Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 May;80(5-6):756–765. doi: 10.1038/sj.bjc.6690419

Boswellic acids and malignant glioma: induction of apoptosis but no modulation of drug sensitivity

T Glaser 1, S Winter 1, P Groscurth 3, H Safayhi 2, E-R Sailer 2, H P T Ammon 2, M Schabet 1, M Weller 1
PMCID: PMC2362292  PMID: 10360653

Abstract

Steroids are essential for the control of oedema in human malignant glioma patients but may interfere with the efficacy of chemotherapy. Boswellic acids are phytotherapeutic anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral oedema. Here, we report that boswellic acids are cytotoxic to malignant glioma cells at low micromolar concentrations. In-situ DNA end labelling and electron microscopy reveal that boswellic acids induce apoptosis. Boswellic acid-induced apoptosis requires protein, but not RNA synthesis, and is neither associated with free radical formation nor blocked by free radical scavengers. The levels of BAX and BCL-2 proteins remain unaltered during boswellic acid-induced apoptosis. p21 expression is induced by boswellic acids via a p53-independent pathway. Ectopic expression of wild-type p53 also induces p21, and facilitates boswellic acid-induced apoptosis. However, targeted disruption of the p21 genes in colon carcinoma cells enhances rather than decreases boswellic acid toxicity. Ectopic expression of neither BCL-2 nor the caspase inhibitor, CRM-A, is protective. In contrast to steroids, subtoxic concentrations of boswellic acids do not interfere with cancer drug toxicity of glioma cells in acute cytotoxicity or clonogenic cell death assays. Also, in contrast to steroids, boswellic acids synergize with the cytotoxic cytokine, CD95 ligand, in inducing glioma cell apoptosis. This effect is probably mediated by inhibition of RNA synthesis and is not associated with changes of CD95 expression at the cell surface. Further studies in laboratory animals and in human patients are required to determine whether boswellic acids may be a useful adjunct to the medical management of human malignant glioma. © 1999 Cancer Research Campaign

Keywords: pentacyclic triterpenes, apoptosis, chemotherapy, brain tumour, glioma cells

Full Text

The Full Text of this article is available as a PDF (993.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ammon H. P. Salai Guggal - Boswellia serrata: from a herbal medicine to a non-redox inhibitor of leukotriene biosynthesis. Eur J Med Res. 1996 May 24;1(8):369–370. [PubMed] [Google Scholar]
  2. Gomez-Manzano C., Fueyo J., Kyritsis A. P., McDonnell T. J., Steck P. A., Levin V. A., Yung W. K. Characterization of p53 and p21 functional interactions in glioma cells en route to apoptosis. J Natl Cancer Inst. 1997 Jul 16;89(14):1036–1044. doi: 10.1093/jnci/89.14.1036. [DOI] [PubMed] [Google Scholar]
  3. Gupta I., Parihar A., Malhotra P., Singh G. B., Lüdtke R., Safayhi H., Ammon H. P. Effects of Boswellia serrata gum resin in patients with ulcerative colitis. Eur J Med Res. 1997 Jan;2(1):37–43. [PubMed] [Google Scholar]
  4. Jung J. M., Bruner J. M., Ruan S., Langford L. A., Kyritsis A. P., Kobayashi T., Levin V. A., Zhang W. Increased levels of p21WAF1/Cip1 in human brain tumors. Oncogene. 1995 Nov 16;11(10):2021–2028. [PubMed] [Google Scholar]
  5. Michalovitz D., Halevy O., Oren M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell. 1990 Aug 24;62(4):671–680. doi: 10.1016/0092-8674(90)90113-s. [DOI] [PubMed] [Google Scholar]
  6. Michieli P., Chedid M., Lin D., Pierce J. H., Mercer W. E., Givol D. Induction of WAF1/CIP1 by a p53-independent pathway. Cancer Res. 1994 Jul 1;54(13):3391–3395. [PubMed] [Google Scholar]
  7. Naumann U., Durka S., Weller M. Dexamethasone-mediated protection from drug cytotoxicity: association with p21WAF1/CIP1 protein accumulation? Oncogene. 1998 Sep 24;17(12):1567–1575. doi: 10.1038/sj.onc.1202071. [DOI] [PubMed] [Google Scholar]
  8. Reber U., Wüllner U., Trepel M., Baumgart J., Seyfried J., Klockgether T., Dichgans J., Weller M. Potentiation of treosulfan toxicity by the glutathione-depleting agent buthionine sulfoximine in human malignant glioma cells: the role of bcl-2. Biochem Pharmacol. 1998 Feb 1;55(3):349–359. doi: 10.1016/s0006-2952(97)00480-2. [DOI] [PubMed] [Google Scholar]
  9. Roth W., Fontana A., Trepel M., Reed J. C., Dichgans J., Weller M. Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother. 1997 Mar;44(1):55–63. doi: 10.1007/s002620050355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Rowe T. C., Chen G. L., Hsiang Y. H., Liu L. F. DNA damage by antitumor acridines mediated by mammalian DNA topoisomerase II. Cancer Res. 1986 Apr;46(4 Pt 2):2021–2026. [PubMed] [Google Scholar]
  11. Ruan S., Okcu M. F., Ren J. P., Chiao P., Andreeff M., Levin V., Zhang W. Overexpressed WAF1/Cip1 renders glioblastoma cells resistant to chemotherapy agents 1,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. Cancer Res. 1998 Apr 1;58(7):1538–1543. [PubMed] [Google Scholar]
  12. Safayhi H., Mack T., Sabieraj J., Anazodo M. I., Subramanian L. R., Ammon H. P. Boswellic acids: novel, specific, nonredox inhibitors of 5-lipoxygenase. J Pharmacol Exp Ther. 1992 Jun;261(3):1143–1146. [PubMed] [Google Scholar]
  13. Safayhi H., Rall B., Sailer E. R., Ammon H. P. Inhibition by boswellic acids of human leukocyte elastase. J Pharmacol Exp Ther. 1997 Apr;281(1):460–463. [PubMed] [Google Scholar]
  14. Safayhi H., Sailer E. R., Ammon H. P. Mechanism of 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid. Mol Pharmacol. 1995 Jun;47(6):1212–1216. [PubMed] [Google Scholar]
  15. Sailer E. R., Subramanian L. R., Rall B., Hoernlein R. F., Ammon H. P., Safayhi H. Acetyl-11-keto-beta-boswellic acid (AKBA): structure requirements for binding and 5-lipoxygenase inhibitory activity. Br J Pharmacol. 1996 Feb;117(4):615–618. doi: 10.1111/j.1476-5381.1996.tb15235.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Schulz J. B., Weller M., Klockgether T. Potassium deprivation-induced apoptosis of cerebellar granule neurons: a sequential requirement for new mRNA and protein synthesis, ICE-like protease activity, and reactive oxygen species. J Neurosci. 1996 Aug 1;16(15):4696–4706. doi: 10.1523/JNEUROSCI.16-15-04696.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Sheikh M. S., Chen Y. Q., Smith M. L., Fornace A. J., Jr Role of p21Waf1/Cip1/Sdi1 in cell death and DNA repair as studied using a tetracycline-inducible system in p53-deficient cells. Oncogene. 1997 Apr 17;14(15):1875–1882. doi: 10.1038/sj.onc.1201004. [DOI] [PubMed] [Google Scholar]
  18. Strasser A., Harris A. W., Huang D. C., Krammer P. H., Cory S. Bcl-2 and Fas/APO-1 regulate distinct pathways to lymphocyte apoptosis. EMBO J. 1995 Dec 15;14(24):6136–6147. doi: 10.1002/j.1460-2075.1995.tb00304.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Trepel M., Groscurth P., Malipiero U., Gulbins E., Dichgans J., Weller M. Chemosensitivity of human malignant glioma: modulation by p53 gene transfer. J Neurooncol. 1998 Aug;39(1):19–32. doi: 10.1023/a:1005910323338. [DOI] [PubMed] [Google Scholar]
  20. Van Meir E. G., Kikuchi T., Tada M., Li H., Diserens A. C., Wojcik B. E., Huang H. J., Friedmann T., de Tribolet N., Cavenee W. K. Analysis of the p53 gene and its expression in human glioblastoma cells. Cancer Res. 1994 Feb 1;54(3):649–652. [PubMed] [Google Scholar]
  21. Wagenknecht B., Gulbins E., Lang F., Dichgans J., Weller M. Lipoxygenase inhibitors block CD95 ligand-mediated apoptosis of human malignant glioma cells. FEBS Lett. 1997 Jun 2;409(1):17–23. doi: 10.1016/s0014-5793(97)00468-7. [DOI] [PubMed] [Google Scholar]
  22. Wagenknecht B., Schulz J. B., Gulbins E., Weller M. Crm-A, bcl-2 and NDGA inhibit CD95L-induced apoptosis of malignant glioma cells at the level of caspase 8 processing. Cell Death Differ. 1998 Oct;5(10):894–900. doi: 10.1038/sj.cdd.4400435. [DOI] [PubMed] [Google Scholar]
  23. Waldman T., Kinzler K. W., Vogelstein B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 1995 Nov 15;55(22):5187–5190. [PubMed] [Google Scholar]
  24. Waldman T., Lengauer C., Kinzler K. W., Vogelstein B. Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21. Nature. 1996 Jun 20;381(6584):713–716. doi: 10.1038/381713a0. [DOI] [PubMed] [Google Scholar]
  25. Weller M., Frei K., Groscurth P., Krammer P. H., Yonekawa Y., Fontana A. Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest. 1994 Sep;94(3):954–964. doi: 10.1172/JCI117462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Weller M., Malipiero U., Aguzzi A., Reed J. C., Fontana A. Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest. 1995 Jun;95(6):2633–2643. doi: 10.1172/JCI117965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Weller M., Malipiero U., Rensing-Ehl A., Barr P. J., Fontana A. Fas/APO-1 gene transfer for human malignant glioma. Cancer Res. 1995 Jul 1;55(13):2936–2944. [PubMed] [Google Scholar]
  28. Weller M., Rieger J., Grimmel C., Van Meir E. G., De Tribolet N., Krajewski S., Reed J. C., von Deimling A., Dichgans J. Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses. Int J Cancer. 1998 Dec 18;79(6):640–644. doi: 10.1002/(sici)1097-0215(19981218)79:6<640::aid-ijc15>3.0.co;2-z. [DOI] [PubMed] [Google Scholar]
  29. Weller M., Schmidt C., Roth W., Dichgans J. Chemotherapy of human malignant glioma: prevention of efficacy by dexamethasone? Neurology. 1997 Jun;48(6):1704–1709. doi: 10.1212/wnl.48.6.1704. [DOI] [PubMed] [Google Scholar]
  30. Weller M., Trepel M., Grimmel C., Schabet M., Bremen D., Krajewski S., Reed J. C. Hypericin-induced apoptosis of human malignant glioma cells is light-dependent, independent of bcl-2 expression, and does not require wild-type p53. Neurol Res. 1997 Oct;19(5):459–470. [PubMed] [Google Scholar]
  31. Weller M., Winter S., Schmidt C., Esser P., Fontana A., Dichgans J., Groscurth P. Topoisomerase-I inhibitors for human malignant glioma: differential modulation of p53, p21, bax and bcl-2 expression and of CD95-mediated apoptosis by camptothecin and beta-lapachone. Int J Cancer. 1997 Nov 27;73(5):707–714. doi: 10.1002/(sici)1097-0215(19971127)73:5<707::aid-ijc16>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  32. Winter S., Roth W., Dichgans J., Weller M. Synergy of CD95 ligand and teniposide: no role of cleavable complex formation and enhanced CD95 expression. Eur J Pharmacol. 1998 Jan 12;341(2-3):323–328. doi: 10.1016/s0014-2999(97)01478-7. [DOI] [PubMed] [Google Scholar]
  33. Winter S., Weller M. Potentiation of CD95L-induced apoptosis of human malignant glioma cells by topotecan involves inhibition of RNA synthesis but not changes in CD95 or CD95L protein expression. J Pharmacol Exp Ther. 1998 Sep;286(3):1374–1382. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES