The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin.
The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin.
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DOI：
10.1097/jto.0b013e31820c9e3c
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发表时间：
2011-04
期刊：
影响因子：
--
通讯作者：
Potter DA
中科院分区：
文献类型：
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作者：
Srirangam A;Milani M;Mitra R;Guo Z;Rodriguez M;Kathuria H;Fukuda S;Rizzardi A;Schmechel S;Skalnik DG;Pelus LM;Potter DA
利托那韦是一种潜在的肺癌治疗药物，但其在肺腺癌中的靶点及其活性的候选生物标志物尚不清楚。 RNAi 用于鉴定其表达影响利托那韦敏感性的基因。通过等效线图分析测试了利托那韦、吉西他滨和顺铂之间的协同作用。 Ritonavir 抑制 K-ras 突变型肺腺癌系 A549、H522、H23 和 K-ras 野生型系 H838 的生长。利托那韦导致 G0/G1 停滞和细胞凋亡。与 G0/G1 停滞相关，利托那韦下调细胞周期蛋白依赖性激酶、细胞周期蛋白 D1 和 Rb 磷酸化。利托那韦与诱导细胞凋亡相关，可将生存素 mRNA 和蛋白质水平降低 2 倍以上。 Ritonavir 抑制 c-Src 和 STAT3 的磷酸化（这是生存素基因表达和生长的重要事件），并诱导 PARP1 裂解。虽然敲低生存素、c-Src 或 STAT3 会抑制细胞生长，但只有敲除生存素才能增强利托那韦对生长的抑制作用，而生存素过度表达会促进利托那韦耐药。利托那韦与吉西他滨或顺铂联合进行测试，分别表现出协同作用和相加作用。在临床可行的利托那韦浓度（<10 μM）下，利托那韦/吉西他滨/顺铂的组合在 A549 系中具有协同作用，在 H522 系中具有相加作用。利托那韦对肺腺癌治疗很感兴趣，而生存素是其敏感性的重要靶点和潜在生物标志物。利托那韦与吉西他滨/顺铂的合作可能是由于 PARP1 参与修复顺铂介导的 DNA 损伤，而生存素参与修复吉西他滨介导的双链 DNA 断裂 (DSB)。
Ritonavir is a potential therapeutic agent in lung cancer, but its targets in lung adenocarcinoma are unknown, as are candidate biomarkers for its activity. RNAi was used to identify genes whose expression affects ritonavir sensitivity. Synergy between ritonavir, gemcitabine and cisplatin was tested by isobologram analysis. Ritonavir inhibits growth of K-ras mutant lung adenocarcinoma lines A549, H522, H23 and K-ras wild type line H838. Ritonavir causes G0/G1 arrest and apoptosis. Associated with G0/G1 arrest, ritonavir down-regulates cyclin dependent kinases, cyclin D1 and Rb phosphorylation. Associated with induction of apoptosis, ritonavir reduces survivin mRNA and protein levels more than 2-fold. Ritonavir inhibits phosphorylation of c-Src and STAT3, which are important events for survivin gene expression and growth, and induces cleavage of PARP1. While knock down of survivin, c-Src or STAT3 inhibits cell growth, only survivin knock down enhances ritonavir inhibition of growth and survivin over-expression promotes ritonavir resistance. Ritonavir was tested in combination with gemcitabine or cisplatin exhibiting synergistic and additive effects, respectively. The combination of ritonavir/gemcitabine/cisplatin is synergistic in the A549 line and additive in the H522 line, at clinically feasible ritonavir concentrations (<10 μM). Ritonavir is of interest for lung adenocarcinoma therapeutics and survivin is an important target and potential biomarker for its sensitivity. Ritonavir cooperation with gemcitabine/cisplatin might be explained by involvement of PARP1 in repair of cisplatin-mediated DNA damage and survivin in repair of gemcitabine-mediated double stranded DNA breaks (DSB).