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01-10-2019 | PRECLINICAL STUDIES

Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer

Authors: Eriko Yokoi, Seiji Mabuchi, Kotaro Shimura, Naoko Komura, Katsumi Kozasa, Hiromasa Kuroda, Ryoko Takahashi, Tomoyuki Sasano, Mahiru Kawano, Yuri Matsumoto, Michiko Kodama, Kae Hashimoto, Kenjiro Sawada, Tadashi Kimura

Published in: Investigational New Drugs | Issue 5/2019

Summary

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.

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Title: Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer
Authors: Eriko Yokoi
Seiji Mabuchi
Kotaro Shimura
Naoko Komura
Katsumi Kozasa
Hiromasa Kuroda
Ryoko Takahashi
Tomoyuki Sasano
Mahiru Kawano
Yuri Matsumoto
Michiko Kodama
Kae Hashimoto
Kenjiro Sawada
Tadashi Kimura
Publication date: 01-10-2019
Publisher: Springer US
Published in: Investigational New Drugs / Issue 5/2019
Print ISSN: 0167-6997
Electronic ISSN: 1573-0646
DOI: https://doi.org/10.1007/s10637-018-0686-6

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