High Magnetic Field Laboratory, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, China.
University of Science and Technology of China, Hefei, 230026, China.
Acta Pharmacol Sin. 2022 Aug;43(8):2119-2127. doi: 10.1038/s41401-021-00817-y. Epub 2021 Dec 10.
The response rate of topotecan, as a second-line chemotherapeutic drug for small cell lung cancer, is ~20%. DNA/RNA helicase SLFN11 (schlafen family member 11), a member of the Schlafen (SLFN) family, is a crucial determinant of response to many DNA damaging agents, expression of SLFN11 tends to augment the antitumor effects of the commonly used DNA-targeting agents. In the present study we investigated how SLFN11 expression regulated the sensitivity of small cell lung cancer to topotecan. We showed that SLFN11 expression levels were positively associated with the sensitivity to topotecan in a panel of seven SCLC cell lines. Topotecan treatment induced different patterns of the DNA response network in SCLC cells: DNA damage response (DDR) was more prominently activated in SLFN11-deficient SCLC cell line H82 than in SLFN11-plentiful SCLC cell line DMS273, whereas topotecan induced significant accumulation of p-Chk1, p-RPA2 and Rad51 in H82 cells, but not in DMS273 cells. We unraveled that SLFN11 expression was highly negatively correlated to the methylation of the SLFN11 promoter. HDAC inhibitors FK228 and SAHA dose-dependently increased SLFN11 expression through suppressing DNA methylation at the SLFN11 promoter, thereby sensitizing SCLC cells to topotecan. Finally, we assessed the methylation status of the SLFN11 promoter in 27 SCLC clinical specimens, and found that most of the clinical samples (24/27) showed DNA methylation at the SLFN11 promoter. In conclusion, it is feasible to combine topotecan with FK228 to improve the response rate of topotecan in SCLC patients.
拓扑替康作为小细胞肺癌的二线化疗药物，其缓解率约为 20%。DNA/RNA 解旋酶 SLFN11（ Schlafen 家族成员 11）是许多 DNA 损伤剂反应的关键决定因素，SLFN11 的表达往往会增强常用的 DNA 靶向药物的抗肿瘤作用。在本研究中，我们研究了 SLFN11 表达如何调节小细胞肺癌对拓扑替康的敏感性。我们表明，在七个小细胞肺癌细胞系的面板中，SLFN11 表达水平与对拓扑替康的敏感性呈正相关。拓扑替康处理在 SLFN11 缺失的小细胞肺癌细胞系 H82 中比在 SLFN11 丰富的小细胞肺癌细胞系 DMS273 中更明显地激活了 DNA 反应网络：DNA 损伤反应（DDR），而拓扑替康诱导 H82 细胞中 p-Chk1、p-RPA2 和 Rad51 的明显积累，但在 DMS273 细胞中则没有。我们发现 SLFN11 表达与 SLFN11 启动子的甲基化高度负相关。HDAC 抑制剂 FK228 和 SAHA 通过抑制 SLFN11 启动子的 DNA 甲基化，剂量依赖性地增加 SLFN11 的表达，从而使小细胞肺癌细胞对拓扑替康敏感。最后，我们评估了 27 个小细胞肺癌临床标本中 SLFN11 启动子的甲基化状态，发现大多数临床标本（24/27）在 SLFN11 启动子处显示出 DNA 甲基化。总之，将拓扑替康与 FK228 联合使用可以提高小细胞肺癌患者拓扑替康的反应率。
