Characterization of NVX-207, a novel betulinic acid-derived anti-cancer compound

European Journal of Clinical Investigation

Volumn 39, Issue 5, 2009, Pages 384-394

  Willmann, M ^b   Wacheck, V ^a   Buckley, J ^c,d   Nagy, K ^a   Thalhammer, J ^b   Paschke, R ^e   Triche, T ^c,f   Jansen, B ^a,c   Selzer, E ^a  

^a MEDICAL UNIVERSITY OF VIENNA   (Austria)

^b UNIVERSITY OF VETERINARY MEDICINE   (Austria)

^c Novelix Pharmaceuticals Inc   (United States)

^d UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^e MARTIN LUTHER UNIVERSITY HALLE WITTENBERG   (Germany)

^f RADY CHILDREN'S HOSPITAL   (United States)

Author keywords

Betulinic acid derivative; Cancer therapy; Gene expression; Lipid metabolism; Triterpene

Indexed keywords

3 ACETYLBETULINIC ACID 2 AMINO 3 HYDROXY 2 HYDROXYMETHYLPROPANOATE; 3 HYDROXY 3 METHYLGLUTARYL COENZYME A; ANTINEOPLASTIC AGENT; APOLIPOPROTEIN A1; BETULIC ACID; CASPASE 3; CASPASE 7; CASPASE 9; CISPLATIN; LOW DENSITY LIPOPROTEIN RECEPTOR; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; NVX 207; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER CELL CULTURE; CANCER REGRESSION; CELL SURVIVAL; CHOLESTEROL TRANSPORT; CONTROLLED STUDY; DOG; DRUG MECHANISM; DRUG PROTEIN BINDING; GENE; GENE CONTROL; GENE EXPRESSION PROFILING; HUMAN; HUMAN CELL; IC 50; INSULIN INDUCED GENE 1; LIPID METABOLISM; MATRIX ASSISTED LASER DESORPTION IONIZATION TIME OF FLIGHT MASS SPECTROMETRY; MICROARRAY ANALYSIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ANALYSIS; UPREGULATION;

ANIMALS; ANTICARCINOGENIC AGENTS; ANTINEOPLASTIC AGENTS, PHYTOGENIC; CELL LINE, TUMOR; DOGS; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; MICE; MODELS, ANIMAL; TRITERPENES;

EID: 63849111753     PISSN: 00142972     EISSN: 13652362     Source Type: Journal    
DOI: 10.1111/j.1365-2362.2009.02105.x     Document Type: Article

References (36)

1. Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol 2005 100 : 72 9.
2. 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.
3. Eiznhamer DA, Xu ZQ. Betulinic acid: a promising anticancer candidate. IDrugs 2004 7 : 359 73.
4. 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 51.
5. 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 64.
6. 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 8.
7. Schmidt ML, Kuzmanoff KL, Ling-Indeck L, Pezzuto JM. Betulinic acid induces apoptosis in human neuroblastoma cell lines. Eur J Cancer 1997 33 : 2007 10.
8. 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 40.
9. 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 USA 2003 100 : 13555 60.
10. Ehrhardt H, Fulda S, Führer M, Debatin KM, Jeremias I. Betulinic acid-induced apoptosis in leukemia cells. Leukemia 2004 18 : 1406 12.
11. Fulda S, Jeremias I, Debatin KM. Cooperation of betulinic acid and TRAIL to induce apoptosis in tumor cells. Oncogene 2004 23 : 7611 20.
12. Thallinger C, Wolschek MF, Maierhofer H, Skvara H, Pehamberger H, Monia BP et al. Mcl-1 is a novel therapeutic target for human sarcoma: synergistic inhibition of human sarcoma xenotransplants by a combination of Mcl-1 antisense oligonucleotides with low-dose cyclophosphamide. Clin Cancer Res 2004 10 : 4185 91.
13. Selzer E, Thallinger C, Hoeller C, Oberkleiner P, Wacheck V, Pehamberger H et al. Betulinic acid-induced Mcl-1 expression in human melanoma-mode of action and functional significance. Mol Med 2002 8 : 877 84.
14. 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 75.
15. 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 2005 8 : 1135 43.
16. 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 30.
17. 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 86.
18. Kasperczyk H, La Ferla-Brühl 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 56.
19. Huang L, Ho P, Chen CH. Activation and inhibition of the proteasome by betulinic acid and its derivatives. FEBS Lett 2007 581 : 4955 9.
20. Chowdhury AR, Mandal S, Goswami A, Ghosh M, Mandal L, Chakraborty D et al. Dihydrobetulinic acid induces apoptosis in Leishmania donovani by targeting DNA topoisomerase I and II: implications in antileishmanial therapy. Mol Med 2003 9 : 26 36.
21. 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 58.
22. 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 4.
23. Chintharlapalli S, Papineni S, Liu S, Jutooru I, Chadalapaka G, Cho SD et al. 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 28 : 2337 46.
24. 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 23.
25. Jansen B, Wadl H, Inoue SA, Trülzsch B, Selzer E, Duchêne M et al. Phosphorothioate oligonucleotides reduce melanoma growth in a SCID-hu mouse model by a nonantisense mechanism. Antisense Res Dev 1995 5 : 271 7.
26. Modiano JF, Ritt MG, Wojcieszyn J, Smith R III. Growth arrest of melanoma cells is differentially regulated by contact inhibition and serum deprivation. DNA Cell Biol 1999 18 : 357 67.
27. DeVinney R, Gold WM. Establishment of two dog mastocytoma cell lines in continuous culture. Am J Respir Cell Mol Biol 1990 3 : 413 20.
28. Kovar H, Auinger A, Jug G, Aryee D, Zoubek A, Salzer-Kuntschik M et al. Narrow spectrum of infrequent p53 mutations and absence of MDM2 amplification in Ewing tumours. Oncogene 1993 8 : 2683 90.
29. Anderson MJ, Casey G, Fasching CL, Stanbridge EJ. Evidence that wild-type TP53, and not genes on either chromosome 1 or 11, controls the tumorigenic phenotype of the human fibrosarcoma HT1080. Genes Chromosomes Cancer 1994 9 : 266 81.
30. Vollmer CM, Ribas A, Butterfield LH, Dissette VB, Andrews KJ, Eilber FC et al. p53 selective and nonselective replication of an E1B-deleted adenovirus in hepatocellular carcinoma. Cancer Res 1999 59 : 4369 74.
31. 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 lnvest Dermatol 2000 114 : 935 40.
32. Bensch WR, Gadski RA, Bean JS, Beavers LS, Schmidt RJ, Perry DN et al. Effects of LY295427, a low-density lipoprotein (LDL) receptor up-regulator, on LDL receptor gene transcription and cholesterol metabolism in normal and hypercholesterolemic hamsters. J Pharmacol Exp Ther 1999 289 : 85 92.
33. Janowski BA, Shan B, Russell DW. The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols. J Biol Chem 2001 276 : 45408 16.
34. Janowski BA. The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP. Proc Natl Acad Sci U S A 2002 99 : 12675 80.
35. Lin HS, Rampersaud AA, Archer RA, Pawlak JM, Beavers LS, Schmidt RJ et al. Synthesis and biological evaluation of a new series of sterols as potential hypocholesterolemic agents. J Med Chem 1995 38 : 277 88.
36. Grommes C, Landreth GE, Heneka MT. Antineoplastic effects of peroxisome proliferator-activated receptor gamma agonists. Lancet Oncol 2004 5 : 419 29.