A review on extraction, synthesis and anticancer activity of betulinic acid

Current Bioactive Compounds

Volumn 5, Issue 2, 2009, Pages 160-168

  Tripathi, Laxmi ^a   Kumar, Praveen ^a   Singh, Ranjit ^b  

^a SD College of Pharmacy & Vocational Studies   (India)

^b SHOBHIT UNIVERSITY   (India)

Author keywords

Angiogenesis; Anticancer activity; Apoptosis; Betulinic acid; Structure activity relationship

Indexed keywords

AMINOPEPTIDASE; ANTINEOPLASTIC AGENT; BETULIC ACID; CASPASE 3; CASPASE 8; DNA DIRECTED DNA POLYMERASE BETA; DNA TOPOISOMERASE; DNA TOPOISOMERASE (ATP HYDROLYSING); FLUOROURACIL; GYRASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IRINOTECAN; MITOGEN ACTIVATED PROTEIN KINASE; OXALIPLATIN; REACTIVE OXYGEN METABOLITE; VINCRISTINE;

ANTIANGIOGENIC ACTIVITY; ANTIMALARIAL ACTIVITY; ANTINEOPLASTIC ACTIVITY; ANTIVIRAL ACTIVITY; APOPTOSIS; BRAIN CANCER; CANCER CELL; CANCER COMBINATION CHEMOTHERAPY; CONGENITAL NEVUS; DRUG ISOLATION; DRUG MECHANISM; DRUG POTENTIATION; DRUG STRUCTURE; DRUG SYNTHESIS; GLIOBLASTOMA; HUMAN; IMMUNOMODULATION; MELANOMA; NONHUMAN; PRIORITY JOURNAL; REVIEW; STRUCTURE ACTIVITY RELATION;

EID: 70449725237     PISSN: 15734072     EISSN: None     Source Type: Journal    
DOI: 10.2174/157340709788452019     Document Type: Review

References (59)

1. Simone, F. (2008) Betulinic acid for cancer treatment and prevention. Int. J. Mol. Sci., 9, 1096-1107. (Pubitemid 351948841)
2. John, M., Darrick, S. (1998) Methods of manufacturing of Betulinic acid, US Patent No. 5804575.
3. Steele, J.C., Warhurst, D.C., Kirby, G.C., Simmonds M.S. (1999) In vitro and In vivo evaluation of betulinic acid as an antimalarial. Phytother. Res., 13(2), 115-119. (Pubitemid 29129443)
4. Tadashi, H., Karen, T.L., Xiaobo, S., Chitra, S., Yukiko, H. (2006) Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A. Bioorg. Med. Chem. Lett., 16(24), 6306-6309.
5. Flekhter, O.B., Boreko, E.I., Nigmatullina, L.R., Pavlova, N.I., Nikolaeva, S.N., Savinova, O.V., Eremin, V.F., Baltina, L.A., Galin, F.Z., Tolstikov, G.A. (2003) Synthesis and antiviral activity of hydrazides and substituted benzalhydrazides of betulinic acid and its derivatives. Bioorg. Khim., 29(3), 326-332.
6. Hashimoto, F., Kashiwada, Y., Cosentino, L.M., Chen, C.H., Garrett, P.E., Lee, K.H. (1997) Anti-AIDS agents-XXVII. Synthesis and anti-HIV activity of betulinic acid and dihydrobetulinic acid derivatives. Bioorg. Med. Chem., 5(12), 2133-2143 (Pubitemid 28012601)
7. Yun, Y., Han, S., Park, E., Yim, D., Lee, S., Lee, C.K., Cho, K., Kim, K. (2003) Immunomodulatory activity of betulinic acid by producing pro-inflammatory cytokines and activation of macrophages. Arch. Pharm. Res., 26(12), 1087-1095.
8. Thurnther, D., Turhani, D., Pelzmann, M.; Wannemacher, B., Knerer, B., Formanek, M., Wacheck, V., Selzer, E. (2003) Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck, 25(9), 730-740. (Pubitemid 37034260)
9. Rzeski, W., Stepulak, A., Szymański, M., Sifringer, M., Kaczor, J., Wejksza, K., Zdzisńska, B., Kandefer, S.M. (2006) Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch. Pharmacol., 374(1), 11-20.
10. Jeremias, I., Steiner, H.H., Benner, A., Debatin, K.M., Mende, C.H. (2004) Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multifo. Acta Neurochir., 146, 721-729. (Pubitemid 38856623)
11. Ehrhardt, H., Fulda, S., Führer, M., Debatin, K.M., Jeremias I. (2004) Betulinic acid-induced apoptosis in leukemia cells. Leukemia, 18(8), 1406-1412. (Pubitemid 39136751)
12. Salti, G.I., Kichina, J.V., Gupta, D., Uddin, T.K., Bratescu, S., Pezzuto, L., Mehta, J.M., Constantinou, A.I. (2001) Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent. Melanoma Res., 11(2), 99-104.
13. Tong, X., Lin, S., Fujii, M., Hou, D. (2004) Molecular mechanisms of echinocystic acid-induced apoptosis in HepG2 cells. Biochem. Biophys. Res. Commun., 321(3), 539-546. (Pubitemid 39118377)
14. Fulda, S., Scaffidi, C., Susin, S.A., Krammer, P.H., Kroemer, G., Peter, M.E., Debatin, K.M. (1998) Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J. Biol. Chem., 273(51), 33942-33948. (Pubitemid 29008858)
15. Wick, W., Grimmel, C., Wagenknecht, B., Dichgans, J., Weller, M. (1999) 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., 289(3), 1306-1312. (Pubitemid 29246659)
16. Fulda, S., Debatin, K.M. (2000) Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumors. Med. Pediatr. Oncol., 35(6), 616-618.
17. Fulda, S., Jeremias, I., Steiner, H.H., Pietsch, T., Debatin, K.M. (1999) Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. Int. J. Cancer, 82(3), 435-441. (Pubitemid 29302986)
18. Kasperczyk, H., Ferla, K., Westhoff, M.A., Behrend, L., Zwacka, R.M., Debatin, K.M., Fulda, S. (2005) Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene, 24(46), 6945-6956. (Pubitemid 41509417)
19. Tan, Y., Yu, R., Pezzuto, J.M. (2003) Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin. Cancer Res., 9(7), 2866-2875. (Pubitemid 36842133)
20. Chintharlapalli, S., Papineni, S., Ramaiah, S.K., Safe, S. (2007) Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res., 67(6), 2816-2823. (Pubitemid 46548971)
21. Wachsberger, P.R., Bard, R., Wahl, M.L., Luper, D.B. (2002) Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia. Int. J. Hyperther., 18(2), 153-164.
22. Fulda, S., Jeremias, I., Debatin, K.M. (2004) Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene, 23(46), 7611-7620. (Pubitemid 39424919)
23. Salti, G.I., Kichina, J.V., DasGupta, T.K., Uddin, S., Bratescu, L., Pezzuto, J.M., Mehta, R.G. (2001) Constantinou AI. Betulinic acid reduces ultraviolet-C-induced DNA breakage in congenital melanocytic naeval cells: evidence for a potential role as a chemopreventive agent. Melanoma Res., 11(2), 99-104. (Pubitemid 32385812)
24. Rajendran, P., Jaggi, M., Manoj, K., Mukherjee, R., Burman, A.C. (2008) Pharmacological evaluation of C-3 modified Betulinic acid derivatives with potent anticancer activity. Invest. New Drugs, 26, 25-34.
25. Chowdary, A.R., Mandal, S., Mittra, B., Sharma, S., Mukhopadhyay, S., Majumder, H.K. (2002) 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., 8(7), BR254-265.
26. Mukherjee, R., Jaggi, M., Rajendran, P., Mohammad, J.A., Siddiqui, S.K., Burman, C. (2004) Betulinic acid and its derivatives as anti-angiogenic agents. Bioorg. Med. Chem. Lett., 14(9), 2181-2184.
27. Kwon, H.J, Shim, J.S., Kim, J.H., Cho, H.Y., Yum, Y.N., Kim, S.H., Yu, J. (2002) Betulinic acid inhibits growth factor-induced in vitro angiogenesis via the modulation of mitochondrial function in endothelial cells. Jpn. J. Cancer Res., 93(4), 417-425.
28. Melzig, M.F., Barman, H. (1998) Betulinic acid inhibits aminopeptidase N activity. Planta Med., 64(7), 655-657.
29. Gao, Z., Maloney, D.J., Dedkova, L.M., Hecht, S.M. (2008) Inhibitors of DNA polymerase beta: activity and mechanism. Bioorg. Med. Chem., 16(8), 4331-4340.
30. Wada, S., Tanaka, R. (2005) Betulinic acid and its derivatives, potent DNA topoisomerase II inhibitors, from the bark of Bischofia javanica. Chem. Biodivers., 2(5), 689-694
31. Fulda, S., Friesen, C., Los, M., Scaffidi, C., Mier, W., Benedict, M., Nuñez, G., Krammer, P.H., Peter, M.E., Debatin, K.M. (1997) Betulinic acid triggers CD95 (APO-1/Fas)- and p53-independent apoptosis via activation of caspases in neuroectodermal tumors. Cancer Res., 57(21), 4956-4964.
32. Sawada, N., Kataoka, K., Kondo, K., Arimochi, H., Fujino, H., Takahashi, Y., Miyoshi, T., Kuvahara, T., Mondan, Y., Ohnishi, Y. (2004) Betulinic acid augments the inhibitory effects of vincristine on growth and lung metastasis of B16F10 melanoma cells in mice. Br. J. Cancer, 90(8), 1672-1678.
33. Fulda, S., Debatin, K.M. (2005) Sensitization for anticancer drug-induced apoptosis by betulinic Acid. Neoplasia, 7(2), 162-170.
34. Jung, G.R., Kim, K.J., Choi, C.H., Lee, T.B., Han, S.I., Han, H.K., Lim, S.C. (2007) Effect of betulinic acid on anticancer drug-resistant colon cancer cells. Basic Clin. Pharmacol. Toxicol., 101(4), 277-285.
35. Selzer, E., Pimentel, E., Wacheck, V., Schlegel, W., Pehamberger, H., Gansen, B., Kody, M.R. (2000) Effects of betulinic acid alone and in combination with irradiation in human melanoma cells. J. Invest. Dermatol., 114, 935-940.
36. Mukherjee, R., Kumar, V., Srivastava, S.K., Agarwal, S.K., Burman, A.C. (2006) Betulinic acid derivatives as anticancer agents: structure activity relationship. Anticancer Agents Med. Chem., 6(3), 271-279. (Pubitemid 43796644)
37. Liby, K., Honda, T., Williams, C.R., Risingsong, R., Royce, D.B., Suh, N., Dinkova-Kostova, A.T., Stephenson, K.K,; Talalay, P., Sundararajan, C., Gribble, G.W., Sporn, M.B. (2007) Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. Mol. Cancer Ther., 6(7), 2113-2119.
38. Jeong, H.J., Chai, H.B., Park, S.Y., Kim, D.S. (1999) Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Biorg. Med. Chem. Lett., 19(8), 1201-1204.
39. Kim, J.Y., Koo, H.M., Kim, D.S. (2001) Development of C-20 modified betulinic acid derivatives as antitumor agents. Bioorg. Med. Chem. Lett., 11, 2405-2408.
40. Braca, A., Autore, G., Simone, F., Marzocco, S., Morelli, I., Venturella, F., Tommansi, N. (2004) Cytotoxic saponins from Schefflera rotundifolia. Planta Med., 70(10), 960.
41. Gu, J.Q., Wang, Y., Franzblau, S.G., Montenegro, G., Yung, D., Timmermann, B.N. (2004) Antitubercular constituents of Valeriana laxiflora. Planta Med., 70(6), 509.
42. Nguyen, Q.C., Nguyen, V.H., Santarsiero, B.D., Mesecar, A.D., Nguyen, M.C., Soejarto, D.D., Pezzuto, J.M., Fong, H., Tan, G.T. (2004) New 3-O-acyl betulinic acids from Strychnos vanprukii craib. J. Nat. Prod., 67(6), 994.
43. Mutai, C., Abatis, D., Vagias, C., Moreau, D., Roussakis, C. Roussis, V. (2004) Cytotoxic lupane-type triterpenoids from Acacia mellifera. Phytochemistry, 65(8), 1159.
44. Duker, E.G., Jaroszewski, J.W., Asomaning, W.A., Oppong, B.F., Brogger, C.S., (2004) Antiplasmodial constituents of Cajanus cajan. Phytother. Res., 18(2), 128-130.
45. Chaturvedula, S., Gao, Z., Sidney H.M., Jones S.H., Kingston, D.I. (2003) A new acylated oleanane triterpenoid from Couepia polyandra that inhibits the lyase activity of DNA polymerase β. J. Nat. Prod., 66(11), 1463-1465. (Pubitemid 37490395)
46. Gao, H., Wu, L., Kuroyangi, M., Harda, K., Kawahara, N., Nakane, T., Unehara, K., Hirasawa, A., Nukanura, Y. (2003) Antitumor-promoting constituents from Chaenomeles sinensis koehne and their activities in JB6 mouse epidermal cells. Chem. Pharm. Bull., (Tokyo), 51(11), 1318.
47. Suksamrarn, A., Tanachatchairantan, T., Kanokmedhakul, S. (2003) Antiplasmodial triterpenes from twigs of Gardenia saxatilis. J. Ethnopharmacol., 88(2-3), 275.
48. Enwerem, N.M., Okogun, J.I., Wambebe, C.O., Okorie, D.A., Akah, P.A. (2001) Anthelmintic activity of the stem bark extracts of and one of its active principles, Betulinic acid. Phytomedicine, 8(2), 112.
49. Takeoka, G., Dao, L., Teraniski, R., Wong, R., Flessa, S., Harden, L., Edward, R. (2000) Identification of three triterpenoids in Almond Hulls. J. Agric. Food Chem., 48(8), 3437. (Pubitemid 30681051)
50. Kim, Y.K., Yoon, S.K., Ryu, S.Y. (2000) Cytotoxic triterpenes from stem bark of Physocarpus intermedius. Planta Med., 66(5), 485.
51. Setzer, W.N., Setzer, M.C., Bates, R.B., Jackes, B.R. (2002) Biologically active triterpenoids of Syncarpia glomulifera bark extract from Paluma, North Qeensland, Australia. Planta Med., 66(2), 176.
52. Ma, J., Starch, S.R., Hecnt, S.M. (1999) DNA Polymerase β Inhibitors from Tetracera boiviniana. J. Nat. Prod., 62(2), 176.
53. Ma, C., Nakamura, N., Miyashiro, H., Hattori, M., Shimotohno, K. (1999) Inhibitory effects of constituents from Cynomorium songaricum and related triterpene derivatives on HIV-1 protease. Chem. Pharm. Bull. (Tokyo), 47(2), 141. (Pubitemid 29114049)
54. Ogura, M., Cordella, G.A., Farnswarth, R. (1997) Potential anticancer agents. IV. Constituents of Jacaranda caucana Pittier (Bignoniaceae). Lloydia, 40(2), 157.
55. Pisha, E., Chai, H., Lee, I.S., Chagwedera, T.E., Farnsworth, N.R., Cordell, G.A., Beecher, C.W., Fong, H.H., Kinghorn, A.D., Brown, D.M., Wani, M.C., Wall, M.E., Hieken T.J., Das Gupta T.K., Pezzuto T.J. (1995) Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nat. Med., 1, 1046-1051.
56. Schmidt, M.L., Kuzmanoff, K.L., Ling, I.L., Pezzuto, J.M. (1997) Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur. J. Cancer, 33(12), 2007-2010. (Pubitemid 28123444)
57. Debatin, K.M., Fulda, S., Wiessler, M., Los, M., Mier, W. (2002) Betulinic acid and derivatives thereof useful for the treatment of neuroectodermal tumor. US Patent 20026369109.
58. Zuco, V., Supino, R., Righetti, S.C., Cleris, L., Marchesi, E., Gambacorti-Passerini, C., Formelli, F. (2002) Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett., 175, 17-25. (Pubitemid 33153040)
59. Ehrhardt, H., Fulda, S., Fuhrer, M., Debatin, K.M., Jeremias, I. (2004) Betulinic acid-induced apoptosis in leukemia cells. Leukemia, 18, 1406-1412. (Pubitemid 39136751)