Department of Pharmacology and Toxicology, The University of Alabama at Birmingham, Birmingham, Alabama, USA.
Mol Cancer Ther. 2013 May;12(5):663-74. doi: 10.1158/1535-7163.MCT-12-0785. Epub 2013 Feb 26.
Nonsteroidal anti-inflammatory drugs such as sulindac sulfide have shown promising antineoplastic activity in multiple tumor types, but toxicities resulting from COX inhibition limit their use in cancer therapy. We recently described a N,N-dimethylethyl amine derivative of sulindac sulfide, sulindac sulfide amide (SSA), that does not inhibit COX-1 or -2, yet displays potent tumor cell growth-inhibitory activity. Here, we studied the basis for the growth-inhibitory effects of SSA on human lung adenocarcinoma cell lines. SSA potently inhibited the growth of lung tumor cells with IC50 values of 2 to 5 μmol/L compared with 44 to 52 μmol/L for sulindac sulfide. SSA also suppressed DNA synthesis and caused a G0-G1 cell-cycle arrest. SSA-induced cell death was associated with characteristics of autophagy, but significant caspase activation or PARP cleavage was not observed after treatment at its IC50 value. siRNA knockdown of Atg7 attenuated SSA-induced autophagy and cell death, whereas pan-caspase inhibitor ZVAD was not able to rescue viability. SSA treatment also inhibited Akt/mTOR signaling and the expression of downstream proteins that are regulated by this pathway. Overexpression of a constitutively active form of Akt was able to reduce autophagy markers and confer resistance to SSA-induced cell death. Our findings provide evidence that SSA inhibits lung tumor cell growth by a mechanism involving autophagy induction through the suppression of Akt/mTOR signaling. This unique mechanism of action, along with its increased potency and lack of COX inhibition, supports the development of SSA or related analogs for the prevention and/or treatment of lung cancer.
非甾体抗炎药如舒林酸硫醚在多种肿瘤类型中显示出有希望的抗肿瘤活性，但 COX 抑制引起的毒性限制了它们在癌症治疗中的应用。我们最近描述了舒林酸硫醚的 N，N-二甲基乙胺衍生物，舒林酸硫醚酰胺（SSA），它不抑制 COX-1 或 -2，但显示出强烈的肿瘤细胞生长抑制活性。在这里，我们研究了 SSA 对人肺腺癌细胞系生长抑制作用的基础。与舒林酸硫醚的 IC50 值为 44 至 52 μmol/L 相比，SSA 强烈抑制肺肿瘤细胞的生长，IC50 值为 2 至 5 μmol/L。SSA 还抑制 DNA 合成并导致 G0-G1 细胞周期停滞。SSA 诱导的细胞死亡与自噬的特征有关，但在其 IC50 值下处理时未观察到明显的 caspase 激活或 PARP 切割。Atg7 的 siRNA 敲低减弱了 SSA 诱导的自噬和细胞死亡，而泛 caspase 抑制剂 ZVAD 不能挽救活力。SSA 处理还抑制 Akt/mTOR 信号通路和受该途径调节的下游蛋白的表达。组成型激活形式的 Akt 的过表达能够减少自噬标记物并赋予对 SSA 诱导的细胞死亡的抗性。我们的研究结果提供了证据，表明 SSA 通过抑制 Akt/mTOR 信号通路诱导自噬来抑制肺肿瘤细胞的生长。这种独特的作用机制，以及其增加的效力和缺乏 COX 抑制作用，支持 SSA 或相关类似物的开发，用于预防和/或治疗肺癌。
