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Investigational New Drugs

, Volume 37, Issue 5, pp 818–827 | Cite as

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 Yokoi
  • Seiji MabuchiEmail author
  • Kotaro Shimura
  • Naoko Komura
  • Katsumi Kozasa
  • Hiromasa Kuroda
  • Ryoko Takahashi
  • Tomoyuki Sasano
  • Mahiru Kawano
  • Yuri Matsumoto
  • Michiko Kodama
  • Kae Hashimoto
  • Kenjiro Sawada
  • Tadashi Kimura
PRECLINICAL STUDIES

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.

Keywords

Chemotherapy Cervical cancer Cancer stem cells Lurbinectedin 

Notes

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.

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.

Ethical approval

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.

Informed consent

For this type of study, formal consent is not required.

Supplementary material

10637_2018_686_MOESM1_ESM.pptx (1.3 mb)
ESM 1 (PPTX 1353 kb)

References

  1. 1.
    Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J Clin 65:87–108.  https://doi.org/10.3322/caac.21262 CrossRefGoogle Scholar
  2. 2.
    Leath CA, Straughn JM (2013) Chemotherapy for advanced and recurrent cervical carcinoma: results from cooperative group trials. Gynecol Oncol 129:251–257.  https://doi.org/10.1016/j.ygyno.2012.12.035 CrossRefGoogle Scholar
  3. 3.
    Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM et al (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370:734–743.  https://doi.org/10.1056/NEJMoa1309748 CrossRefGoogle Scholar
  4. 4.
    Moore DH, Tian C, Monk BJ, Long HJ, Omura GA, Bloss JD (2010) Prognostic factors for response to cisplatin-based chemotherapy in advanced cervical carcinoma: a gynecologic oncology group study. Gynecol Oncol 116:44–49.  https://doi.org/10.1016/j.ygyno.2009.09.006 CrossRefGoogle Scholar
  5. 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
  6. 6.
    Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells - what challenges do they pose? Nat Rev Drug Discov 13:497–512.  https://doi.org/10.1038/nrd4253 CrossRefGoogle Scholar
  7. 7.
    Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3:730–737CrossRefGoogle Scholar
  8. 8.
    López J, Poitevin A, Mendoza-Martínez V, Pérez-Plasencia C, García-Carrancá A (2012) Cancer-initiating cells derived from established cervical cell lines exhibit stem-cell markers and increased radioresistance. BMC Cancer 12:48.  https://doi.org/10.1186/1471-2407-12-48 CrossRefGoogle Scholar
  9. 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
  10. 10.
    Chhabra R (2015) Cervical cancer stem cells: opportunities and challenges. J Cancer Res Clin Oncol 141:1889–1897.  https://doi.org/10.1007/s00432-014-1905-y CrossRefGoogle Scholar
  11. 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. 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
  13. 13.
    Kuroda H, Mabuchi S, Kozasa K, Yokoi E, Matsumoto Y, Komura N, Kawano M, Hashimoto K, Sawada K, Kimura T (2017) PM01183 inhibits myeloid-derived suppressor cells in vitro and in vivo. Immunotherapy 9:805–817.  https://doi.org/10.2217/imt-2017-0046 CrossRefGoogle Scholar
  14. 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. 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. 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. 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. 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
  19. 19.
    Liu SY, Zheng PS (2013) High aldehyde dehydrogenase activity identifies cancer stem cells in human cervical cancer. Oncotarget 4:2462–2475.  https://doi.org/10.18632/oncotarget.1578 Google Scholar
  20. 20.
    Wang L, Guo H, Lin C, Yang L, Wang X (2014) Enrichment and characterization of cancer stem-like cells from a cervical cancer cell line. Mol Med Rep 9:2117–2123.  https://doi.org/10.3892/mmr.2014.2063 CrossRefGoogle Scholar
  21. 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. 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. 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. 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
  25. 25.
    Aztopal N, Erkisa M, Erturk E, Ulukaya E, Tokullugil AH, Ari F (2018) Valproic acid, a histone deacetylase inhibitor, induces apoptosis in breast cancer stem cells. Chem Biol Interact 280:51–58.  https://doi.org/10.1016/j.cbi.2017.12.003 CrossRefGoogle Scholar
  26. 26.
    Di Pompo G, Salerno M, Rotili D, Valente S, Zwergel C, Avnet S et al (2015) Novel histone deacetylase inhibitors induce growth arrest, apoptosis, and differentiation in sarcoma cancer stem cells. J Med Chem 58:4073–4079.  https://doi.org/10.1021/acs.jmedchem.5b00126 CrossRefGoogle Scholar
  27. 27.
    Bahadori HR, Green MR, Catapano CV (2001) Synergistic interaction between topotecan and microtubule-interfering agents. Cancer Chemother Pharmacol 48:188–196CrossRefGoogle Scholar
  28. 28.
    Tiersten AD, Selleck MJ, Hershman DL, Smith D, Resnik EE, Troxel AB, Brafman LB, Shriberg L (2004) Phase II study of topotecan and paclitaxel for recurrent, persistent, or metastatic cervical carcinoma. Gynecol Oncol 92:635–638.  https://doi.org/10.1016/j.ygyno.2003.11.019 CrossRefGoogle Scholar
  29. 29.
    Kim BW, Cho H, Choi CH, Ylaya K, Chung JY, Kim JH, Hewitt SM (2015) Clinical significance of OCT4 and SOX2 protein expression in cervical cancer. BMC Cancer 15:1015.  https://doi.org/10.1186/s12885-015-2015-1 CrossRefGoogle Scholar
  30. 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. 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
  32. 32.
    Major AG, Pitty LP, Farah CS (2013) Cancer stem cell markers in head and neck squamous cell carcinoma. Stem Cells Int 2013:319489–319413.  https://doi.org/10.1155/2013/319489 CrossRefGoogle Scholar
  33. 33.
    Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (2005) Transcriptional regulation of nanog by OCT4 and SOX2. J Biol Chem 280:24731–24737.  https://doi.org/10.1074/jbc.M502573200 CrossRefGoogle Scholar
  34. 34.
    Miyajima C, Inoue Y, Hayashi H (2015) Pseudokinase tribbles 1 (TRB1) negatively regulates tumor-suppressor activity of p53 through p53 deacetylation. Biol Pharm Bull 38:618–624.  https://doi.org/10.1248/bpb.b15-00003 CrossRefGoogle Scholar
  35. 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
  36. 36.
    Li M, He Y, Dubois W, Wu X, Shi J, Huang J (2012) Distinct regulatory mechanisms and functions for p53-activated and p53-repressed DNA damage response genes in embryonic stem cells. Mol Cell 46:30–42.  https://doi.org/10.1016/j.molcel.2012.01.020 CrossRefGoogle Scholar
  37. 37.
    Takebe N, Miele L, Harris PJ, Jeong W, Bando H, Kahn M, Yang SX, Ivy SP (2015) Targeting notch, hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12:445–464.  https://doi.org/10.1038/nrclinonc.2015.61 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Eriko Yokoi
    • 1
  • Seiji Mabuchi
    • 1
    Email author
  • Kotaro Shimura
    • 1
  • Naoko Komura
    • 1
  • Katsumi Kozasa
    • 1
  • Hiromasa Kuroda
    • 1
  • Ryoko Takahashi
    • 1
  • Tomoyuki Sasano
    • 1
  • Mahiru Kawano
    • 1
  • Yuri Matsumoto
    • 1
  • Michiko Kodama
    • 1
  • Kae Hashimoto
    • 1
  • Kenjiro Sawada
    • 1
  • Tadashi Kimura
    • 1
  1. 1.Department of Obstetrics and GynecologyOsaka University Graduate School of MedicineOsakaJapan

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