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A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products

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Abstract

Background

Choline kinase alpha (ChoKα) is a critical enzyme in the synthesis of phosphatidylcholine, a major structural component of eukaryotic cell membranes. ChoKα is overexpressed in a large variety of tumor cells and has been proposed as a target for personalized medicine, both in cancer therapy and rheumatoid arthritis.

Materials and methods

Triterpene quinone methides (TPQ) bioactive compounds isolated from plants of the Celastraceae family and a set of their semisynthetic derivatives were tested against the recombinant human ChoKα. Those found active as potent enzymatic inhibitors were tested in vitro for antiproliferative activity against HT29 colorectal adenocarcinoma cells, and one of the active compounds was tested for in vivo antitumoral activity in mice xenographs of HT29 cells.

Results

Among 59 natural and semisynthetic TPQs tested in an ex vivo system, 14 were highly active as inhibitors of the enzyme ChoKα with IC50 <10 μM. Nine of these were potent antiproliferative agents (IC50 <10 μM) against tumor cells. At least one compound was identified as a new antitumoral drug based on its in vivo activity against xenographs of human HT-29 colon adenocarcinoma cells.

Conclusions

The identification of a new family of natural and semisynthetic compounds with potent inhibitory activity against ChoKα and both in vitro antiproliferative and in vivo antitumoral activity supports further research on these inhibitors as potential anticancer agents. Their likely role as antiproliferative drugs deserves further studies in models of rheumatoid arthritis.

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References

  1. Lykidis A, Jackowski S. Regulation of mammalian cell membrane biosynthesis. Prog Nucleic Acid Res Mol Biol. 2001;65:361–93.

    Article  CAS  PubMed  Google Scholar 

  2. Aoyama C, Liao H, Ishidate K. Structure and function of choline kinase isoforms in mammalian cells. Progr Lipid Res. 2004;43:266–81.

    Article  CAS  Google Scholar 

  3. Lacal JC. Choline kinase: a novel target for antitumor drugs. IDrugs. 2001;4:419–26.

    CAS  PubMed  Google Scholar 

  4. Ramirez de Molina A, Gallego-Ortega D, Sarmentero J, Bañez-Coronel M, Martin-Cantalejo Y, Lacal JC. Choline kinase is a novel oncogene that potentiates RhoA-induced carcinogenesis. Cancer Res. 2005;65:5647–53.

    Article  CAS  PubMed  Google Scholar 

  5. Ramirez de Molina A, Sarmentero-Estrada J, Belda-Iniesta C, Taron M, Ramirez de Molina V, Cejas P, et al. Expression of ChoKα to predict outcome in patients with early-stage non-small-cell lung cancer: a retrospective study. Lancet Oncol. 2007;8:889–97.

    Article  CAS  PubMed  Google Scholar 

  6. Kwee SA, Hernandez B, Chan O, Wong L. Choline kinase alpha and hexokinase-2 protein expression in hepatocellular carcinoma: association with survival. PLoS One. 2012;7(10):e46591.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Ramirez de Molina A, Gutierrez R, Ramos MA, Silva JM, Silva J, Bonilla F, et al. Increased choline kinase activity in human breast carcinomas: clinical evidence for a potential novel antitumor strategy. Oncogene. 2002;21:4317–22.

    Article  CAS  PubMed  Google Scholar 

  8. Eliyahu G, Kreizman T, Degani H. Phosphocholine as a biomarker of breast cancer: molecular and biochemical studies. Int J Cancer. 2007;120:1721–30.

    Article  CAS  PubMed  Google Scholar 

  9. Iorio E, Mezzanzanica D, Alberti P, Spadaro F, Ramoni C, D’Ascenzo S, et al. Alterations of choline phospholipid metabolism in ovarian tumor progression. Cancer Res. 2005;65:9369–76.

    Article  CAS  PubMed  Google Scholar 

  10. Hernando E, Sarmentero-Estrada J, Koppie T, Belda-Iniesta C, Ramirez de Molina V, Cejas P, et al. A critical role for choline kinase-alpha in the aggressiveness of bladder carcinomas. Oncogene. 2009;28:2425–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Iorio E, Ricci A, Bagnoli M, Pisanu ME, Castellano G, Di Vito M, et al. Activation of phosphatidylcholine cycle enzymes in human epithelial ovarian cancer cells. Cancer Res. 2010;70:2126–35.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Hernandez-Alcoceba R, Saniger L, Campos J, Nunez MC, Khaless F, Gallo MA, et al. Choline kinase inhibitors as a novel approach for antiproliferative drug design. Oncogene. 1997;15:2289–301.

    Article  CAS  PubMed  Google Scholar 

  13. Rubio-Ruíz B, Conejo-García A, Rios-Marco P, Carrasco-Jiménez P, Segovia J, Marco C, et al. Design, synthesis, theorical calculations and biological evaluation of new no-symmetrical choline kinase inhibitors. Eur J Med Chem. 2012;50:154–62.

    Article  PubMed  Google Scholar 

  14. Martín-Cantalejo Y, Sáez B, Monterde MI, Murillo MT, Braña MF. Synthesis and biological activity of new bispyridinium salts of 4,4′-bispyridil-5,5′-perfluoroalkyl-2,2′-bisoxazoles. Eur J Med Chem. 2011;46:5662–7.

    Article  PubMed  Google Scholar 

  15. Hernandez-Alcoceba R, Fernandez F, Lacal JC. In vivo antitumor activity of choline kinase inhibitors: a novel target for anticancer drug discovery. Cancer Res. 1999;59:3112–8.

    CAS  PubMed  Google Scholar 

  16. Lacal JC, Campos JM Preclinical characterization of RSM-932A, a novel anticancer drug targeting the human choline kinase alpha, an enzyme involved in increased lipid metabolism of cancer cells. Mol Cancer Therap. doi:10.1158/1535-7163.MCT-14-0531.

  17. Rodriguez-Gonzalez A, Ramirez de Molina A, Fernandez F, Ramos MA, Nunez MC, Campos J, et al. Inhibition of choline kinase as a specific cytotoxic strategy in oncogene-transformed cells. Oncogene. 2003;22:8803–12.

    Article  CAS  PubMed  Google Scholar 

  18. Rodriguez-Gonzalez A, Ramirez de Molina A, Fernandez F, Lacal JC. Choline kinase inhibition induces the increase in ceramides resulting in a highly specific and selective cytotoxic antitumoral strategy as a potential mechanism of action. Oncogene. 2004;23:8247–59.

    Article  CAS  PubMed  Google Scholar 

  19. Ramirez de Molina A, Gallego-Ortega D, Sarmentero-Estrada J, Lagares D, Gomez del Pulgar T, Bandres E, et al. Choline kinase as a link connecting phospholipid metabolism and cell cycle regulation: implications in cancer therapy. Int J Biochem Cell Biol. 2008;40:1753–63.

    Article  CAS  PubMed  Google Scholar 

  20. Glunde K, Raman V, Mori N, Bhujwalla ZM. RNA interference-mediated choline kinase suppression in breast cancer cells induces differentiation and reduces proliferation. Cancer Res. 2005;65:11034–43.

    Article  CAS  PubMed  Google Scholar 

  21. Bañez-Coronel M, Ramirez de Molina A, Rodriguez-Gonzalez A, Sarmentero J, Ramos MA, Garcia-Cabezas MA, et al. Choline kinase alpha depletion selectively kills tumoral cells. Curr Cancer Drug Targets. 2008;8:709–19.

    Article  PubMed  Google Scholar 

  22. Gallego-Ortega D, Ramirez de Molina A, Ramos MA, Valdes-Mora F, Barderas MG, Sarmentero-Estrada J, et al. Differential role of choline kinase alpha and beta isoforms in human carcinogenesis. PLoS One. 2009;4:e7819.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Gruber J, See Too WC, Wong MT, Lavie A, McSorley T, Konrad M. Balance of human choline kinase isoforms is critical for cell cycle regulation. Implications for the development of choline kinase-targeted cancer therapy. FEBS J. 2012;279:1915–28.

    Article  CAS  PubMed  Google Scholar 

  24. Clem BF, Clem AL, Yalcin A, Goswami U, Arumugam S, Telang S, et al. A novel small molecule antagonist of choline kinase-α that simultaneously suppresses MAPK and PI3K/AKT signaling. Oncogene. 2011;30:3370–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Hudson CS, Knegtel RM, Brown K, Charlton PA. Kinetic and mechanistic characterisation of choline kinase-α. Biochim Biophys Acta. 2013;1834:1107–16.

    Article  CAS  PubMed  Google Scholar 

  26. Trousil S, Carroll L, Kalusa A, Aberg O, Kaliszczak M, Aboagye EO. Design of symmetrical and nonsymmetrical N, N-dimethylamino pyridine derivatives as highly potent choline kinase alpha inhibitors. Med Chem Commun. 2013;4:693–6.

    Article  CAS  Google Scholar 

  27. Sánchez Martín R, Campos JM, Conejo-García A, Cruz-López L, Báñez-Coronel M, Rodríguez-González A, et al. Symmetrical bis-quinolinium compounds: new human choline kinase inhibitors with antiproliferative activity against the HT-29 cell line. J Med Chem. 2005;48:3354–63.

    Article  PubMed  Google Scholar 

  28. Milanese L, Espinosa A, Campos JM, Gallo MA, Entrena A. Insight into the inhibition of human choline kinase: homology modeling and molecular dynamics simulations. Chem Med Chem. 2006;1:1216–28.

    Article  CAS  PubMed  Google Scholar 

  29. Sahún-Roncero M, Rubio-Ruiz B, Saladino G, Conejo-García A, Espinosa A, Velázquez Campoy A, et al. The mechanism of allosteric coupling in choline kinase α1 revealed by the action of a rationally designed inhibitor. Angew Chem Int Ed Engl. 2013;52:4582–6.

    Article  PubMed  Google Scholar 

  30. Schiaffino-Ortega S, López-Cara LC, Ríos-Marco P, Carrasco-Jimenez MP, Gallo MA, Espinosa A, et al. New non-symmetrical choline kinase inhibitors. Bioorg Med Chem. 2013;22:7146–54.

    Article  Google Scholar 

  31. Conejo-Garcia A, Bañez-Coronel M, Sanchez-Martin RM, Rodriguez-Gonzalez A, Ramos A, Ramirez de Molina A, et al. Influence of the linker in bispyridium compounds on the inhibition of human choline kinase. J Med Chem. 2004;47:5433–40.

    Article  CAS  PubMed  Google Scholar 

  32. Zimmerman T, Moneriz C, Diez A, Bautista JM, Gómez del Pulgar T, Cebrián A, et al. RSM-932A is a promising synergistic inhibitor of the choline kinase of plasmodium falciparum. Antimicrob Agents Chemother. 2013;57:5878–88.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Guma M, Sanchez-Lopez E, Lodi A, Garcia-Carbonell R, Tiziani S, Karin M, et al. Choline kinase inhibition in rheumatoid arthritis. Ann Rheum Dis. 2014;. doi:10.1136/annrheumdis-2014-205696.

    PubMed  Google Scholar 

  34. Morris GM, Goodsell DS, Hallyday RS, Huey R, Hart WE, Belew RK, et al. Automated docking using a Lamarckian genetic algorithm and a empirical binding free energy function. J Comput Chem. 1998;19:1639–62.

    Article  CAS  Google Scholar 

  35. DeLano W PyMOL, version 0.99. DeLano Scientific LLC, South San Francisco. http://www.pymol.sourceforge.net/.

  36. Alvarenga N, Ferro E. Bioactive triterpenes and related compounds from Celastraceae. Stud Nat Prod Chem. 2005;30:635–702 [bioactive natural products (part K)].

    Article  CAS  Google Scholar 

  37. Gutierrez F, Estevez-Braun A, Ravelo AG, Astudillo L, Zarate R. Terpenoids from the Medicinal Plant Maytenus ilicifolia. J Nat Prod. 2007;70:1049–52.

    Article  CAS  PubMed  Google Scholar 

  38. Ravelo A, Estévez-Braun A, Chávez H, Pérez-Sacau E, Mesa-Siverio D. Recent studies on natural products as anticancer agents. Curr Top Med Chem. 2004;4:241–65.

    Article  CAS  PubMed  Google Scholar 

  39. Chavez H, Rodriguez G, Estevez-Braun A, Ravelo AG, Estevez-Reyes R, Gonzalez AG, et al. Macrocarpins A-D, new cytotoxic nor-triterpenes from Maytenus macrocarpa. Bioorg Med Chem Lett. 2000;10:759–62.

    Article  CAS  PubMed  Google Scholar 

  40. Chavez H, Estevez-Braun A, Ravelo AG, Gonzalez AG. New phenolic and quinone-methide triterpenes from maytenus amazonica. J Nat Prod. 1999;62:434–6.

    Article  CAS  PubMed  Google Scholar 

  41. Chavez H, Valdivia E, Estevez-Braun A, Ravelo AG. Structure of new bioactive triterpenes related to 22β-hydroxytingenone. Tetrahedron. 1998;54:13579–90.

    Article  CAS  Google Scholar 

  42. Mesa-Siverio D, Chavez H, Estevez-Braun A, Ravelo AG, Cheiloclines A-I. First examples of octacyclic sesquiterpene-triterpene hetero-Diels-Alder adducts. Tetrahedron. 2005;61:429–36.

    Article  CAS  Google Scholar 

  43. Oramas-Royo S, Chávez H, Martín-Rodríguez P, Fernández-Pérez L, Ravelo AG, Estévez-Braun A. Cytotoxic Triterpenoids from Maytenus retusa. J Nat Prod. 2010;73:2029–34.

    Article  CAS  PubMed  Google Scholar 

  44. Nakanishi K, Takahashi Y, Budzikiewicz H. Pristimerine. Spectroscopic properties of the dienone-phenol-type rearrangement products and other derivatives. J Org Chem. 1965;30:1729–34.

    Article  CAS  Google Scholar 

  45. Hong BS, Allali-Hassani A, Tempel W, Finerty PJ, MacKenzie F, Dimov S, et al. Crystal structures of human choline kinase isoforms in complex with hemicholinium-3. J Biol Chem. 2010;285:16330–4.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

The authors appreciate the contribution to experimental performance of Dulce Mesa Siverio and Haydee Chávez. This work has been supported by grants to JCL from Ministerio de Ciencia e Innovación (SAF2008-03750, SAF2011-29699, RD06-0020-0016 and RD12/0036/0019) and by grants to AEB and AGR from Ministerio de Ciencia e Innovación (SAF 2012-37344-C03-01 and SAF 2009-13296-C02-01) and Instituto Canario de Investigación del Cáncer (ICIC).

Conflict of interest

JCL is a stockholder of TCD Pharma SL. All the remaining authors declare no competing financial interest.

Author information

Authors and Affiliations

  1. Instituto Universitario de Bio-Orgánica “Antonio González”, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez 2, 38206, La Laguna, Tenerife, Spain

    A. Estévez-Braun, A. G. Ravelo & E. Pérez-Sacau

  2. Instituto Canario de Investigación del Cáncer (ICIC), Las Palmas, Spain

    A. Estévez-Braun, A. G. Ravelo & E. Pérez-Sacau

  3. Centro Atlántico del Medicamento (CEAMED), Parque Científico Tecnológico de Tenerife (PCTT), Avda. de la Trinidad s/n 38204, San Cristóbal de La Laguna, S/C Tenerife, Spain

    E. Pérez-Sacau

  4. Traslational Oncology, IdiPaz, Paseo de la Castellana 261, 28046, Madrid, Spain

    J. C. Lacal

Authors
  1. A. Estévez-Braun
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  2. A. G. Ravelo
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  3. E. Pérez-Sacau
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  4. J. C. Lacal
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Correspondence to J. C. Lacal.

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Estévez-Braun, A., Ravelo, A.G., Pérez-Sacau, E. et al. A new family of choline kinase inhibitors with antiproliferative and antitumor activity derived from natural products. Clin Transl Oncol 17, 74–84 (2015). https://doi.org/10.1007/s12094-014-1260-0

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  • DOI: https://doi.org/10.1007/s12094-014-1260-0

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