Lurbinectedin (PM01183), a selective inhibitor of active transcription, effectively eliminates both cancer cells and cancer stem cells in preclinical models of uterine cervical cancer
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.
KeywordsChemotherapy Cervical cancer Cancer stem cells Lurbinectedin
We thank Moe Matsui for her secretarial assistance and Ayako Okamura for her technical assistance.
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.
Compliance with ethical standards
Conflicts of interest statement
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.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
For this type of study, formal consent is not required.
- 5.Hisamatsu T, Mabuchi S, Yoshino K, Fujita M, Enomoto T, Hamasaki T, Kimura T (2012) Prediction of progression-free survival and response to paclitaxel plus carboplatin in patients with recurrent or advanced cervical cancer. Int J Gynecol Cancer 22:623–629. https://doi.org/10.1097/IGC.0b013e3182473277 CrossRefGoogle Scholar
- 9.Kumazawa S, Kajiyama H, Umezu T, Mizuno M, Suzuki S, Yamamoto E, Mitsui H, Sekiya R, Shibata K, Kikkawa F (2014) Possible association between stem-like hallmark and radioresistance in human cervical carcinoma cells. J Obstet Gynaecol Res 40:1389–1398. https://doi.org/10.1111/jog.12357 CrossRefGoogle Scholar
- 11.Leal JF, Martínez-Díez M, García-Hernández V, Moneo V, Domingo A, Bueren-Calabuig JA, Negri A, Gago F, Guillén-Navarro MJ, Avilés P, Cuevas C, García-Fernández LF, Galmarini CM (2010) PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol 161:1099–1110. https://doi.org/10.1111/j.1476-5381.2010.00945.x CrossRefGoogle Scholar
- 12.Takahashi R, Mabuchi S, Kawano M, Sasano T, Matsumoto Y, Kuroda H, Kozasa K, Hashimoto K, Sawada K, Kimura T (2016) Preclinical investigations of PM01183 (Lurbinectedin) as a single agent or in combination with other anticancer agents for clear cell carcinoma of the ovary. PLoS One 11:e0151050. https://doi.org/10.1371/journal.pone.0151050 CrossRefGoogle Scholar
- 14.Poveda A, Del Campo JM, Ray-Coquard I, Alexandre J, Provansal M, Guerra Alía EM et al (2017) Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer. Ann Oncol 28:1280–1287. https://doi.org/10.1093/annonc/mdx111 CrossRefGoogle Scholar
- 15.NCT02421588 Clinical Trials. gov. A Service of the U.S. National Institute of Health. Available from: http://www.clinicaltrials.gov (Accessed; August 30, 2015)
- 16.Nozawa S, Tsukazaki K, Sakayori M, Jeng CH, Iizuka R (1988) Establishment of a human ovarian clear cell carcinoma cell line (RMG-I) and its single cell cloning--with special reference to the stem cell of the tumor. Hum Cell 1:426–435Google Scholar
- 17.Mabuchi S, Altomare DA, Cheung M, Zhang L, Poulikakos PI, Hensley HH, Schilder RJ, Ozols RF, Testa JR (2007) RAD001 inhibits human ovarian cancer cell proliferation, enhances cisplatin-induced apoptosis, and prolongs survival in an ovarian cancer model. Clin Cancer Res 13:4261–4270. https://doi.org/10.1158/1078-0432.CCR-06-2770 CrossRefGoogle Scholar
- 18.Vidal A, Muñoz C, Guillén MJ, Moretó J, Puertas S, Martínez-Iniesta M et al (2012) Lurbinectedin (PM01183), a new DNA minor groove binder, inhibits growth of orthotopic primary graft of cisplatin-resistant epithelial ovarian cancer. Clin Cancer Res 18:5399–5411. https://doi.org/10.1158/1078-0432.CCR-12-1513 CrossRefGoogle Scholar
- 21.Wang L, Liu X, Ren Y, Zhang J, Chen J, Zhou W, Guo W, Wang X, Chen H, Li M, Yuan X, Zhang X, Yang J, Wu C (2017) Cisplatin-enriching cancer stem cells confer multidrug resistance in non-small cell lung cancer via enhancing TRIB1/HDAC activity. Cell Death Dis 8:e2746. https://doi.org/10.1038/cddis.2016.409 CrossRefGoogle Scholar
- 22.Chikamatsu K, Ishii H, Murata T, Sakakura K, Shino M, Toyoda M, Takahashi K, Masuyama K (2013) Alteration of cancer stem cell-like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck. Cancer Sci 104:1468–1475. https://doi.org/10.1111/cas.12271 CrossRefGoogle Scholar
- 23.Del Bufalo D, Desideri M, De Luca T, Di Martile M, Gabellini C, Monica V et al (2014) Histone deacetylase inhibition synergistically enhances pemetrexed cytotoxicity through induction of apoptosis and autophagy in non-small cell lung cancer. Mol Cancer 13:230. https://doi.org/10.1186/1476-4598-13-230 CrossRefGoogle Scholar
- 24.Salvador MA, Wicinski J, Cabaud O, Toiron Y, Finetti P, Josselin E, Lelievre H, Kraus-Berthier L, Depil S, Bertucci F, Collette Y, Birnbaum D, Charafe-Jauffret E, Ginestier C (2013) The histone deacetylase inhibitor abexinostat induces cancer stem cells differentiation in breast cancer with low Xist expression. Clin Cancer Res 19:6520–6531. https://doi.org/10.1158/1078-0432.CCR-13-0877 CrossRefGoogle Scholar
- 30.Martinez-Cruzado L, Tornin J, Rodriguez A, Santos L, Allonca E, Fernandez-Garcia MT, Astudillo A, Garcia-Pedrero JM, Rodriguez R (2017) Trabectedin and Campthotecin synergistically eliminate Cancer stem cells in cell-of-origin sarcoma models. Neoplasia 19:460–470. https://doi.org/10.1016/j.neo.2017.03.004 CrossRefGoogle Scholar
- 31.Elez ME, Tabernero J, Geary D, Macarulla T, Kang SP, Kahatt C, Pita ASM, Teruel CF, Siguero M, Cullell-Young M, Szyldergemajn S, Ratain MJ (2014) First-in-human phase I study of Lurbinectedin (PM01183) in patients with advanced solid tumors. Clin Cancer Res 20:2205–2214. https://doi.org/10.1158/1078-0432.CCR-13-1880 CrossRefGoogle Scholar
- 35.Liu K, Lee J, Kim JY, Wang L, Tian Y, Chan ST, et al. Mitophagy Controls the Activities of Tumor Suppressor p53 to Regulate Hepatic Cancer Stem Cells. Mol Cell. 2017;68:281–292.e5. https://doi.org/10.1016/j.molcel.2017.09.022