A438079 通过抑制 P2X7 受体影响结直肠癌细胞增殖、迁移、凋亡和细胞焦亡。
A438079 affects colorectal cancer cell proliferation, migration, apoptosis, and pyroptosis by inhibiting the P2X7 receptor.
机构信息
Department of Clinical Oncology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Shenyang 110022, China; Medical Research Center of Shengjing Hospital, China Medical University, Shenyang 110004, China; Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Liaoning Province, China.
Medical Research Center of Shengjing Hospital, China Medical University, Shenyang 110004, China; Key Laboratory of Research and Application of Animal Model for Environmental and Metabolic Diseases, Liaoning Province, China.
出版信息
Biochem Biophys Res Commun. 2021 Jun 18;558:147-153. doi: 10.1016/j.bbrc.2021.04.076. Epub 2021 Apr 26.
BACKGROUND
Our previous study identified elevated expression of the P2X7 receptor (P2X7R) in colorectal cancer (CRC) patients, suggesting the receptor is a target for predicting poor disease prognosis. A438079 is a highly selective P2X7R antagonist, however, no studies have identified A438079 effects and mechanisms toward the biological behavior of CRC cells, and its therapeutic in vivo potential in CRC nude mice.
METHODS
The CRC cell lines, HCT-116 and SW620 were treated with 10 μM A438079, after which proliferation, migration, invasion, and apoptosis were assessed. SW620 cell xenografted BALB/c nude male mice were randomly divided into control, 5-FU, and A438079 groups. Mouse weight and tumor dimensions were also measured every two days. Furthermore, the expression of apoptosis related indicators (P2X7R, Bcl-2, Bax, caspase9, cleaved caspase9, caspase3, and cleaved caspase3) and pyroptosis related indicators (NLRP3, ASC, cleaved caspase1, and interleukin (IL)-β) were investigated in vitro and in vivo.
RESULTS
A438079 inhibited HCT-116 and SW620 cell proliferation, invasion and migration, and inhibited the growth of CRC xenografts in nude mice. A438079 promoted apoptosis via the Bcl-2/caspase9/caspase3 pathway and inhibited pyroptosis through the NLRP3/caspase1 pathway by inhibiting P2X7R in vitro and in vivo.
CONCLUSIONS
We preliminarily confirmed the therapeutic potential of A438079 toward CRC, and we provide a sound theoretical basis for A438079 as a new drug for the clinical treatment of CRC.
背景
我们之前的研究表明，嘌呤能受体 P2X7（P2X7R）在结直肠癌（CRC）患者中的表达升高，表明该受体是预测疾病预后不良的靶点。A438079 是一种高度选择性的 P2X7R 拮抗剂，然而，目前尚无研究确定 A438079 对 CRC 细胞生物学行为的影响及其机制，以及其在 CRC 裸鼠体内的治疗潜力。
方法
用 10 μM A438079 处理 CRC 细胞系 HCT-116 和 SW620，然后评估增殖、迁移、侵袭和凋亡。将 SW620 细胞异种移植到 BALB/c 裸鼠中，将裸鼠随机分为对照组、5-FU 组和 A438079 组。每隔两天还测量小鼠体重和肿瘤尺寸。此外，还在体外和体内研究了凋亡相关指标（P2X7R、Bcl-2、Bax、caspase9、cleaved caspase9、caspase3 和 cleaved caspase3）和焦亡相关指标（NLRP3、ASC、cleaved caspase1 和白细胞介素（IL）-β）的表达。
结果
A438079 抑制 HCT-116 和 SW620 细胞增殖、侵袭和迁移，并抑制裸鼠 CRC 异种移植瘤的生长。A438079 通过抑制 P2X7R 在体外和体内抑制 NLRP3/caspase1 通路，通过 Bcl-2/caspase9/caspase3 通路促进凋亡。
结论
我们初步证实了 A438079 对 CRC 的治疗潜力，并为 A438079 作为 CRC 临床治疗的新药提供了可靠的理论依据。
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