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

• Published in: Investigational new drugs 2019-10, Vol.37 (5), p.818-827
• Main Authors: Yokoi, Eriko, Mabuchi, Seiji, Shimura, Kotaro, Komura, Naoko, Kozasa, Katsumi, Kuroda, Hiromasa, Takahashi, Ryoko, Sasano, Tomoyuki, Kawano, Mahiru, Matsumoto, Yuri, Kodama, Michiko, Hashimoto, Kae, Sawada, Kenjiro, Kimura, Tadashi
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Biotechnology; Cancer; Carbolines - pharmacology; Cell Proliferation; Cervical cancer; Cervix; Cisplatin; Cisplatin - pharmacology; Drug Resistance, Neoplasm - drug effects; Female; Gene expression; Heterocyclic Compounds, 4 or More Rings - pharmacology; Human papillomavirus; Humans; Medicine; Medicine & Public Health; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Oct-4 protein; Oncology; Paclitaxel; Pharmacology/Toxicology; Platinum; Preclinical Studies; Stem cell transplantation; Stem cells; Studies; Transcription; Tumor cell lines; Tumor Cells, Cultured; Uterine cancer; Uterine Cervical Neoplasms - pathology; Uterine Cervical Neoplasms - prevention & control; Uterus; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-018-0686-6

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.