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Betulinic acid

Description of betulinic acid: betulinic acid is a pentacyclic lupane-type triterpene derivative of betulin (isolated from the bark of Betula alba, the common white birch) with antiinflammatory, anti-HIV and antineoplastic activities. Betulinic acid induces apoptosis through induction of changes in mitochondrial membrane potential, production of reactive oxygen species, and opening of mitochondrial permeability transition pores, resulting in the release of mitochondrial apogenic factors, activation of caspases, and DNA fragmentation. Although originally thought to exhibit specific cytotoxicity against melanoma cells, this agent has been found to be cytotoxic against non-melanoma tumor cell types including neuroectodermal.and brain tumor cells. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus).

Betulinic acid is a naturally occurring pentacyclic triterpenoid which has anti-retroviral, anti-malarial, and anti-inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase.  It is found in the bark of several species of plants, principally the white birch (Betula pubescens)  from which it gets its name, but also the Ber tree (Ziziphus mauritiana), selfheal (Prunella vulgaris), the tropical carnivorous plants Triphyophyllum peltatum and Ancistrocladus heyneanus, Diospyros leucomelas a member of the persimmon family, Tetracera boiviniana, the jambul (Syzygium formosanum),  flowering quince (Chaenomeles sinensis), Rosemary, and Pulsatilla chinensis. see: http://en.wikipedia.org/wiki/Betulinic_acid.

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 1: Chaouki W, Leger DY, Eljastimi J, Beneytout JL, Hmamouchi M. Antiproliferative effect of extracts from Aristolochia baetica and Origanum compactum on human breast cancer cell line MCF-7. Pharm Biol. 2010 Mar;48(3):269-74. PubMed PMID: 20645812.

2: Parrondo R, Pozas Ade L, Reiner T, Rai P, Perez-Stable C. NF-kappaB activation enhances cell death by antimitotic drugs in human prostate cancer cells. Mol Cancer. 2010 Jul 9;9:182. PubMed PMID: 20618955.

3: Li Y, He K, Huang Y, Zheng D, Gao C, Cui L, Jin YH. Betulin induces mitochondrial cytochrome c release associated apoptosis in human cancer cells. Mol Carcinog. 2010 Jul;49(7):630-40. PubMed PMID: 20564340.

4: Eichenmüller M, Hemmerlein B, von Schweinitz D, Kappler R. Betulinic acid induces apoptosis and inhibits hedgehog signalling in rhabdomyosarcoma. Br J Cancer. 2010 Jun 29;103(1):43-51. Epub 2010 Jun 1. PubMed PMID: 20517313; PubMed Central PMCID: PMC2905279.

5: Cheng MJ, Chen JJ, Wu MD, Yang PS, Yuan GF. Isolation and structure determination of one new metabolite isolated from the red fermented rice of Monascus purpureus. Nat Prod Res. 2010 Jun;24(10):979-88. PubMed PMID: 20496238.

6: Ahmad FB, Ghaffari Moghaddam M, Basri M, Abdul Rahman MB. Anticancer activity of 3-O-acylated betulinic acid derivatives obtained by enzymatic synthesis. Biosci Biotechnol Biochem. 2010;74(5):1025-9. Epub 2010 May 7. PubMed PMID: 20460723.

7: Kommera H, Kaluderović GN, Dittrich S, Kalbitz J, Dräger B, Mueller T, Paschke R. Carbamate derivatives of betulinic acid and betulin with selective cytotoxic activity. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3409-12. Epub 2010 Apr 18. PubMed PMID: 20451375.

8: Chadalapaka G, Jutooru I, Burghardt R, Safe S. Drugs that target specificity proteins downregulate epidermal growth factor receptor in bladder cancer cells. Mol Cancer Res. 2010 May;8(5):739-50. Epub 2010 Apr 20. PubMed PMID: 20407012; PubMed Central PMCID: PMC2872686.

9: da Silveira CV, Trevisan MT, Rios JB, Erben G, Haubner R, Pfundstein B, Owen RW. Secondary plant substances in various extracts of the leaves, fruits, stem and bark of Caraipa densifolia Mart. Food Chem Toxicol. 2010 Jun;48(6):1597-606. Epub 2010 Mar 27. PubMed PMID: 20347919.

10: Eder-Czembirek C, Erovic BM, Czembirek C, Brunner M, Selzer E, Pötter R, Thurnher D. Betulinic Acid a Radiosensitizer in Head and Neck Squamous Cell Carcinoma Cell Lines. Strahlenther Onkol. 2010 Feb 22. [Epub ahead of print] PubMed PMID: 20339825.

11: Csuk R, Barthel A, Schwarz S, Kommera H, Paschke R. Synthesis and biological evaluation of antitumor-active gamma-butyrolactone substituted betulin derivatives. Bioorg Med Chem. 2010 Apr 1;18(7):2549-58. Epub 2010 Mar 2. PubMed PMID: 20299226.

12: Liu EH, Qi LW, Wu Q, Peng YB, Li P. Anticancer agents derived from natural products. Mini Rev Med Chem. 2009 Nov 1;9(13):1547-55. Review. PubMed PMID: 20205636.

13: Kommera H, Kaluderović GN, Bette M, Kalbitz J, Fuchs P, Fulda S, Mier W, Paschke R. In vitro anticancer studies of alpha- and beta-D-glucopyranose betulin anomers. Chem Biol Interact. 2010 Apr 29;185(2):128-36. Epub 2010 Mar 1. PubMed PMID: 20193672.

14: Lee KH. Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach. J Nat Prod. 2010 Mar 26;73(3):500-16. Review. PubMed PMID: 20187635; PubMed Central PMCID: PMC2893734.

15: Li S, Shi Y, Shang XY, Cui BS, Yuan Y, Chen XG, Yang YC, Shi JG. Triterpenoids from the roots of Pterospermum heterophyllum Hance. J Asian Nat Prod Res. 2009 Jul;11(7):652-7. PubMed PMID: 20183302.

16: Ng KW, Salhimi SM, Majid AM, Chan KL. Anti-angiogenic and cytotoxicity studies of some medicinal plants. Planta Med. 2010 Jun;76(9):935-40. Epub 2010 Jan 28. PubMed PMID: 20112179.

17: Effenberger K, Breyer S, Schobert R. Terpene conjugates of the Nigella sativa seed-oil constituent thymoquinone with enhanced efficacy in cancer cells. Chem Biodivers. 2010 Jan;7(1):129-39. PubMed PMID: 20087986.

18: Mullauer FB, Kessler JH, Medema JP. Betulinic acid, a natural compound with potent anticancer effects. Anticancer Drugs. 2010 Mar;21(3):215-27. Review. PubMed PMID: 20075711.

19: Yang LJ, Chen Y, Ma Q, Fang J, He J, Cheng YQ, Wu QL. Effect of betulinic acid on the regulation of Hiwi and cyclin B1 in human gastric adenocarcinoma AGS cells. Acta Pharmacol Sin. 2010 Jan;31(1):66-72. Epub 2009 Dec 28. PubMed PMID: 20037601.

20: Martucciello S, Balestrieri ML, Felice F, Estevam Cdos S, Sant'Ana AE, Pizza C, Piacente S. Effects of triterpene derivatives from Maytenus rigida on VEGF-induced Kaposi's sarcoma cell proliferation. Chem Biol Interact. 2010 Feb 12;183(3):450-4. Epub 2009 Dec 21. PubMed PMID: 20026015.

21: Kommera H, Kaluđerović GN, Kalbitz J, Paschke R. Lupane Triterpenoids-Betulin and Betulinic acid derivatives induce apoptosis in tumor cells. Invest New Drugs. 2009 Dec 4. [Epub ahead of print] PubMed PMID: 19957199.

22: Pandey MK, Sung B, Aggarwal BB. Betulinic acid suppresses STAT3 activation pathway through induction of protein tyrosine phosphatase SHP-1 in human multiple myeloma cells. Int J Cancer. 2010 Jul 15;127(2):282-92. PubMed PMID: 19937797; PubMed Central PMCID: PMC2877157.

23: Berman B, Amini S, Valins W, Block S. Pharmacotherapy of actinic keratosis. Expert Opin Pharmacother. 2009 Dec;10(18):3015-31. Review. PubMed PMID: 19925043.

24: Tokiwano T, Satoh H, Obara T, Hirota H, Yoshizawa Y, Yamamoto Y. A lichen substance as an antiproliferative compound against HL-60 human leukemia cells: 16-O-acetyl-leucotylic acid isolated from Myelochroa aurulenta. Biosci Biotechnol Biochem. 2009 Nov;73(11):2525-7. Epub 2009 Nov 7. PubMed PMID: 19897905.

25: Füllbeck M, Dunkel M, Hossbach J, Daniel PT, Preissner R. Cellular fingerprints: a novel approach using large-scale cancer cell line data for the identification of potential anticancer agents. Chem Biol Drug Des. 2009 Nov;74(5):439-48. Epub 2009 Oct 2. PubMed PMID: 19799613.

26: Laszczyk MN. Pentacyclic triterpenes of the lupane, oleanane and ursane group as tools in cancer therapy. Planta Med. 2009 Dec;75(15):1549-60. Epub . Review. PubMed PMID: 19742422.

27: Eichenmüller M, von Schweinitz D, Kappler R. Betulinic acid treatment promotes apoptosis in hepatoblastoma cells. Int J Oncol. 2009 Oct;35(4):873-9. PubMed PMID: 19724925.

28: Bar FM, Khanfar MA, Elnagar AY, Liu H, Zaghloul AM, Badria FA, Sylvester PW, Ahmad KF, Raisch KP, El Sayed KA. Rational design and semisynthesis of betulinic acid analogues as potent topoisomerase inhibitors. J Nat Prod. 2009 Sep;72(9):1643-50. PubMed PMID: 19691293.

29: Santos RC, Salvador JA, Marín S, Cascante M. Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity. Bioorg Med Chem. 2009 Sep 1;17(17):6241-50. Epub 2009 Jul 25. PubMed PMID: 19674909.

30: Drag-Zalesinska M, Kulbacka J, Saczko J, Wysocka T, Zabel M, Surowiak P, Drag M. Esters of betulin and betulinic acid with amino acids have improved water solubility and are selectively cytotoxic toward cancer cells. Bioorg Med Chem Lett. 2009 Aug 15;19(16):4814-7. Epub 2009 Jun 14. PubMed PMID: 19560351.

31: Fulda S, Kroemer G. Targeting mitochondrial apoptosis by betulinic acid in human cancers. Drug Discov Today. 2009 Sep;14(17-18):885-90. Epub 2009 Jun 9. Review. PubMed PMID: 19520182.

32: Nakagawa-Goto K, Yamada K, Taniguchi M, Tokuda H, Lee KH. Cancer preventive agents 9. Betulinic acid derivatives as potent cancer chemopreventive agents. Bioorg Med Chem Lett. 2009 Jul 1;19(13):3378-81. Epub 2009 May 18. PubMed PMID: 19481937; PubMed Central PMCID: PMC2747314.

33: Karna E, Palka JA. Mechanism of betulinic acid inhibition of collagen biosynthesis in human endometrial adenocarcinoma cells. Neoplasma. 2009;56(4):361-6. PubMed PMID: 19469659.

34: Yamai H, Sawada N, Yoshida T, Seike J, Takizawa H, Kenzaki K, Miyoshi T, Kondo K, Bando Y, Ohnishi Y, Tangoku A. 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 Aug 15;125(4):952-60. PubMed PMID: 19462449.

35: Drag M, Surowiak P, Drag-Zalesinska M, Dietel M, Lage H, Oleksyszyn J. Comparision of the cytotoxic effects of birch bark extract, betulin and betulinic acid towards human gastric carcinoma and pancreatic carcinoma drug-sensitive and drug-resistant cell lines. Molecules. 2009 Apr 24;14(4):1639-51. PubMed PMID: 19396022.

36: Fulda S. Betulinic Acid for cancer treatment and prevention. Int J Mol Sci. 2008 Jun;9(6):1096-107. Epub 2008 Jun 27. PubMed PMID: 19325847; PubMed Central PMCID: PMC2658785.

37: Willmann M, Wacheck V, Buckley J, Nagy K, Thalhammer J, Paschke R, Triche T, Jansen B, Selzer E. Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound. Eur J Clin Invest. 2009 May;39(5):384-94. PubMed PMID: 19309323.

38: Du YC, Lin AS, Wu CC, Hsieh PW, Chen YH, Chen IH, Chen SL, Yen HF, Lübken T, Chang FR, Wu YC. New cytotoxic lupane triterpenes from Perrottetia arisanensis. Planta Med. 2009 Jun;75(8):848-55. Epub 2009 Mar 18. PubMed PMID: 19296430.

39: Koohang A, Majewski ND, Szotek EL, Mar AA, Eiznhamer DA, Flavin MT, Xu ZQ. Synthesis and cytotoxicity of 2-cyano-28-hydroxy-lup-1-en-3-ones. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2168-71. Epub 2009 Mar 3. PubMed PMID: 19286375.

40: Theo A, Masebe T, Suzuki Y, Kikuchi H, Wada S, Obi CL, Bessong PO, Usuzawa M, Oshima Y, Hattori T. Peltophorum africanum, a traditional South African medicinal plant, contains an anti HIV-1 constituent, betulinic acid. Tohoku J Exp Med. 2009 Feb;217(2):93-9. PubMed PMID: 19212101.

41: Lena A, Rechichi M, Salvetti A, Bartoli B, Vecchio D, Scarcelli V, Amoroso R, Benvenuti L, Gagliardi R, Gremigni V, Rossi L. Drugs targeting the mitochondrial pore act as cytotoxic and cytostatic agents in temozolomide-resistant glioma cells. J Transl Med. 2009 Feb 5;7:13. PubMed PMID: 19196452; PubMed Central PMCID: PMC2661321.

42: 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 Jan;72(1):72-81. PubMed PMID: 19115839.

43: 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 Feb;14(2):191-202. PubMed PMID: 19115109.

44: 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 Technolog Med Sci. 2008 Dec;28(6):634-8. Epub 2008 Dec 24. PubMed PMID: 19107355.

45: Chen Z, Wu QL, Chen Y, He J. [Effect of betulinic acid on proliferation and apoptosis in Jurkat cells and its mechanism]. Zhonghua Zhong Liu Za Zhi. 2008 Aug;30(8):588-92. Chinese. PubMed PMID: 19102935.

46: Lin AS, Lin CR, Du YC, Lübken T, Chiang MY, Chen IH, Wu CC, Hwang TL, Chen SL, Yen MH, Chang FR, Wu YC. Acasiane A and B and farnesirane A and B, diterpene derivatives from the roots of Acacia farnesiana. Planta Med. 2009 Feb;75(3):256-61. Epub 2008 Dec 19. PubMed PMID: 19101886.

47: Fulda S. Betulinic acid: a natural product with anticancer activity. Mol Nutr Food Res. 2009 Jan;53(1):140-6. Review. PubMed PMID: 19065582.

48: Ma CY, Musoke SF, Tan GT, Sydara K, Bouamanivong S, Southavong B, Soejarto DD, Fong HH, Zhang HJ. Study of antimalarial activity of chemical constituents from Diospyros quaesita. Chem Biodivers. 2008 Nov;5(11):2442-8. PubMed PMID: 19035573.

49: Subramanyam R, Gollapudi A, Bonigala P, Chinnaboina M, Amooru DG. Betulinic acid binding to human serum albumin: a study of protein conformation and binding affinity. J Photochem Photobiol B. 2009 Jan 9;94(1):8-12. Epub 2008 Sep 16. PubMed PMID: 18945624.

50: Arai MA, Tateno C, Hosoya T, Koyano T, Kowithayakorn T, Ishibashi M. Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg Med Chem. 2008 Nov 1;16(21):9420-4. Epub 2008 Sep 24. PubMed PMID: 18842418.

51: Wang LL, Li ZL, Song DD, Sun L, Pei YH, Jing YK, Hua HM. Two novel triterpenoids with antiproliferative and apoptotic activities in human leukemia cells isolated from the resin of Garcinia hanburyi. Planta Med. 2008 Nov;74(14):1735-40. Epub 2008 Sep 9. PubMed PMID: 18781544.

52: Kumar V, Rani N, Aggarwal P, Sanna VK, Singh AT, Jaggi M, Joshi N, Sharma PK, Irchhaiya R, Burman AC. Synthesis and cytotoxic activity of heterocyclic ring-substituted betulinic acid derivatives. Bioorg Med Chem Lett. 2008 Sep 15;18(18):5058-62. Epub 2008 Aug 6. PubMed PMID: 18752941.

53: 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 Dec;47(12):964-73. PubMed PMID: 18444250; PubMed Central PMCID: PMC2864721.

54: Pan MH, Chen CM, Lee SW, Chen ZT. Cytotoxic triterpenoids from the root bark of Helicteres angustifolia. Chem Biodivers. 2008 Apr;5(4):565-74. PubMed PMID: 18421748.

55: Choi JY, Choi EH, Jung HW, Oh JS, Lee WH, Lee JG, Son JK, Kim Y, Lee SH. Melanogenesis inhibitory compounds from Saussureae Radix. Arch Pharm Res. 2008 Mar;31(3):294-9. Epub 2008 Apr 13. PubMed PMID: 18409040.

56: Cmoch P, Pakulski Z, Swaczynová J, Strnad M. Synthesis of lupane-type saponins bearing mannosyl and 3,6-branched trimannosyl residues and their evaluation as anticancer agents. Carbohydr Res. 2008 May 5;343(6):995-1003. Epub 2008 Feb 20. PubMed PMID: 18328468.

57: Ganguly A, Das B, Roy A, Sen N, Dasgupta SB, Mukhopadhayay S, Majumder HK. 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 Dec 15;67(24):11848-58. PubMed PMID: 18089815.

58: Tian Z, Pan R, Chang Q, Si J, Xiao P, Wu E. Cimicifuga foetida extract inhibits proliferation of hepatocellular cells via induction of cell cycle arrest and apoptosis. J Ethnopharmacol. 2007 Nov 1;114(2):227-33. Epub 2007 Aug 12. PubMed PMID: 17881166.

59: 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 Feb;26(1):25-34. Epub 2007 Sep 13. PubMed PMID: 17851638.

60: Jung GR, Kim KJ, Choi CH, Lee TB, Han SI, Han HK, Lim SC. Effect of betulinic acid on anticancer drug-resistant colon cancer cells. Basic Clin Pharmacol Toxicol. 2007 Oct;101(4):277-85. PubMed PMID: 17845510.

61: Chintharlapalli S, Papineni S, Liu S, Jutooru I, Chadalapaka G, Cho SD, Murthy RS, You Y, Safe S. 2-cyano-lup-1-en-3-oxo-20-oic acid, a cyano derivative of betulinic acid, activates peroxisome proliferator-activated receptor gamma in colon and pancreatic cancer cells. Carcinogenesis. 2007 Nov;28(11):2337-46. Epub 2007 Aug 27. PubMed PMID: 17724373.

62: Liby K, Honda T, Williams CR, Risingsong R, Royce DB, Suh N, Dinkova-Kostova AT, Stephenson KK, Talalay P, Sundararajan C, Gribble GW, Sporn MB. Novel semisynthetic analogues of betulinic acid with diverse cytoprotective, antiproliferative, and proapoptotic activities. Mol Cancer Ther. 2007 Jul;6(7):2113-9. PubMed PMID: 17620440.

63: Thibeault D, Gauthier C, Legault J, Bouchard J, Dufour P, Pichette A. Synthesis and structure-activity relationship study of cytotoxic germanicane- and lupane-type 3beta-O-monodesmosidic saponins starting from betulin. Bioorg Med Chem. 2007 Sep 15;15(18):6144-57. Epub 2007 Jun 20. PubMed PMID: 17614290.

64: Muceniece R, Saleniece K, Riekstina U, Krigere L, Tirzitis G, Ancans J. Betulin binds to melanocortin receptors and antagonizes alpha-melanocyte stimulating hormone induced cAMP generation in mouse melanoma cells. Cell Biochem Funct. 2007 Sep-Oct;25(5):591-6. PubMed PMID: 17605140.

65: Urban M, Sarek J, Kvasnica M, Tislerova I, Hajduch M. Triterpenoid pyrazines and benzopyrazines with cytotoxic activity. J Nat Prod. 2007 Apr;70(4):526-32. Epub 2007 Mar 20. PubMed PMID: 17371067.

66: Chintharlapalli S, Papineni S, Ramaiah SK, Safe S. Betulinic acid inhibits prostate cancer growth through inhibition of specificity protein transcription factors. Cancer Res. 2007 Mar 15;67(6):2816-23. PubMed PMID: 17363604.

67: Bi Y, Xu J, Wu X, Ye W, Yuan S, Zhang L. Synthesis and cytotoxic activity of 17-carboxylic acid modified 23-hydroxy betulinic acid ester derivatives. Bioorg Med Chem Lett. 2007 Mar 1;17(5):1475-8. Epub 2006 Oct 4. PubMed PMID: 17275295.

68: Bastos DZ, Pimentel IC, de Jesus DA, de Oliveira BH. Biotransformation of betulinic and betulonic acids by fungi. Phytochemistry. 2007 Mar;68(6):834-9. Epub 2007 Jan 26. PubMed PMID: 17258248.

69: 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 Jun 18;251(1):132-45. Epub 2006 Dec 13. PubMed PMID: 17169485.

70: Laszczyk M, Jäger S, Simon-Haarhaus B, Scheffler A, Schempp CM. Physical, chemical and pharmacological characterization of a new oleogel-forming triterpene extract from the outer bark of birch (betulae cortex). Planta Med. 2006 Dec;72(15):1389-95. Epub 2006 Nov 7. PubMed PMID: 17091432.

71: Rzeski W, Stepulak A, Szymański M, Sifringer M, Kaczor J, Wejksza K, Zdzisińska B, Kandefer-Szerszeń M. Betulinic acid decreases expression of bcl-2 and cyclin D1, inhibits proliferation, migration and induces apoptosis in cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2006 Oct;374(1):11-20. Epub 2006 Sep 9. PubMed PMID: 16964520.

72: Gauthier C, Legault J, Lebrun M, Dufour P, Pichette A. Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents. Bioorg Med Chem. 2006 Oct 1;14(19):6713-25. Epub 2006 Jun 19. PubMed PMID: 16787747.

73: Pokrovskii AG, Shintyapina AB, Pronkina NV, Kozhevnikov VS, Plyasunova OA, Shul'ts EE, Tolstikov GA. Activation of apoptosis by derivatives of betulinic acid in human tumor cells in vitro. Dokl Biochem Biophys. 2006 Mar-Apr;407:94-7. PubMed PMID: 16776075.

74: Fang L, Ito A, Chai HB, Mi Q, Jones WP, Madulid DR, Oliveros MB, Gao Q, Orjala J, Farnsworth NR, Soejarto DD, Cordell GA, Swanson SM, Pezzuto JM, Kinghorn AD. Cytotoxic constituents from the stem bark of Dichapetalum gelonioides collected in the Philippines. J Nat Prod. 2006 Mar;69(3):332-7. PubMed PMID: 16562829; PubMed Central PMCID: PMC2543135.

75: Tolstikova TG, Sorokina IV, Tolstikov GA, Tolstikov AG, Flekhter OB. [Biological activity and pharmacological prospects of lupane terpenoids: I. Natural lupane derivatives]. Bioorg Khim. 2006 Jan-Feb;32(1):42-55. Review. Russian. PubMed PMID: 16523720.

76: Amico V, Barresi V, Condorelli D, Spatafora C, Tringali C. Antiproliferative terpenoids from almond hulls (Prunus dulcis): identification and structure-activity relationships. J Agric Food Chem. 2006 Feb 8;54(3):810-4. PubMed PMID: 16448187.

77: Garg AK, Buchholz TA, Aggarwal BB. Chemosensitization and radiosensitization of tumors by plant polyphenols. Antioxid Redox Signal. 2005 Nov-Dec;7(11-12):1630-47. Review. PubMed PMID: 16356126.

78: Castor TP. Phospholipid nanosomes. Curr Drug Deliv. 2005 Oct;2(4):329-40. Review. PubMed PMID: 16305436.

79: André N, Rome A, Carré M; Société Francophone de Recherche en Pédiatrie (SFRP). [Antimitochondrial agents: a new class of anticancer agents]. Arch Pediatr. 2006 Jan;13(1):69-75. Epub 2005 Nov 16. Review. French. PubMed PMID: 16298120.

80: Bauvois B, Dauzonne D. Aminopeptidase-N/CD13 (EC 3.4.11.2) inhibitors: chemistry, biological evaluations, and therapeutic prospects. Med Res Rev. 2006 Jan;26(1):88-130. Review. PubMed PMID: 16216010.

81: Galgon T, Wohlrab W, Dräger B. Betulinic acid induces apoptosis in skin cancer cells and differentiation in normal human keratinocytes. Exp Dermatol. 2005 Oct;14(10):736-43. PubMed PMID: 16176281.

82: 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 Mar 1;118(5):1135-43. PubMed PMID: 16152620.

83: Eder-Czembirek C, Czembirek C, Erovic BM, Selzer E, Turhani D, Vormittag L, Thurnher D. Combination of betulinic acid with cisplatin--different cytotoxic effects in two head and neck cancer cell lines. Oncol Rep. 2005 Sep;14(3):667-71. PubMed PMID: 16077972.

84: Qiu L, Wang Q, Di W, Jiang Q, Schefeller E, Derby S, Wanebo H, Yan B, Wan Y. 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 Sep;27(3):823-30. PubMed PMID: 16077934.

85: Núñez MJ, Reyes CP, Jiménez IA, Moujir L, Bazzocchi IL. Lupane triterpenoids from Maytenus species. J Nat Prod. 2005 Jul;68(7):1018-21. PubMed PMID: 16038541.

86: Kasperczyk H, La Ferla-Brühl K, Westhoff MA, Behrend L, Zwacka RM, Debatin KM, Fulda S. Betulinic acid as new activator of NF-kappaB: molecular mechanisms and implications for cancer therapy. Oncogene. 2005 Oct 20;24(46):6945-56. PubMed PMID: 16007147.

87: Symon AV, Veselova NN, Kaplun AP, Vlasenkova NK, Fedorova GA, Liutik AI, Gerasimova GK, Shvrts VI. [Synthesis and antitumor activity of cyclopropane derivatives of betulinic and betulonic acids]. Bioorg Khim. 2005 May-Jun;31(3):320-5. Russian. PubMed PMID: 16004391.

88: Karpova MB, Sanmun D, Henter JI, Smirnov AF, Fadeel B. Betulinic acid, a natural cytotoxic agent, fails to trigger apoptosis in human Burkitt's lymphoma-derived B-cell lines. Int J Cancer. 2006 Jan 1;118(1):246-52. PubMed PMID: 16003746.

89: Ceruti S, Mazzola A, Abbracchio MP. Resistance of human astrocytoma cells to apoptosis induced by mitochondria-damaging agents: possible implications for anticancer therapy. J Pharmacol Exp Ther. 2005 Aug;314(2):825-37. Epub 2005 May 5. Erratum in: J Pharmacol Exp Ther. 2005 Oct;315(1):475. PubMed PMID: 15879006.

90: 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 May 16;13(10):3447-54. PubMed PMID: 15848757.

91: Fulda S, Debatin KM. Sensitization for anticancer drug-induced apoptosis by betulinic Acid. Neoplasia. 2005 Feb;7(2):162-70. PubMed PMID: 15802021; PubMed Central PMCID: PMC1501129.

92: 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 Mar 15;155(3):343-51. PubMed PMID: 15649617.

93: Urech K, Scher JM, Hostanska K, Becker H. Apoptosis inducing activity of viscin, a lipophilic extract from Viscum album L. J Pharm Pharmacol. 2005 Jan;57(1):101-9. PubMed PMID: 15638998.

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