 1;308:120911. doi: 10.1016/j.lfs.2022.120911. Epub 2022 Aug 27.
Colorectal cancer (CRC) is a very heterogeneous disease. One of its hallmarks is the dysregulation of protein kinases, which leads to molecular events related to carcinogenesis. Hence, kinase inhibitors have been developed and are a new strategy with promising potential for CRC therapy. This study aims to explore AD80, a multikinase inhibitor, as a drug option for CRC, with evaluation of the PI3K/AKT/mTOR and MAPK (ERK1/2) status of CRC cells' panel and the cytotoxicity of AD80 in those cells, as well as in normal colon cells.
Cellular and molecular mechanisms, such as clonogenicity, cell cycle, morphology, protein and mRNA expression, were investigated in CRC cells after AD80 exposure.
Results show that PI3K/AKT/mTOR and MAPK signaling pathways are upregulated in CRC cellular models, with increased phosphorylation of mTOR, P70S6K, S6RP, 4EBP1, and ERK1/2. Hence, AD80 selectively reduces cell viability of CRC cells. Therefore, the antitumor mechanisms of AD80, such as clonogenicity inhibition (reduction of colony number and size), G/M arrest (increased G/M population, and CDKN1B mRNA expression), DNA damage (increased H2AX and ERK1/2 phosphorylation, and CDKN1A and GADD45A mRNA expression), apoptosis (increased PARP1 cleavage, and BAX, PMAIP1, BBC3 mRNA expression) and inhibition of S6RP phosphorylation were validated in CRC model.
Our findings reinforce kinases as promising cancer therapeutic targets for the treatment of colorectal cancer, suggesting AD80 as a drug candidate.
结直肠癌（CRC）是一种非常异质性的疾病。其特征之一是蛋白激酶的失调，这导致了与癌变相关的分子事件。因此，已经开发出了激酶抑制剂，并且作为 CRC 治疗的一种新策略具有很大的潜力。本研究旨在探索 AD80，一种多激酶抑制剂，作为 CRC 的一种药物选择，评估 CRC 细胞系中 PI3K/AKT/mTOR 和 MAPK（ERK1/2）状态以及 AD80 在这些细胞以及正常结肠细胞中的细胞毒性。
在 AD80 暴露后，研究了 CRC 细胞中的细胞和分子机制，如集落形成、细胞周期、形态、蛋白和 mRNA 表达。
结果表明，PI3K/AKT/mTOR 和 MAPK 信号通路在 CRC 细胞模型中上调，mTOR、P70S6K、S6RP、4EBP1 和 ERK1/2 的磷酸化增加。因此，AD80 选择性地降低 CRC 细胞的活力。因此，AD80 的抗肿瘤机制，如集落形成抑制（减少集落数量和大小）、G/M 期阻滞（增加 G/M 期细胞比例和 CDKN1B mRNA 表达）、DNA 损伤（增加 H2AX 和 ERK1/2 磷酸化以及 CDKN1A 和 GADD45A mRNA 表达）、凋亡（增加 PARP1 切割以及 BAX、PMAIP1、BBC3 mRNA 表达）和 S6RP 磷酸化抑制在 CRC 模型中得到了验证。
我们的发现强化了激酶作为治疗结直肠癌的有前途的癌症治疗靶点的作用，提示 AD80 是一种候选药物。
