Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Anticancer Res. 2020 Apr;40(4):1867-1874. doi: 10.21873/anticanres.14140.
BACKGROUND/AIM: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM.
Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated.
NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling.
The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.
背景/目的：针对实体瘤，已经成功开发出了分子靶向药物，并且也正在研究将其用于治疗恶性胸膜间皮瘤（MPM）。我们之前曾报道过通过大规模平行测序技术在 MPM 患者样本中检测到的 von Hippel Lindau（VHL）突变。在这里，我们进行了一项体外研究，以探讨 VHL 突变型 MPM 的治疗方法。
使用了带有或不带有 VHL 突变的三种 MPM 细胞系，并评估了分子靶向药物对生长抑制的影响。基于表现出生长抑制作用的分子靶向药物的特征，还评估了 siRNA 敲低的效果。
携带 VHL L89H 突变的 NCI-H28 MPM 细胞对 YC-1（一种缺氧诱导因子 1α（HIF-1α）抑制剂）敏感，YC-1 处理以剂量和时间依赖性方式诱导大量细胞凋亡。siRNA 下调 HIF-1α 部分抑制了 NCI-H28 细胞的生长，这表明可能需要额外的阻断来完全抑制生长信号。
VHL 突变可能预测肿瘤对 HIF-1α 抑制剂 YC-1 的反应。
