Lurbinectedin (PM01183), a Selective Inhibitor of Active Transcription, Effectively Eliminates Both Cancer Cells and Cancer Stem Cells in Preclinical Models of Uterine Cervical Cancer.Eriko YokoiSeiji MabuchiEmail authorKotaro ShimuraNaoko KomuraKatsumi KozasaHiromasa KurodaRyoko TakahashiTomoyuki SasanoMahiru KawanoYuri MatsumotoMichiko KodamaKae HashimotoKenjiro SawadaTadashi Kimura
First Online: 30 October 2018 .
Objective :
The objective of this study was to evaluate the antitumor effects of lurbinectedin on cervical cancer with a special focus on its effects on cancer stem cells (CSCs).
Methods :
Using two cervical cell lines (ME180 and CaSki cells), the antitumor effects of lurbinectedin were assessed in vitro using the MTS assay and colony formation assay. The growth inhibitory effects of paclitaxel and cisplatin were also evaluated as controls. By employing ALDH1 activity as a marker of CSCs, the antitumor effects of lurbinectedin on cervical CSCs and non-CSCs were individually evaluated. Finally, we investigated the mechanisms by which lurbinectedin eliminated cervical CSCs.
Results :
Lurbinectedin had significant antitumor activity toward cervical cancer cells at low nanomolar concentrations in vitro. Mouse xenografts of cervical cancer revealed that lurbinectedin significantly inhibits tumor growth. The growth-inhibitory effect of lurbinectedin was greater than that of cisplatin and paclitaxel. ALDH-high CSCs were observed in both cervical cancer cell lines (4.4% and 2.4% in ME180 and CaSki cells, respectively). Lurbinectedin downregulated stem cell-related gene expression (Oct4, Nanog, and SOX2), inhibited HDAC1 activity, and effectively eliminated ALDH-high CSCs.
Conclusions :
Lurbinectedin is highly effective on uterine cervical cancer because it eliminates CSCs, and lurbinectedin is a promising agent to overcome platinum resistance in cervical cancer.