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

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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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Acknowledgements

We thank Moe Matsui for her secretarial assistance and Ayako Okamura for her technical assistance.

Funding

This study was supported by Grants-in-aid for General Scientific Research no. T17 K16849, A15H025640, and T17 K112760 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    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

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  1. Eriko Yokoi
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  2. Seiji Mabuchi
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Correspondence to Seiji Mabuchi.

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All authors have declared that they have no conflict of interests to disclose.

Eriko Yokoi declares that he has no conflict of interest. Seiji Mabuchi declares that he has no conflict of interest. Kotaro Shimura declares that he has no conflict of interest. Naoko Komura declares that he has no conflict of interest. Katsumi Kozasa declares that he has no conflict of interest. Hiromasa Kuroda declares that he has no conflict of interest. Ryoko Takahashi declares that he has no conflict of interest. Tomoyuki Sasano declares that he has no conflict of interest. Mahiru Kawano declares that he has no conflict of interest. Yuri Matsumoto declares that he has no conflict of interest. Michiko Kodama declares that he has no conflict of interest. Kae Hashimoto declares that he has no conflict of interest. Kenjiro Sawada declares that he has no conflict of interest.

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Yokoi, E., Mabuchi, S., Shimura, K. et al. Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer. Invest New Drugs 37, 818–827 (2019). https://doi.org/10.1007/s10637-018-0686-6

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