Amphiregulin as a Novel Resistance Factor for Amrubicin in Lung Cancer Cells

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.

Materials and methods: 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.

Results: 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.

Conclusion: Amphiregulin plays an important role in resistance to AMR-OH.

Keywords: Amrubicin; amphiregulin; cetuximab; lung cancer.

MeSH terms

  • Amphiregulin / genetics*
  • Animals
  • Anthracyclines / pharmacology*
  • Anthracyclines / therapeutic use
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice, Inbred BALB C
  • Mice, Nude
  • RNA, Small Interfering
  • Tumor Burden / drug effects


  • Amphiregulin
  • Anthracyclines
  • Antineoplastic Agents
  • RNA, Small Interfering
  • amrubicinol
  • amrubicin