Betulinic acid: A natural product with anticancer activity

Molecular Nutrition and Food Research

Volumn 53, Issue 1, 2009, Pages 140-146

  Fulda, Simone ^a  

^a UNIVERSITY HOSPITAL ULM   (Germany)

Author keywords

Apoptosis; Betulinic acid; Cancer; Mitochondria

Indexed keywords

ANTINEOPLASTIC AGENT; BETULIC ACID; BIOLOGICAL PRODUCT; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; TRITERPENE;

APOPTOSIS; AUTOPHAGY; CELL DEATH; DRUG EFFECT; DRUG RESISTANCE; HUMAN; ISOLATION AND PURIFICATION; MITOCHONDRIAL MEMBRANE; PERMEABILITY; PHYSIOLOGY; REVIEW;

ANTINEOPLASTIC AGENTS, PHYTOGENIC; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; APOPTOSIS; AUTOPHAGY; BIOLOGICAL PRODUCTS; CELL DEATH; DRUG RESISTANCE, NEOPLASM; HUMANS; MITOCHONDRIAL MEMBRANES; NF-KAPPA B; PERMEABILITY; TRITERPENES;

EID: 58149357667     PISSN: 16134125     EISSN: 16134133     Source Type: Journal    
DOI: 10.1002/mnfr.200700491     Document Type: Review

References (50)

1. Newman, D. J., Cragg, G. M., Snader, K. M., Natural products as sources of new drugs over the period 1981-2002, J. Nat. Prod. 2003, 66, 1022-1037,
2. Alakurtti, S., Makela, T., Koskimies, S., Yli-Kauhaluoma, J., Pharmacological properties of the ubiquitous natural product betulin, Eur. J. Pharm. Sci. 2006, 29, 1 -13.
3. Evan, G. I., Vousden, K. H., Proliferation, cell cycle and apoptosis in cancer, Nature 2001, 411, 342-348.
4. Johnstone, R. W., Ruefli, A. A., Lowe, S. W., Apoptosis: A link between cancer genetics and chemotherapy, Cell 2002, 108, 153-164.
5. Fulda, S., Debatin, K.-M., Targeting apoptosis pathways in cancer therapy, Curr. Cancer Drug Targets 2004, 4, 569 - 576.
6. Degterev, A., Boyce, M., Yuan, J., A decade of caspases, Oncogene 2003, 22, 8543-8567.
7. Walczak, H., Krammer, P. H., The CD95 (APO-1/Fas) and the TRAIL (APO-2L) apoptosis systems, Exp. Cell Res. 2000, 256, 58-66.
8. Saelens, X., Festjens, N., Vande Walle, L., van Gurp, M., et al., Toxic proteins released from mitochondria in cell death, Oncogene 2004, 23, 2861 -2874.
9. Pisha, E., Chai, H., Lee, I. S., Chagwedera, T. E. et al., Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis, Nat. Med. 1995, 1, 1046-1051.
10. Schmidt, M. L., Kuzmanoff, K. L., Ling-Indeck, L., Pezzuto, J. M., Betulinic acid induces apoptosis in human neuroblastoma cell lines, Eur. J. Cancer 1997, 33, 2007-2010.
11. Thurnher, D., Turhani, D., Pelzmann, M., Wannemacher, B., et al., Betulinic acid: A new cytotoxic compound against malignant head and neck cancer cells, Head Neck 2003, 25, 732-740.
12. Wick, W., Grimmel, C., Wagenknecht, B., Dichgans, J., Weller, M., Betulinic acid-induced apoptosis in glioma cells: A sequential requirement for new protein synthesis, formation of reactive oxygen species, and caspase processing, J. Pharmacol. Exp. Ther 1999, 289, 1306-1312.
13. Zuco, V., Supino, R., Righetti, S. C., Cleris, L., et al., Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells, Cancer Lett. 2002, 175, 17-25.
14. Sarek, J., Klinot, J., Dzubak, P., Klinotova, E., et al., New lupane derived compounds with proapoptotic activity in cancer cells: Synthesis and structure-activity relationships, J. Med. Chem. 2003, 46, 5402-5415.
15. Kim, J. Y., Koo, H. M., Kim, D. S., Development of C-20 modified betulinic acid derivatives as antitumor agents, Bio-org. Med. Chem. Lett. 2001, 11, 2405-2408.
16. You, Y.-J., Kim, Y., Nam, N.-H., Ahn, B.-Z., Synthesis and cytotoxic activity of A-ring modified betulinic acid derivatives, Bioorg. Med. Chem. Lett. 2003, A3, 3137-3140.
17. Ehrhardt, H., Fulda, S., Fuhrer, M., Debatin, K. M., Jeremias, I., Betulinic acid-induced apoptosis in leukemia cells, Leukemia 2004, 18, 1406-1412.
18. Fulda, S., Friesen, C., Los, M., Scaffidi, C., et al., Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors, Cancer Res. 1997, 57, 4956-4964.
19. Fulda, S., Jeremias, I., Pietsch, T., Debatin, K. M., Betulinic acid: A new chemotherapeutic agent in the treatment of neuroectodermal tumors, Klin. Padiatr. 1999, 211, 319-322.
20. Fulda, S., Jeremias, I., Steiner, H. H., Pietsch, T., Debatin, K. M., Betulinic acid: A new cytotoxic agent against malignant brain-tumor cells, Int. J. Cancer 1999, 82, 435-441.
21. Rieber, M., Strasberg Rieber, M., Induction of p53 without increase in p21 WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma, DNA Cell Biol. 1998, 77, 399-406.
22. Selzer, E., Pimentel, E., Wacheck, V., Schlegel, W., et al., Effects of betulinic acid alone and in combination with irradiation in human melanoma cells, J. Invest. Dermatol. 2000, 114, 935-940.
23. Fulda, S., Debatin, K.-M., Sensitization for anticancer drug-induced apoptosis by betulinic acid, Neoplasia 2005, 7, 162 - 170.
24. Sawada, N., Kataoka, K., Kondo, K., Arimochi, H., et al., Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice, Br. J. Cancer 2004, 90, 1672-1678.
25. Fulda, S., Jeremias, I., Debatin, K.-M., Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells, Oncogene 2004, 23, 7611 -7620.
26. Shin, Y. G., Cho, K. H., Chung, S. M., Graham, J., et al., Determination of betulinic acid in mouse blood, tumor and tissue homogenates by liquid chromatography-electrospray mass spectrometry, J. Chromatogr. B Biomed. Sci. Appl. 1999, 732, 331-336.
27. Udeani, G. O., Zhao, G. M., Geun Shin, Y., Cooke, B. P., et al., Pharmacokinetics and tissue distribution of betulinic acid in CD-I mice, Biopharm. Drug Dispos. 1999, 20, 379-383.
28. Green, D. R., Kroemer, G., The pathophysiology of mitochondrial cell death, Science 2004, 305, 626-629.
29. Galluzzi, L., Larochette, N., Zamzami, N., Kroemer, G., Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 2006, 25, 4812-4830.
30. Fulda, S., Scaffidi, C., Susin, S. A., Krammer, P. H., et al., Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid, J. Biol. Chem. 1998, 273, 33942-33948.
31. Tan, Y., Yu, R., Pezzuto, J. M., Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation, Clin. Cancer Res. 2003, 9, 2866-2875.
32. Adams, J. M., Cory, S., The Bcl-2 apoptotic switch in cancer development and therapy, Oncogene 2007, 26, 1324-1337.
33. Letai, A., Bassik, M. C., Walensky, L. D., Sorcinelli, M. D., et al., Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics, Cancer Cell 2002, 2, 183-192.
34. Chen, L., Willis, S. N., Wei, A., Smith, B. J., et al., Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function, Mol. Cell 2005, 77, 393-403.
35. Willis, S. N., Fletcher, J. I., Kaufmann, T., van Delft, M. F., et al, Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak, Science 2007, 315, 856-859.
36. Willis, S. N., Chen, L., Dewson, G., Wei, A., et al., Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins, Genes Dev. 2005, 19, 1294-1305.
37. Selzer, E., Thallinger, C., Hoeller, C., Oberkleiner, P., et al., Betulinic acid-induced Mcl-1 expression in human melanoma - Mode of action and functional significance, Mol. Med. 2002, 5, 877-884.
38. Fulda, S., Debatin, K. M., Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors, Med. Pediatr. Oncol. 2000, 35, 616-618.
39. Meng, R. D., El-Deiry, W. S., p53-independent up-regulation of KILLER/DR5 TRAIL receptor expression by glucocorticoids and interferon-gamma, Exp. Cell Res. 2001, 262, 154-169.
40. Salti, G. I., Kichina, J. V., Das Gupta, T. K., Uddin, S., et al., Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: Evidence for a potential role as a chemopreventive agent, Melanoma Res. 2001, 11, 99-104.
41. Takada, Y., Aggarwal, B. B., Betulinic acid suppresses carcinogen-induced NF-kappa B activation through inhibition of I kappa B alpha kinase and p65 phosphorylation: Abrogation of cyclooxygenase-2 and matrix metalloprotease-9, J. Immunol 2003, 777, 3278-3286.
42. Kwon, H. J., Shim, J. S., Kim, J. H., Cho, H. Y., et al., Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells, Jpn. J. Cancer Res. 2002, 93, 417-425.
43. Melzig, M. F., Bormann, H., Betulinic acid inhibits aminopeptidase N activity, Planta Med. 1998, 64, 655-657.
44. Sjostrom, H., Noren, O., Olsen, J., Structure and function of aminopeptidase N, Adv. Exp. Med. Biol. 2000, 477, 25-34.
45. Chowdhury, A. R., Mandal, S., Mittra, B., Sharma, S., et al., Betulinic acid, a potent inhibitor of eukaryotic topoisomerase I: Identification of the inhibitory step, the major functional group responsible and development of more potent derivatives, Med. Sci. Monit. 2002, 8, BR254-BR265.
46. Cichewicz, R. H., Kouzi, S. A., Chemistry, biological activity, and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection, Med. Res. Rev. 2004, 24, 90-114.
47. De Clercq, E., Current lead natural products for the chemotherapy of human immunodeficiency virus (HIV) infection, Med. Res. Rev. 2000, 20, 323-349.
48. Kanamoto, T., Kashiwada, Y., Kanbara, K., Gotoh, K., et al., Anti-human immunodeficiency virus activity of YK-FH312 (a betulinic acid derivative), a novel compound blocking viral maturation, Antimicrob. Agents Chemother. 2001, 45, 1225-1230.
49. Aiken, C., Chen, C., H., Betulinic acid derivatives as HIV-1 antivirals, Trends Mol. Med. 2005, 11, 31 -36.
50. Bringmann, G., Saeb, W., Assi, L. A., Francois, G., et al., Betulinic acid: Isolation from Triphyophyllum peltatum and Ancistrocladus heyneanus, antimalarial activity, and crystal structure of the benzyl ester, Planta Med. 1997, 63, 255-257.