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Boldine: a potential new antiproliferative drug against glioma cell lines

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Summary

Malignant gliomas are the most common and devastating primary tumors of the central nervous system. Currently no efficient treatment is available. This study evaluated the effect and underlying mechanisms of boldine, an aporphine alkaloid of Peumus boldus, on glioma proliferation and cell death. Boldine decreased the cell number of U138-MG, U87-MG and C6 glioma lines at concentrations of 80, 250 and 500 μM. We observed that cell death caused by boldine was cell-type specific and dose-dependent. Exposure to boldine for 24 h did not activate key mediators of apoptosis. However, it induced alterations in the cell cycle suggesting a G2/M arrest in U138-MG cells. Boldine had no toxic effect on non-tumor cells when used at the same concentrations as those used on tumor cells. Based on these results, we speculate that boldine may be a promising compound for evaluation as an anti-cancer agent.

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References

  1. Aygeropoulos NG, Batchelor TT (1999) New treatment strategies for malignant gliomas. Oncologist 4:209–224

    Google Scholar 

  2. Davis FG, McCarthy BJ, Freels S (1999) The conditional probability of survival of patients with primary malignant brain tumors: surveillance, epidemiology, and end results (SEER) data. Cancer 85:85–491, doi:10.1002/(SICI)1097-0142(19990101)85:1<85::AID-CNCR12>3.0.CO;2-A

    Article  Google Scholar 

  3. Maher EA, Furnari FB, Bachoo RM et al (2001) Malignant glioma: genetics and biology of a grave matter. Genes Dev 15:1311–1333, doi:10.1101/gad.891601

    Article  CAS  PubMed  Google Scholar 

  4. Weller M, Fontana A (1995) The failure of current immunotherapy for malignant glioma. Tumor-derived TGF-beta, T-cell apoptosis, and the immune privilege of the brain. Brain Res Brain Res Rev 21:128–151, doi:10.1016/0165-0173(95)00010-0

    Article  CAS  PubMed  Google Scholar 

  5. Trog D, Fountoulakis M, Friedlein A et al (2006) Is current therapy of malignant gliomas beneficial for patients? Proteomics evidence of shifts in glioma cells expression patterns under clinically relevant treatment conditions. Proteomics 6:2924–2930, doi:10.1002/pmic.200500587

    Article  CAS  PubMed  Google Scholar 

  6. Phillipson JD (2001) Phytochemistry and medicinal plants. Phytochemistry 56:237–243, doi:10.1016/S0031-9422(00)00456-8

    Article  CAS  PubMed  Google Scholar 

  7. Newman DJ, Cragg GM, Snader KM (2003) Natural products as sources of new drugs over the period 1981–2002. J Nat Prod 66:1022–1037, doi:10.1021/np030096l

    Article  CAS  PubMed  Google Scholar 

  8. Stévigny C, Bailly C, Quetin-Leclercq J (2005) Cytotoxic and antitumour potentialities of aporphinoid alkaloids. Curr Med Chem Anti-Canc Agents 5:173–182

    Article  Google Scholar 

  9. Hidalgo ME, Farah M, Carrasco L et al (2005) Photostability and photoprotection factor of boldine and glaucine. J Photochem Photobiol B 80:65–69, doi:10.1016/j.jphotobiol.2005.01.005

    Article  CAS  PubMed  Google Scholar 

  10. Speisky H, Cassels BK, Lissi E et al (1991) Antioxidant properties of the alkaloid boldine in systems undergoing lipid peroxidation and enzyme inactivation. Biochem Pharmacol 41:1575–1581, doi:10.1016/0006-2952(91)90156-Y

    Article  CAS  PubMed  Google Scholar 

  11. Martínez J, Ríos L, Payá M et al (1992) Inhibition of non-enzymic lipid peroxidation by benzylisoquinoline alkaloids. Free Radic Biol Med 12:287–292, doi:10.1016/0891-5849(92)90116-X

    Article  PubMed  Google Scholar 

  12. Cederbaum A, Kikielka E, Speisky H (1992) Inhibition of rat liver microsomal lipid peroxidation by boldine. Biochem Pharmacol 44:1765–1772, doi:10.1016/0006-2952(92)90070-Y

    Article  CAS  PubMed  Google Scholar 

  13. Lanhers MC, Joyeux M, Soulimani R et al (1991) Hepatoprotective and anti-inflammatory effects of a traditional medicinal plant of Chile, Peumus boldus. Planta Med 57:110–115, doi:10.1055/s-2006-960043

    Article  CAS  PubMed  Google Scholar 

  14. Hoet S, Stévigny C, Block S et al (2004) Alkaloids from Cassytha filiformis and related aporphines: antitrypanosomal activity, cytotoxicity, and interaction with DNA and topoisomerases. Planta Med 70:407–413, doi:10.1055/s-2004-818967

    Article  CAS  PubMed  Google Scholar 

  15. Skehan P, Storeng R, Scudiero D et al (1990) New colorimetric cytotoxicity assay for anti-cancer-drug screening. J Natl Cancer Inst 82:1107–1112, doi:10.1093/jnci/82.13.1107

    Article  CAS  PubMed  Google Scholar 

  16. Bernardi A, Jacques-Silva MC, Delgado-Cañedo A et al (2006) Nonsteroidal anti-inflamatory drugs inhibit the growth of C6 and U138-MG glioma cell lines. Eur J Pharmacol 532:214–222, doi:10.1016/j.ejphar.2006.01.008

    Article  CAS  PubMed  Google Scholar 

  17. Overton WR, McCoy JP Jr (1994) Reversing the effect of formalin on the binding of propidium iodide to DNA. Cytometry 16:351–356, doi:10.1002/cyto.990160410

    Article  CAS  PubMed  Google Scholar 

  18. Stoppini L, Buchs PA, Muller D (1991) A simple method for organotypic cultures of nervous tissue. J Neurosci Methods 37:173–182, doi:10.1016/0165-0270(91)90128-M

    Article  CAS  PubMed  Google Scholar 

  19. Valentim LM, Rodnight R, Geyer AB (2003) Changes in heat shock protein 27 phosphorylation and immunocontent in response to preconditioning to oxygen and glucose deprivation in organotypic hippocampal cultures. Neuroscience 118:379–386, doi:10.1016/S0306-4522(02)00919-3

    Article  CAS  PubMed  Google Scholar 

  20. Horn AP, Gerhardt D, Geyer AB (2005) Cellular death in hippocampus in response to PI3-K pathway inhibition and oxygen and glucose deprivation. Neurochem Res 30:355–361, doi:10.1007/s11064-005-2609-0

    Article  CAS  PubMed  Google Scholar 

  21. Tsuiki H, Nitta M, Tada M (2001) Mechanism of hyperploid cell formation induced by microtubule inhibiting drug in glioma cell lines. Oncogene 20:420–429, doi:10.1038/sj.onc.1204126

    Article  CAS  PubMed  Google Scholar 

  22. Hartmann A, Speit G (1997) The contribution of cytotoxicity to DNA-effects in the single cell gel test (comet assay). Toxicol Lett 90:183–188, doi:10.1016/S0378-4274(96)03847-7

    Article  CAS  PubMed  Google Scholar 

  23. Collins AR (2004) The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol 26:249–261, doi:10.1385/MB:26:3:249

    Article  CAS  PubMed  Google Scholar 

  24. Zhang W, Fei Z, Zhen H et al (2007) Resveratrol inhibits cell growth and induces apoptosis of rat C6 glioma cells. J Neurooncol 81:231–240, doi:10.1007/s11060-006-9226-x

    Article  CAS  PubMed  Google Scholar 

  25. Liu X, Wang J, Sun B et al (2007) Cell growth inhibition, G2M cell cycle arrest, and apoptosis induced by the novel compound Alternol in human gastric carcinoma cell line MGC803. Invest New Drugs 25:505–517, doi:10.1007/s10637-007-9057-4

    Article  PubMed  Google Scholar 

  26. Van den Bent MJ, Hegi ME, Stupp R (2006) Recent developments in the use of chemotherapy in brain tumours. Eur J Cancer 42:582–588, doi:10.1016/j.ejca.2005.06.031

    Article  PubMed  Google Scholar 

  27. Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619–642, doi:10.1146/annurev.physiol.60.1.619

    Article  CAS  PubMed  Google Scholar 

  28. Morgan DO (1995) Principles of cdk regulation. Nature 374:131–134, doi:10.1038/374131a0

    Article  CAS  PubMed  Google Scholar 

  29. Dirks PB, Rutka JT (1997) Current concepts in neuro-oncology: the cell cycle—a review. Neurosurgery 40:1000–1013, doi:10.1097/00006123-199705000-00025

    Article  CAS  PubMed  Google Scholar 

  30. Fiers W, Beyaert R, Declercq W et al (1999) More than one way to die: apoptosis, necrosis and reactive oxygen damage. Oncogene 18:7719–7730, doi:10.1038/sj.onc.1203249

    Article  CAS  PubMed  Google Scholar 

  31. Borner C, Monney L (1999) Apoptosis without caspases: an inefficient molecular guillotine? Cell Death Differ 6:497–507, doi:10.1038/sj.cdd.4400525

    Article  CAS  PubMed  Google Scholar 

  32. Mochizuki T, Asai A, Saito N et al (2002) Akt protein kinase inhibits non-apoptotic programmed cell death induced by ceramide. J Biol Chem 277:2790–2797, doi:10.1074/jbc.M106361200

    Article  CAS  PubMed  Google Scholar 

  33. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407:770–776, doi:10.1038/35037710

    Article  CAS  PubMed  Google Scholar 

  34. Chandna S (2004) Single-cell gel electrophoresis assay monitors precise kinetics of DNA fragmentation induced during programmed cell death. Cytometry A 61:127–133, doi:10.1002/cyto.a.20071

    Article  PubMed  Google Scholar 

  35. Trog D, Moenkemann H, Breipohl W et al (2007) Non-sufficient cell cycle control as possible clue for the resistance of human malignant glioma cells to clinically relevant treatment conditions. Amino Acids 32:373–379, doi:10.1007/s00726-006-0456-1

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). The authors thank Alessandra Heizelmann for the excellent technical assistance.

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Authors and Affiliations

  1. Programa de Pós graduação em Ciências Biológicas: Bioquímica, Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos 2600, 90035.003, Porto Alegre, RS, Brazil

    Daniéli Gerhardt, Ana Paula Horn, Mariana Maier Gaelzer, Rudimar Luiz Frozza & Christianne Salbego

  2. Laboratório de Cardiologia Molecular e Celular, IC/FUC-RS, Avenida Princesa Isabel 370-3° andar, 90620.000, Porto Alegre, RS, Brazil

    Andrés Delgado-Cañedo

  3. Departamento de Biofísica, Instituto de Biociências, UFRGS, Avenida Bento Gonçalves 9500, 91501.970, Porto Alegre, RS, Brazil

    Alessandra Luiza Pelegrini & Guido Lenz

  4. Departamento de Produção de Matéria Prima, Faculdade de Farmácia, UFRGS, Avenida Ipiranga 2752, 90610.000, Porto Alegre, RS, Brazil

    Amélia T. Henriques

Authors
  1. Daniéli Gerhardt
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  2. Ana Paula Horn
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  9. Christianne Salbego
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Correspondence to Christianne Salbego.

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Gerhardt, D., Horn, A.P., Gaelzer, M.M. et al. Boldine: a potential new antiproliferative drug against glioma cell lines. Invest New Drugs 27, 517–525 (2009). https://doi.org/10.1007/s10637-008-9203-7

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