Translational Radiation Biology Laboratory, Juravinski Cancer Center, Hamilton, Ontario, Canada.
J Thorac Oncol. 2011 Mar;6(3):439-50. doi: 10.1097/JTO.0b013e3182049d8b.
In this study, we investigated the effect of the 3-hydroxy-3-methylgutaryl-CoA reductase inhibitor lovastatin, as a sensitizer of lung cancer cells to ionizing radiation (IR).
A549 lung adenocarcinoma cells were treated with 0 to 50 μM lovastatin alone or in combination with 0 to 8 Gy IR and subjected to clonogenic survival and proliferation assays. To assess the mechanism of drug action, we examined the effects of lovastatin and IR on the epidermal growth factor (EGF) receptor and AMP-activated kinase (AMPK) pathways and on apoptotic markers and the cell cycle.
Lovastatin inhibited basal clonogenic survival and proliferation of A549 cells and sensitized them to IR. This was reversed by mevalonate, the product of 3-hydroxy-3-methylgutaryl-CoA reductase. Lovastatin attenuated selectively EGF-induced phosphorylation of EGF receptor and Akt, and IR-induced Akt phosphorylation, in a mevalonate-sensitive fashion, without inhibition on extracellular signal-regulated kinase 1/2 phosphorylation by either stimulus. IR phosphorylated and activated the metabolic sensor and tumor suppressor AMPK, but lovastatin enhanced basal and IR-induced AMPK phosphorylation. The drug inhibited IR-induced expression of p53 and the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1), but caused a redistribution of cells from G1-S phase (control and radiated cells) and G2-M phase (radiated cells) of cell cycle into apoptosis. The latter was also evident by induction of nuclear fragmentation and cleavage of caspase 3 by lovastatin in both control and radiated cells.
We suggest that lovastatin inhibits survival and induces radiosensitization of lung cancer cells through induction of apoptosis, which may be mediated by a simultaneous inhibition of the Akt and activation of the AMPK signaling pathways.
在这项研究中，我们研究了 3-羟基-3-甲基戊二酰辅酶 A 还原酶抑制剂洛伐他汀作为肺癌细胞对电离辐射（IR）增敏剂的作用。
用 0 至 50μM 洛伐他汀单独或与 0 至 8GyIR 联合处理 A549 肺腺癌细胞，并进行集落形成存活和增殖测定。为了评估药物作用的机制，我们研究了洛伐他汀和 IR 对表皮生长因子（EGF）受体和 AMP 激活的蛋白激酶（AMPK）途径以及凋亡标志物和细胞周期的影响。
洛伐他汀抑制 A549 细胞的基础集落形成存活和增殖，并使它们对 IR 敏感。这可以被 3-羟基-3-甲基戊二酰辅酶 A 还原酶的产物甲羟戊酸逆转。洛伐他汀以甲羟戊酸敏感的方式选择性地减弱了 EGF 诱导的 EGF 受体和 Akt 的磷酸化，以及 IR 诱导的 Akt 磷酸化，但对两种刺激物引起的细胞外信号调节激酶 1/2 磷酸化没有抑制作用。IR 磷酸化并激活代谢传感器和肿瘤抑制因子 AMPK，但洛伐他汀增强了基础和 IR 诱导的 AMPK 磷酸化。该药物抑制了 IR 诱导的 p53 和细胞周期蛋白依赖性激酶抑制剂 p21(cip1)和 p27(kip1)的表达，但导致细胞从细胞周期的 G1-S 期（对照和辐射细胞）和 G2-M 期（辐射细胞）重新分布到细胞凋亡。洛伐他汀在对照和辐射细胞中诱导核片段化和 caspase 3 的裂解，也证明了这一点。
我们认为，洛伐他汀通过诱导细胞凋亡抑制肺癌细胞的存活并诱导放射增敏，这可能是通过同时抑制 Akt 和激活 AMPK 信号通路介导的。
