Tokunaga Shuntaro, Nagano Tatsuya, Kobayashi Kazuyuki, Katsurada Masahiro, Nakata Kyosuke, Yamamoto Masatsugu, Tachihara Motoko, Kamiryo Hiroshi, Yokozaki Hiroshi, Nishimura Yoshihiro
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
Anticancer Res. 2017 May;37(5):2225-2231. doi: 10.21873/anticanres.11558.
BACKGROUND/AIM: Amrubicin (AMR) has shown promising activity for lung cancer. However, little is known about the mechanism underlying resistance to this agent. The aim of this study was to elucidate the mechanism underlying resistance to AMR.
We first developed amrubicinol (AMR-OH)-resistant cell lines (H520/R and DMS53/R) by exposing lung cancer cell lines (H520 and DMS53) to increasing concentrations of AMR-OH and performed functional analysis by using these cell lines.
Transcriptome analyses showed that amphiregulin (AREG) was the most highly up-regulated gene in both AMR-OH-resistant cell lines compared to parent cells. Conditioned medium from DMS53/R cells reduced the sensitivity to AMR-OH in DMS53 cells. In contrast, DMS53/R cells transfected with siRNA directed against AREG recovered their sensitivity to AMR-OH. An additional administration of cetuximab with amrubicinol also restored the sensitivity to AMR-OH.
Amphiregulin plays an important role in resistance to AMR-OH.
背景/目的：氨柔比星（AMR）对肺癌显示出有前景的活性。然而，关于对该药物耐药的潜在机制知之甚少。本研究的目的是阐明对AMR耐药的潜在机制。
我们首先通过将肺癌细胞系（H520和DMS53）暴露于浓度递增的氨柔比星醇（AMR-OH）来建立氨柔比星醇耐药细胞系（H520/R和DMS53/R），并使用这些细胞系进行功能分析。
转录组分析表明，与亲本细胞相比，在两个氨柔比星醇耐药细胞系中双调蛋白（AREG）是上调最显著的基因。来自DMS53/R细胞的条件培养基降低了DMS53细胞对氨柔比星醇的敏感性。相反，用针对AREG的小干扰RNA转染的DMS53/R细胞恢复了对氨柔比星醇的敏感性。西妥昔单抗与氨柔比星醇联合给药也恢复了对氨柔比星醇的敏感性。
双调蛋白在对氨柔比星醇的耐药中起重要作用。
