Betulinic acid, a natural compound with potent anticancer effects

Anti-Cancer Drugs

Volumn 21, Issue 3, 2010, Pages 215-227

  Mullauer, Franziska B ^a   Kessler, Jan H ^a,b   Medema, Jan Paul ^a  

^a ACADEMIC MEDICAL CENTER   (Netherlands)

^b LEIDEN UNIVERSITY MEDICAL CENTER   (Netherlands)

Author keywords

Apoptosis; Betulinic acid; Cancer; Chemotherapy; Triterpenoids

Indexed keywords

1,4 DIAMINO 1,4 BIS(2 AMINOPHENYLTHIO) 2,3 DICYANOBUTADIENE; 4 (3 BROMOANILINO) 6,7 DIMETHOXYQUINAZOLINE; ACETYL COENZYME A ACYLTRANSFERASE; BENZYLOXYCARBONYLLEUCYLLEUCYLLEUCINAL; BETULIC ACID; BETULIN; BEVIRIMAT; BORTEZOMIB; CAMPTOTHECIN; CYCLOHEXIMIDE; CYTOCHROME C; DIACYLGLYCEROL ACYLTRANSFERASE; ETOPOSIDE; FLUOROURACIL; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INONOTUS OBLIQUUS EXTRACT; IRINOTECAN; MICROSOMAL AMINOPEPTIDASE; MITOGEN ACTIVATED PROTEIN KINASE P38; OXALIPLATIN; PROTEASOME; PROTEIN BAK; PROTEIN BAX; PROTEIN P53; REACTIVE OXYGEN METABOLITE; TRITERPENOID; VINCRISTINE;

ANTIBACTERIAL ACTIVITY; ANTINEOPLASTIC ACTIVITY; CANCER CELL; CARCINOGENESIS; CELL CYCLE; CELL CYCLE REGULATION; CELL DEATH; CLINICAL TRIAL; DOWN REGULATION; HUMAN; IN VITRO STUDY; MELANOMA; METASTASIS INHIBITION; MITOCHONDRION; MULTIPLE MYELOMA; NEUROBLASTOMA CELL; NONHUMAN; OVARY CARCINOMA; PLASMODIUM BERGHEI; PRIORITY JOURNAL; PROTEIN SECRETION; REVIEW; RODENT; TUMOR CELL; TUMOR PROMOTION; UPREGULATION;

ANIMALS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; APOPTOSIS; BIOLOGICAL PRODUCTS; DNA TOPOISOMERASES; HUMANS; MICE; MITOCHONDRIA; MITOGEN-ACTIVATED PROTEIN KINASES; NF-KAPPA B; PROTO-ONCOGENE PROTEINS C-BCL-2; TRITERPENES;

EID: 76649106073     PISSN: 09594973     EISSN: None     Source Type: Journal    
DOI: 10.1097/CAD.0b013e3283357c62     Document Type: Review

References (126)

1. Risinger AL, Giles FJ, Mooberry SL. Microtubule dynamics as a target in oncology. Cancer Treat Rev 2009; 35:255-261.
2. Johnson IS, Armstrong JG, Gorman M, Burnett JP Jr. The vinca alkaloids: a new class of oncolytic agents. Cancer Res 1963; 23:1390-1427.
3. Bensch KG, Malawista SE. Microtubule crystals: a new biophysical phenomenon induced by Vinca alkaloids. Nature 1968; 218:1176-1177.
4. Bensch KG, Malawista SE. Microtubular crystals in mammalian cells. J Cell Biol 1969; 40:95-107.
5. Pasquier E, Kavallaris M. Microtubules: a dynamic target in cancer therapy. IUBMB Life 2008; 60:165-170.
6. Chabner BA, Roberts TG Jr. Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 2005; 5:65-72.
7. Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by taxol. Nature 1979; 277:665-667.
8. McChesney JD, Venkataraman SK, Henri JT. Plant natural products: back to the future or into extinction? Phytochemistry 2007; 68:2015-2022.
9. Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer 2006; 6:789-802.
10. Hortobagyi GN. Anthracyclines in the treatment of cancer. An overview. Drugs 1997; 54 (Suppl 4):1-7.
11. Gershenzon J, Dudareva N. The function of terpene natural products in the natural world. Nat Chem Biol 2007; 3:408-414.
12. Setzer WN, Setzer MC. Plant-derived triterpenoids as potential antineoplastic agents. Mini Rev Med Chem 2003; 3:540-556.
13. Connolly JD, Hill RA. Triterpenoids. Nat Prod Rep 2008; 25:794-830.
14. Fukuda Y, Sakai K, Matsunaga S, Tokuda H, Tanaka R. Cancer chemopreventive effect of orally administrated lupane-type triterpenoid on ultraviolet light B induced photocarcinogenesis of hairless mouse. Cancer Lett 2006; 240:94-101.
15. Willmann M, Wacheck V, Buckley J, Nagy K, Thalhammer J, Paschke R, et al. Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound. Eur J Clin Invest 2009; 39: 384-394.
16. Saleem M, Afaq F, Adhami VM, Mukhtar H. Lupeol modulates NF-kappaB and PI3K/Akt pathways and inhibits skin cancer in CD-1 mice. Oncogene 2004; 23:5203-5214.
17. Chaturvedi PK, Bhui K, Shukla Y. Lupeol: connotations for chemoprevention. Cancer Lett 2008; 263:1-13.
18. Liby KT, Yore MM, Sporn MB. Triterpenoids and rexinoids as multifunctional agents for the prevention and treatment of cancer. Nat Rev Cancer 2007; 7:357-369.
19. Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. Ursolic acid inhibits nuclear factor-kappaB activation induced by carcinogenic agents through suppression of IkappaBalpha kinase and p65 phosphorylation: correlation with down-regulation of cyclooxygenase 2, matrix metalloproteinase 9, and cyclin D1. Cancer Res 2003; 63:4375-4383.
20. Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res 2007; 5:943-955.
21. Chen JC, Chiu MH, Nie RL, Cordell GA, Qiu SX. Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep 2005; 22:386-399.
22. Chen C, Qiang S, Lou L, Zhao W. Cucurbitane-type triterpenoids from the stems of cucumis melo. J Nat Prod 2009; 72:824-829.
23. Yin D,Wakimoto N, Xing H, Lu D, Huynh T,Wang X, et al. Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme. Int J Cancer 2008; 123:1364-1375.
24. Wakimoto N, Yin D, O'Kelly J, Haritunians T, Karlan B, Said J, et al. Cucurbitacin B has a potent antiproliferative effect on breast cancer cells in vitro and in vivo. Cancer Sci 2008; 99:1793-1797.
25. Haritunians T, Gueller S, Zhang L, Badr R, Yin D, Xing H, et al. Cucurbitacin B induces differentiation, cell cycle arrest, and actin cytoskeletal alterations in myeloid leukemia cells. Leuk Res 2008; 32:1366-1373.
26. Thoennissen NH, Iwanski GB, Doan NB, Okamoto R, Lin P, Abbassi S, et al. Cucurbitacin B induces apoptosis by inhibition of the JAK/STAT pathway and potentiates antiproliferative effects of gemcitabine on pancreatic cancer cells. Cancer Res 2009; 69:5876-5884.
27. Liu T, Zhang M, Zhang H, Sun C, Deng Y. Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 2008; 265:1225-1232.
28. Pisha E, Chai H, Lee IS, Chagwedera TE, Farnsworth NR, Cordell GA, 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.
29. Chen QH, Fu ML, Liu J, Zhang HF, He GQ, Ruan H. Optimization of ultrasonic-assisted extraction (UAE) of betulin from white birch bark using response surface methodology. Ultrason Sonochem 2008; 16:599-604.
30. Eiznhamer DA, Xu ZQ. Betulinic acid: a promising anticancer candidate. IDrugs 2004; 7:359-373.
31. Miles DH, Kokpol U, Zalkow LH, Steindel SJ, Nabors JB. Tumor inhibitors. I. Preliminary investigation of antitumor activity of sarracenia flava. J Pharm Sci 1974; 63:613-615.
32. Kingston DG, Munjal RC. Plant anticancer agents. VIII. Constituents of Inga punctata. Lloydia 1978; 41:499-500.
33. Trumbull ER, Bianchi E, Eckert DJ,Wiedhopf RM, Cole JR. Tumor inhibitory agents from Vauquelinia corymbosa (Rosaceae). J Pharm Sci 1976; 65:1407-1408.
34. Cichewicz RH, Kouzi SA. 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.
35. Yogeeswari P, Sriram D. Betulinic acid and its derivatives: a review on their biological properties. Curr Med Chem 2005; 12:657-666.
36. 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.
37. Rzymowska J. The effect of aqueous extracts from Inonotus obliquus on the mitotic index and enzyme activities. Boll Chim Farm 1998; 137:13-15.
38. Fujioka T, Kashiwada Y, Kilkuskie RE, Cosentino LM, Ballas LM, Jiang JB, et al. Anti-AIDS agents, 11. Betulinic acid and platanic acid as anti-HIV principles from Syzigium claviflorum, and the anti-HIV activity of structurally related triterpenoids. J Nat Prod 1994; 57:243-247.
39. Mayaux JF, Bousseau A, Pauwels R, Huet T, Henin Y, Dereu N, et al. Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells. Proc Natl Acad Sci U S A 1994; 91:3564-3568.
40. Li F, Goila-Gaur R, Salzwedel K, Kilgore NR, Reddick M, Matallana C, et al. PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc Natl Acad Sci U S A 2003; 100:13555-13560.
41. Smith PF, Ogundele A, Forrest A, Wilton J, Salzwedel K, Doto J, et al. Phase I and II study of the safety, virologic effect, and pharmacokinetics/ pharmacodynamics of single-dose 3-O-(30,30-dimethylsuccinyl)betulinic acid (bevirimat) against human immunodeficiency virus infection. Antimicrob Agents Chemother 2007; 51:3574-3581.
42. Adamson CS,Waki K, Ablan SD, Salzwedel K, Freed EO. Impact of human immunodeficiency virus type 1 resistance to protease inhibitors on evolution of resistance to the maturation inhibitor bevirimat (PA-457). J Virol 2009; 83:4884-4894.
43. Zhou J, Chen CH, Aiken C. Human immunodeficiency virus type 1 resistance to the small molecule maturation inhibitor 3-O-(30,30- dimethylsuccinyl)- betulinic acid is conferred by a variety of single amino acid substitutions at the CA-SP1 cleavage site in Gag. J Virol 2006; 80:12095-12101.
44. Dang Z, Lai W, Qian K, Ho P, Lee KH, Chen CH, et al. Betulinic acid derivatives as human immunodeficiency virus type 2 (HIV-2) inhibitors (parallel). J Med Chem 2009; 52:7887-7891.
45. Fontanay S, Grare M, Mayer J, Finance C, Duval RE. Ursolic, oleanolic and betulinic acids: antibacterial spectra and selectivity indexes. J Ethnopharmacol 2008; 120:272-276.
46. Steele JC, Warhurst DC, Kirby GC, Simmonds MS. In vitro and in vivo evaluation of betulinic acid as an antimalarial. Phytother Res 1999; 13:115-119.
47. De Sa MS, Costa JF, Krettli AU, Zalis MG, Maia GL, Sette IM, et al. Antimalarial activity of betulinic acid and derivatives in vitro against Plasmodium falciparum and in vivo in P. berghei-infected mice. Parasitol Res 2009; 105:275-279.
48. Gautam R, Jachak SM. Recent developments in anti-inflammatory natural products. Med Res Rev 2009; 29:767-820.
49. Enwerem NM, Okogun JI, Wambebe CO, Okorie DA, Akah PA. Anthelmintic activity of the stem bark extracts of Berlina grandiflora and one of its active principles, betulinic acid. Phytomedicine 2001; 8:112-114.
50. Udeani GO, Zhao GM, Geun SY, Cooke BP, Graham J, Beecher CW, et al. Pharmacokinetics and tissue distribution of betulinic acid in CD-1 mice. Biopharm Drug Dispos 1999; 20:379-383.
51. Fulda S, Friesen C, Los M, Scaffidi C, Mier W, Benedict M, 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.
52. Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM. Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur J Cancer 1997; 33:2007-2010.
53. WickW, Grimmel C,Wagenknecht B, Dichgans J,Weller M. Betulinic acidinduced 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.
54. Fulda S, Jeremias I, Steiner HH, Pietsch T, Debatin KM. Betulinic acid: a new cytotoxic agent against malignant brain-tumor cells. Int J Cancer 1999; 82:435-441.
55. Zuco V, Supino R, Righetti SC, Cleris L, Marchesi E, Gambacorti-Passerini C, et al. Selective cytotoxicity of betulinic acid on tumor cell lines, but not on normal cells. Cancer Lett 2002; 175:17-25.
56. Thurnher D, Turhani D, Pelzmann M, Wannemacher B, Knerer B, Formanek M, et al. Betulinic acid: a new cytotoxic compound against malignant head and neck cancer cells. Head Neck 2003; 25:732-740.
57. Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res 2007; 67:2816-2823.
58. Jung GR, Kim KJ, Choi CH, Lee TB, Han SI, Han HK, et al. Effect of betulinic acid on anticancer drug-resistant colon cancer cells. Basic Clin Pharmacol Toxicol 2007; 101:277-285.
59. Kessler JH, Mullauer FB, de Roo GM, Medema JP. Broad in vitro efficacy of plant-derived betulinic acid against cell lines derived from the most prevalent human cancer types. Cancer Lett 2007; 251:132-145.
60. Rzeski W, Stepulak A, Szymanski M, Sifringer M, Kaczor J,Wejksza K, et al. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch Pharmacol 2006; 374:11-20.
61. Noda Y, Kaiya T, Kohda K, Kawazoe Y. Enhanced cytotoxicity of some triterpenes toward leukemia L1210 cells cultured in low pH media: possibility of a new mode of cell killing. Chem Pharm Bull (Tokyo) 1997; 45:1665-1670.
62. Ehrhardt H, Fulda S, Fuhrer M, Debatin KM, Jeremias I. Betulinic acid-induced apoptosis in leukemia cells. Leukemia 2004; 18:1406-1412.
63. Raghuvar Gopal DV, Narkar AA, Badrinath Y, Mishra KP, Joshi DS. Betulinic acid induces apoptosis in human chronic myelogenous leukemia (CML) cell line K-562 without altering the levels of Bcr-Abl. Toxicol Lett 2005; 155:343-351.
64. Selzer E, Pimentel E,Wacheck V, Schlegel W, Pehamberger H, Jansen B, et al. Effects of betulinic acid alone and in combination with irradiation in human melanoma cells. J Invest Dermatol 2000; 114:935-940.
65. Galgon T, Wohlrab W, Drager B. Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes. Exp Dermatol 2005; 14:736-743.
66. Ju ST, Panka DJ, Cui H, Ettinger R, el-Khatib M, Sherr DH, et al. Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 1995; 373:444-448.
67. Nagata S, Golstein P. The Fas death factor. Science 1995; 267:1449-1456.
68. Greil R, Egle A, Villunger A. On the role and significance of Fas (Apo-1/CD95) ligand (FasL) expression in immune privileged tissues and cancer cells using multiple myeloma as a model. Leuk Lymphoma 1998; 31:477-490.
69. Muzio M, Chinnaiyan AM, Kischkel FC, O'Rourke K, Shevchenko A, Ni J, et al. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996; 85:817-827.
70. Medema JP, Scaffidi C, Kischkel FC, Shevchenko A, Mann M, Krammer PH, et al. FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). EMBO J 1997; 16:2794-2804.
71. 2 family: regulators of the cellular life-or-death switch. Nat Rev Cancer 2002; 2:647-656.
72. Villunger A, Michalak EM, Coultas L, Mullauer F, Bock G, Ausserlechner MJ, et al. p53- and drug-induced apoptotic responses mediated by BH3-only proteins puma and noxa. Science 2003; 302:1036-1038.
73. Johnstone RW, Ruefli AA, Lowe SW. Apoptosis: a link between cancer genetics and chemotherapy. Cell 2002; 108:153-164.
74. Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, et al. Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 2004; 303:1010-1014.
75. Orr GA, Verdier-Pinard P, McDaid H, Horwitz SB. Mechanisms of taxol resistance related to microtubules. Oncogene 2003; 22:7280-7295.
76. 2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell 1999; 3:287-296.
77. Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, et al. Proapoptotic Bcl-2 relative Bim required for certain apoptotic responses, leukocyte homeostasis, and to preclude autoimmunity. Science 1999; 286:1735-1738.
78. Green DR, Kroemer G. Cytoplasmic functions of the tumour suppressor p53. Nature 2009; 458:1127-1130.
79. Fulda S. Betulinic acid for cancer treatment and prevention. Int J Mol Sci 2008; 9:1096-1107.
80. Fulda S. Betulinic acid: a natural product with anticancer activity. Mol Nutr Food Res 2009; 53:140-146.
81. Fulda S, Kroemer G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov Today 2009; 14:885-890.
82. Rieber M, Strasberg RM. Induction of p53 without increase in p21WAF1 in betulinic acid-mediated cell death is preferential for human metastatic melanoma. DNA Cell Biol 1998; 17:399-406.
83. 2 ratio determines the susceptibility of human melanoma cells to CD95/Fas-mediated apoptosis. J Invest Dermatol 2001; 117:333-340.
84. Fulda S, Scaffidi C, Susin SA, Krammer PH, Kroemer G, Peter ME, et al. Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. J Biol Chem 1998; 273:33942-33948.
85. Fulda S, Susin SA, Kroemer G, Debatin KM. Molecular ordering of apoptosis induced by anticancer drugs in neuroblastoma cells. Cancer Res 1998; 58:4453-4460. (Pubitemid 28450051)
86. Mullauer FB, Kessler JH, Medema JP. Betulinic acid induces cytochrome c release and apoptosis in a Bax/Bak-independent, permeability transition pore dependent fashion. Apoptosis 2009; 14:191-202.
87. Fulda S, Jeremias I, Debatin KM. Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 2004; 23:7611-7620.
88. Petrovic N, Schacke W, Gahagan JR, O'Conor CA,Winnicka B, Conway RE, et al. CD13/APN regulates endothelial invasion and filopodia formation. Blood 2007; 110:142-150.
89. Melzig MF, Bormann H. Betulinic acid inhibits aminopeptidase N activity. Planta Med 1998; 64:655-657.
90. Kwon HJ, Shim JS, Kim JH, Cho HY, Yum YN, Kim SH, 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.
91. Lee WS, Im KR, Park YD, Sung ND, Jeong TS. Human ACAT-1 and ACAT-2 inhibitory activities of pentacyclic triterpenes from the leaves of Lycopus lucidus TURCZ. Biol Pharm Bull 2006; 29:382-384.
92. Cases S, Smith SJ, Zheng YW, Myers HM, Lear SR, Sande E, et al. Identification of a gene encoding an acyl CoA: diacylglycerol acyltransferase, a key enzyme in triacylglycerol synthesis. Proc Natl Acad Sci U S A 1998; 95:13018-13023.
93. Chung MY, Rho MC, Lee SW, Park HR, Kim K, Lee IA, et al. Inhibition of diacylglycerol acyltransferase by betulinic acid from Alnus hirsuta. Planta Med 2006; 72:267-269.
94. De Melo CL, Queiroz MG, Arruda Filho AC, Rodrigues AM, de Sousa DF, Almeida JG, et al. Betulinic acid, a natural pentacyclic triterpenoid, prevents abdominal fat accumulation in mice fed a high-fat diet. J Agric Food Chem 2009; 57:8776-8781.
95. Tan Y, Yu R, Pezzuto JM. Betulinic acid-induced programmed cell death in human melanoma cells involves mitogen-activated protein kinase activation. Clin Cancer Res 2003; 9:2866-2875.
96. Rieber M, Rieber MS. Signalling responses linked to betulinic acid-induced apoptosis are antagonized by MEK inhibitor U0126 in adherent or 3D spheroid melanoma irrespective of p53 status. Int J Cancer 2006; 118:1135-1143.
97. Qiu L, Wang Q, Di W, Jiang Q, Schefeller E, Derby S, et al. Transient activation of EGFR/AKT cell survival pathway and expression of survivin contribute to reduced sensitivity of human melanoma cells to betulinic acid. Int J Oncol 2005; 27:823-830.
98. Ferraro C, Quemeneur L, Fournel S, Prigent AF, Revillard JP, Bonnefoy-Berard N. The topoisomerase inhibitors camptothecin and etoposide induce a CD95-independent apoptosis of activated peripheral lymphocytes. Cell Death Differ 2000; 7:197-206.
99. Wada S, Tanaka R. Betulinic acid and its derivatives, potent DNA topoisomerase II inhibitors, from the bark of Bischofia javanica. Chem Biodivers 2005; 2:689-694.
100. Chowdhury AR, Mandal S, Mittra B, Sharma S, Mukhopadhyay S, Majumder HK. 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.
101. Ganguly A, Das B, Roy A, Sen N, Dasgupta SB, Mukhopadhayay S, et al. Betulinic acid, a catalytic inhibitor of topoisomerase I, inhibits reactive oxygen species-mediated apoptotic topoisomerase I-DNA cleavable complex formation in prostate cancer cells but does not affect the process of cell death. Cancer Res 2007; 67:11848-11858.
102. Bar FM, Khanfar MA, Elnagar AY, Liu H, Zaghloul AM, Badria FA, et al. Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors. J Nat Prod 2009; 72:1643-1650.
103. Takada Y, Aggarwal BB. 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; 171:3278-3286.
104. Rabi T, Shukla S, Gupta S. Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells. Mol Carcinog 2008; 47:964-973.
105. Kasperczyk H, La Ferla-Bruhl K, Westhoff MA, Behrend L, Zwacka RM, Debatin KM, et al. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene 2005; 24:6945-6956.
106. Chen Z,Wu Q, Chen Y, He J. Effects of betulinic acid on proliferation and apoptosis in Jurkat cells and its in vitro mechanism. J Huazhong Univ Sci Technol Med Sci 2008; 28:634-638.
107. Sawada N, Kataoka K, Kondo K, Arimochi H, Fujino H, Takahashi Y, 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.
108. Huang L, Ho P, Chen CH. Activation and inhibition of the proteasome by betulinic acid and its derivatives. FEBS Lett 2007; 581:4955-4959.
109. Tsukamoto S, Yokosawa H. Targeting the proteasome pathway. Expert Opin Ther Targets 2009; 13:605-621.
110. Rajendran P, Jaggi M, Singh MK, Mukherjee R, Burman AC. Pharmacological evaluation of C-3 modified betulinic acid derivatives with potent anticancer activity. Invest New Drugs 2008; 26:25-34.
111. Wachsberger PR, Burd R, Wahl ML, Leeper DB. Betulinic acid sensitization of low pH adapted human melanoma cells to hyperthermia. Int J Hyperthermia 2002; 18:153-164.
112. Fulda S, Debatin KM. Sensitization for anticancer drug-induced apoptosis by betulinic acid. Neoplasia 2005; 7:162-170.
113. Eder-Czembirek C, Czembirek C, Erovic BM, Selzer E, Turhani D, Vormittag L, et al. Combination of betulinic acid with cisplatin - different cytotoxic effects in two head and neck cancer cell lines. Oncol Rep 2005; 14:667-671.
114. Yamai H, Sawada N, Yoshida T, Seike J, Takizawa H, Kenzaki K, et al. Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo. Int J Cancer 2009; 125:952-960.
115. Gao H, Wu L, Kuroyanagi M, Harada K, Kawahara N, Nakane T, et al. Antitumor-promoting constituents from Chaenomeles sinensis KOEHNE and their activities in JB6 mouse epidermal cells. Chem Pharm Bull (Tokyo) 2003; 51:1318-1321.
116. Kim DS, Pezzuto JM, Pisha E. Synthesis of betulinic acid derivatives with activity against human melanoma. Bioorg Med Chem Lett 1998; 8:1707-1712.
117. Kvasnica M, Sarek J, Klinotova E, Dzubak P, Hajduch M. Synthesis of phthalates of betulinic acid and betulin with cytotoxic activity. Bioorg Med Chem 2005; 13:3447-3454.
118. Gauthier C, Legault J, Lavoie S, Rondeau S, Tremblay S, Pichette A. Synthesis and cytotoxicity of bidesmosidic betulin and betulinic acid saponins. J Nat Prod 2009; 72:72-81.
119. Pyo JS, Roh SH, Kim DK, Lee JG, Lee YY, Hong SS, et al. Anti-cancer effect of betulin on a human lung cancer cell line: a pharmacoproteomic approach using 2 D SDS page coupled with nano-hplc tandem mass spectrometry. Planta Med 2009; 75:127-131.
120. Mullauer FB, Kessler JH, Medema JP. Betulin is a potent anti-tumor agent that is enhanced by cholesterol. PLoS One 2009; 4:e1.
121. Kim JY, Koo HM, Kim DS. Development of C-20 modified betulinic acid derivatives as antitumor agents. Bioorg Med Chem Lett 2001; 11:2405-2408.
122. Jeong HJ, Chai HB, Park SY, Kim DS. Preparation of amino acid conjugates of betulinic acid with activity against human melanoma. Bioorg Med Chem Lett 1999; 9:1201-1204.
123. Liu WK, Ho JC, Cheung FW, Liu BP, Ye WC, Che CT. Apoptotic activity of betulinic acid derivatives on murine melanoma B16 cell line. Eur J Pharmacol 2004; 498:71-78.
124. Liby K, Honda T, Williams CR, Risingsong R, Royce DB, Suh N, et al. Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. Mol Cancer Ther 2007; 6:2113-2119.
125. Mukherjee R, Kumar V, Srivastava SK, Agarwal SK, Burman AC. Betulinic acid derivatives as anticancer agents: structure activity relationship. Anticancer Agents Med Chem 2006; 6:271-279.
126. Huyke C, Reuter J, Rodig M, Kersten A, Laszczyk M, Scheffler A, et al. Treatment of actinic keratoses with a novel betulin-based oleogel. A prospective, randomized, comparative pilot study. J Dtsch Dermatol Ges 2009; 7:128-133.