From the Department of Anesthesiology, Harbin Medical University Cancer Hospital, Harbin, China.
Department of Anesthesiology, Qilu Hospital of Shandong University, Jinan, China.
Anesth Analg. 2020 Oct;131(4):1270-1280. doi: 10.1213/ANE.0000000000004778.
Propofol is a common sedative-hypnotic drug traditionally used for inducing and maintaining general anesthesia. Recent studies have drawn attention to the nonanesthetic effects of propofol, but the potential mechanism by which propofol suppresses non-small-cell lung cancer (NSCLC) progression has not been fully elucidated.
For the in vitro experiments, we used propofol (0, 2, 5, and 10 µg/mL) to treat A549 cells for 1, 4, and 12 hours and Cell Counting Kit-8 (CCK-8) to detect proliferation. Apoptosis was measured with flow cytometry. We also transfected A549 cells with an microribonucleic acid-21 (miR-21) mimic or negative control ribonucleic acid (RNA) duplex and phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) small interfering ribonucleic acid (siRNA) or negative control. PTEN, phosphorylated protein kinase B (pAKT), and protein kinase B (AKT) expression were detected using Western blotting, whereas miR-21 expression was examined by real-time polymerase chain reaction (RT-PCR). In vivo, nude mice were given injections of A549 cells to grow xenograft tumors; 8 days later, the mice were intraperitoneally injected with propofol (35 mg/kg) or soybean oil. Tumors were then collected from mice and analyzed by immunohistochemistry and Western blotting.
Propofol inhibited growth (1 hour, P = .001; 4 hours, P ≤ .0001; 12 hours, P = .0004) and miR-21 expression (P ≤ .0001) and induced apoptosis (1 hour, P = .0022; 4 hours, P = .0005; 12 hours, P ≤ .0001) in A549 cells in a time and concentration-dependent manner. MiR-21 mimic and PTEN siRNA transfection antagonized the suppressive effects of propofol on A549 cells by decreasing PTEN protein expression (mean differences [MD] [95% confidence interval {CI}], -0.51 [-0.86 to 0.16], P = .0058; MD [95% CI], 0.81 [0.07-1.55], P = .0349, respectively), resulting in an increase in pAKT levels (MD [95% CI] = -0.82 [-1.46 to -0.18], P = .0133) following propofol exposure. In vivo, propofol treatment reduced NSCLC tumor growth (MD [95% CI] = -109.47 [-167.03 to -51.91], P ≤ .0001) and promoted apoptosis (MD [95% CI] = 38.53 [11.69-65.36], P = .0093).
Our study indicated that propofol inhibited A549 cell growth, accelerated apoptosis via the miR-21/PTEN/AKT pathway in vitro, suppressed NSCLC tumor cell growth, and promoted apoptosis in vivo. Our findings provide new implications for propofol in cancer therapy and indicate that propofol is extremely advantageous in surgical treatment.
丙泊酚是一种常用的镇静催眠药物，传统上用于诱导和维持全身麻醉。最近的研究引起了人们对丙泊酚非麻醉作用的关注，但丙泊酚抑制非小细胞肺癌（NSCLC）进展的潜在机制尚未完全阐明。
在体外实验中，我们使用丙泊酚（0、2、5 和 10μg/ml）处理 A549 细胞 1、4 和 12 小时，用细胞计数试剂盒-8（CCK-8）检测增殖。用流式细胞术检测细胞凋亡。我们还将 A549 细胞转染微小 RNA-21（miR-21）模拟物或阴性对照 RNA 双链体和磷酸酶和张力蛋白同源物，缺失 10 号染色体（PTEN）小干扰 RNA（siRNA）或阴性对照。用 Western blot 检测 PTEN、磷酸化蛋白激酶 B（pAKT）和蛋白激酶 B（AKT）的表达，用实时聚合酶链反应（RT-PCR）检测 miR-21 的表达。在体内，裸鼠注射 A549 细胞以生长异种移植肿瘤；8 天后，裸鼠腹腔内注射丙泊酚（35mg/kg）或大豆油。然后从裸鼠中收集肿瘤并进行免疫组织化学和 Western blot 分析。
丙泊酚以时间和浓度依赖的方式抑制 A549 细胞的生长（1 小时，P=0.001；4 小时，P≤0.0001；12 小时，P=0.0004）和 miR-21 表达（P≤0.0001），并诱导细胞凋亡（1 小时，P=0.0022；4 小时，P=0.0005；12 小时，P≤0.0001）。miR-21 模拟物和 PTEN siRNA 转染通过降低 PTEN 蛋白表达（平均差异[MD] [95%置信区间{CI}]，-0.51 [-0.86 至 0.16]，P=0.0058；MD [95% CI]，0.81 [0.07-1.55]，P=0.0349，分别）拮抗丙泊酚对 A549 细胞的抑制作用，导致 pAKT 水平升高（MD [95% CI] =-0.82 [-1.46 至-0.18]，P=0.0133）。在体内，丙泊酚治疗降低了 NSCLC 肿瘤生长（MD [95% CI] =-109.47 [-167.03 至-51.91]，P≤0.0001）并促进细胞凋亡（MD [95% CI] =38.53 [11.69-65.36]，P=0.0093）。
我们的研究表明，丙泊酚通过体外 miR-21/PTEN/AKT 通路抑制 A549 细胞生长，加速细胞凋亡，抑制 NSCLC 肿瘤细胞生长，促进体内细胞凋亡。我们的发现为丙泊酚在癌症治疗中的应用提供了新的启示，并表明丙泊酚在外科治疗中极具优势。
