Halofuginone inhibits multiple myeloma growth in vitro and in vivo and enhances cytotoxicity of conventional and novel agents

British Journal of Haematology

Volumn 157, Issue 6, 2012, Pages 718-731

  Leiba, Merav ^a,b   Jakubikova, Jana ^a,c   Klippel, Steffen ^a   Mitsiades, Constantine S ^a   Hideshima, Teru ^a   Tai, Yu Tzu ^a   Leiba, Adi ^d   Pines, Mark ^e   Richardson, Paul G ^a   Nagler, Arnon ^b   Anderson, Kenneth C ^a  

^a DANA FARBER CANCER INSTITUTE   (United States)

^b SHEBA MEDICAL CENTER   (Israel)

^c CANCER RESEARCH INSTITUTE   (Slovakia)

^d HARVARD MEDICAL SCHOOL   (United States)

^e VOLCANI CENTER   (Israel)

Author keywords

C jun; Halofuginone; JNK; P 53; TGF

Indexed keywords

CASPASE 3; CASPASE 8; CASPASE 9; DEXAMETHASONE; DOXORUBICIN; HALOFUGINONE; HEAT SHOCK PROTEIN 27; LENALIDOMIDE; MELPHALAN; MITOGEN ACTIVATED PROTEIN KINASE P38; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE; PROTEIN C JUN; PROTEIN MCL 1; PROTEIN P53; STRESS ACTIVATED PROTEIN KINASE; X LINKED INHIBITOR OF APOPTOSIS;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; APOPTOSIS; ARTICLE; CANCER INHIBITION; CELL CYCLE G0 PHASE; CELL CYCLE G1 PHASE; COCULTURE; CONTROLLED STUDY; CYTOTOXICITY; DRUG MECHANISM; DRUG POTENTIATION; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; HUMAN; HUMAN CELL; HUMAN CELL CULTURE; IN VITRO STUDY; IN VIVO STUDY; MITOCHONDRIAL MEMBRANE POTENTIAL; MITOSIS INHIBITION; MOUSE; MULTIPLE MYELOMA; NONHUMAN; PERIPHERAL BLOOD MONONUCLEAR CELL; PRIORITY JOURNAL; TUMOR XENOGRAFT;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CASPASES; CELL LINE, TUMOR; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SYNERGISM; FEMALE; G0 PHASE; G1 PHASE; HUMANS; JNK MITOGEN-ACTIVATED PROTEIN KINASES; MALE; MEMBRANE POTENTIAL, MITOCHONDRIAL; MICE; MICE, SCID; MULTIPLE MYELOMA; P38 MITOGEN-ACTIVATED PROTEIN KINASES; PHOSPHORYLATION; PIPERIDINES; PROTO-ONCOGENE PROTEINS C-BCL-2; QUINAZOLINONES; TUMOR SUPPRESSOR PROTEIN P53; X-LINKED INHIBITOR OF APOPTOSIS PROTEIN; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84861532334     PISSN: 00071048     EISSN: 13652141     Source Type: Journal    
DOI: 10.1111/j.1365-2141.2012.09120.x     Document Type: Article

References (52)

1. Abramovitch, R., Dafni, H., Neeman, M., Nagler, A. & Pines, M. (1999) Inhibition of neovascularization and tumor growth, and facilitation of wound repair, by halofuginone, an inhibitor of collagen type I synthesis. Neoplasia, 1, 321-329.
2. Abramovitch, R., Itzik, A., Harel, H., Nagler, A., Vlodavsky, I. & Siegal, T. (2004) Halofuginone inhibits angiogenesis and growth in implanted metastatic rat brain tumor model-an MRI study. Neoplasia, 6, 480-489.
3. Anderson, K.C. (2005) Lenalidomide and thalidomide: mechanisms of action-similarities and differences. Seminars in Hematology, 42, S3-S8.
4. Chauhan, D., Li, G., Hideshima, T., Podar, K., Mitsiades, C., Mitsiades, N., Munshi, N., Kharbanda, S. & Anderson, K.C. (2003) JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells. Journal of Biological Chemistry, 278, 17593-17596.
5. Chou, T.C. & Talalay, P. (1984) Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Advances in Enzyme Regulation, 22, 27-55.
6. Dhanasekaran, D.N. & Reddy, E.P. (2008) JNK signaling in apoptosis. Oncogene, 27, 6245-6251.
7. Elkin, M., Ariel, I., Miao, H.Q., Nagler, A., Pines, M., de-Groot, N., Hochberg, A. & Vlodavsky, I. (1999a) Inhibition of bladder carcinoma angiogenesis, stromal support, and tumor growth by halofuginone. Cancer Research, 59, 4111-4118.
8. Elkin, M., Reich, R., Nagler, A., Aingorn, E., Pines, M., de-Groot, N., Hochberg, A. & Vlodavsky, I. (1999b) Inhibition of matrix metalloproteinase-2 expression and bladder carcinoma metastasis by halofuginone. Clinical Cancer Research, 5, 1982-1988.
9. Elkin, M., Miao, H.Q., Nagler, A., Aingorn, E., Reich, R., Hemo, I., Dou, H.L., Pines, M. & Vlodavsky, I. (2000) Halofuginone: a potent inhibitor of critical steps in angiogenesis progression. FASEB Journal, 14, 2477-2485.
10. Elmore, S. (2007) Apoptosis: a review of programmed cell death. Toxicologic Pathology, 35, 495-516.
11. Feng, R., Oton, A., Mapara, M.Y., Anderson, G., Belani, C. & Lentzsch, S. (2007) The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. British Journal of Haematology, 139, 385-397.
12. Fuchs, S.Y., Adler, V., Pincus, M.R. & Ronai, Z. (1998) MEKK1/JNK signaling stabilizes and activates p53. Proceedings of the National Academy of Sciences of the United States of America, 95, 10541-10546.
13. Gavish, Z., Pinthus, J.H., Barak, V., Ramon, J., Nagler, A., Eshhar, Z. & Pines, M. (2002) Growth inhibition of prostate cancer xenografts by halofuginone. Prostate, 51, 73-83.
14. Genin, O., Rechavi, G., Nagler, A., Ben-Itzhak, O., Nazemi, K.J. & Pines, M. (2008) Myofibroblasts in pulmonary and brain metastases of alveolar soft-part sarcoma: a novel target for treatment? Neoplasia, 10, 940-948.
15. Gnainsky, Y., Spira, G., Paizi, M., Bruck, R., Nagler, A., Genina, O., Taub, R., Halevy, O. & Pines, M. (2006) Involvement of the tyrosine phosphatase early gene of liver regeneration (PRL-1) in cell cycle and in liver regeneration and fibrosis effect of halofuginone. Cell and Tissue Research, 324, 385-394.
16. Gross, D.J., Reibstein, I., Weiss, L., Slavin, S., Dafni, H., Neeman, M., Pines, M. & Nagler, A. (2003) Treatment with halofuginone results in marked growth inhibition of a von Hippel-Lindau pheochromocytoma in vivo. Clinical Cancer Research, 9, 3788-3793.
17. Hideshima, T., Mitsiades, C., Akiyama, M., Hayashi, T., Chauhan, D., Richardson, P., Schlossman, R., Podar, K., Munshi, N.C., Mitsiades, N. & Anderson, K.C. (2003a) Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341. Blood, 101, 1530-1534.
18. Hideshima, T., Akiyama, M., Hayashi, T., Richardson, P., Schlossman, R., Chauhan, D. & Anderson, K.C. (2003b) Targeting p38 MAPK inhibits multiple myeloma cell growth in the bone marrow milieu. Blood, 101, 703-705.
19. Hideshima, T., Bergsagel, P.L., Kuehl, W.M. & Anderson, K.C. (2004) Advances in biology of multiple myeloma: clinical applications. Blood, 104, 607-618.
20. Hideshima, T., Catley, L., Yasui, H., Ishitsuka, K., Raje, N., Mitsiades, C., Podar, K., Munshi, N.C., Chauhan, D., Richardson, P.G. & Anderson, K.C. (2006) Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood, 107, 4053-4062.
21. Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P.G. & Anderson, K.C. (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature Reviews Cancer, 7, 585-598.
22. Jakubikova, J., Cervi, D., Ooi, M., Kim, K., Nahar, S., Klippel, S., Cholujova, D., Leiba, M., Daley, J.F., Delmore, J., Negri, J., Blotta, S., McMillin, D.W., Hideshima, T., Richardson, P.G., Sedlak, J., Anderson, K.C. & Mitsiades, C.S. (2011) Anti-tumor activity and signaling events triggered by the isothiocyanates, sulforaphane and phenethyl isothiocyanate, in multiple myeloma. Haematologica, 96, 1170-1179.
23. de Jonge, M.J., Dumez, H., Verweij, J., Yarkoni, S., Snyder, D., Lacombe, D., Marreaud, S., Yamaguchi, T., Punt, C.J. & van Oosterom, A. (2006) Phase I and pharmacokinetic study of halofuginone, an oral quinazolinone derivative in patients with advanced solid tumours. European Journal of Cancer, 42, 1768-1774.
24. Kobayashi, T., Kuroda, J., Ashihara, E., Oomizu, S., Terui, Y., Taniyama, A., Adachi, S., Takagi, T., Yamamoto, M., Sasaki, N., Horiike, S., Hatake, K., Yamauchi, A., Hirashima, M. & Taniwaki, M. (2010) Galectin-9 exhibits anti-myeloma activity through JNK and p38 MAP kinase pathways. Leukemia, 24, 843-850.
25. Koon, H.B., Fingleton, B., Lee, J.Y., Geyer, J.T., Cesarman, E., Parise, R.A., Egorin, M.J., Dezube, B.J., Aboulafia, D. & Krown, S.E. (2011) Phase II AIDS Malignancy Consortium Trial of Topical Halofuginone in AIDS-Related Kaposi Sarcoma. Journal of Acquired Immune Deficiency Syndromes, 56, 64-68.
26. Leiba, M., Cahalon, L., Shimoni, A., Lider, O., Zanin-Zhorov, A., Hecht, I., Sela, U., Vlodavsky, I. & Nagler, A. (2006) Halofuginone inhibits NF-kappaB and p38 MAPK in activated T cells. Journal of Leukocyte Biology, 80, 399-406.
27. Liu, K., Sekine, S., Goto, Y., Iijima, K., Yamagishi, I., Kondon, K., Matsukawa, M. & Abe, T. (1998) Halofuginone inhibits neointimal formation of cultured rat aorta in a concentration-dependent fashion in vitro. Heart and Vessels, 13, 18-23.
28. McGaha, T.L., Kodera, T., Spiera, H., Stan, A.C., Pines, M. & Bona, C.A. (2002) Halofuginone inhibition of COL1A2 promoter activity via a c-Jun-dependent mechanism. Arthritis and Rheumatism, 46, 2748-2761.
29. Mitsiades, N., Mitsiades, C.S., Poulaki, V., Chauhan, D., Richardson, P.G., Hideshima, T., Munshi, N.C., Treon, S.P. & Anderson, K.C. (2002a) Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications. Blood, 99, 4525-4530.
30. Mitsiades, N., Mitsiades, C.S., Poulaki, V., Chauhan, D., Fanourakis, G., Gu, X., Bailey, C., Joseph, M., Libermann, T.A., Treon, S.P., Munshi, N.C., Richardson, P.G., Hideshima, T. & Anderson, K.C. (2002b) Molecular sequelae of proteasome inhibition in human multiple myeloma cells. Proceedings of the National Academy of Sciences of the United States of America, 99, 14374-14379.
31. Mitsiades, C.S., Mitsiades, N.S., Richardson, P.G., Munshi, N.C. & Anderson, K.C. (2007) Multiple myeloma: a prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment. Journal of Cellular Biochemistry, 101, 950-968.
32. Nagler, A., Katz, A., Aingorn, H., Miao, H.Q., Condiotti, R., Genina, O., Pines, M. & Vlodavsky, I. (1997) Inhibition of glomerular mesangial cell proliferation and extracellular matrix deposition by halofuginone. Kidney International, 52, 1561-1569.
33. Nagler, A., Ohana, M., Shibolet, O., Shapira, M.Y., Alper, R., Vlodavsky, I., Pines, M. & Ilan, Y. (2004) Suppression of hepatocellular carcinoma growth in mice by the alkaloid coccidiostat halofuginone. European Journal of Cancer, 40, 1397-1403.
34. Olivier, M., Eeles, R., Hollstein, M., Khan, M.A., Harris, C.C. & Hainaut, P. (2002) The IARC TP53 database: new online mutation analysis and recommendations to users. Human Mutation, 19, 607-614.
35. Ooi, M.G., Hayden, P.J., Kotoula, V., McMillin, D.W., Charalambous, E., Daskalaki, E., Raje, N.S., Munshi, N.C., Chauhan, D., Hideshima, T., Buon, L., Clynes, M., O'Gorman, P., Richardson, P.G., Mitsiades, C.S., Anderson, K.C. & Mitsiades, N. (2009) Interactions of the Hdm2/p53 and proteasome pathways may enhance the antitumor activity of bortezomib. Clinical Cancer Research, 15, 7153-7160.
36. Pines, M. & Nagler, A. (1998) Halofuginone: a novel antifibrotic therapy. General Pharmacology, 30, 445-450.
37. Pines, M., Snyder, D., Yarkoni, S. & Nagler, A. (2003) Halofuginone to treat fibrosis in chronic graft-versus-host disease and scleroderma. Biol Blood Marrow Transplant, 9, 417-425.
38. Prabhala, R.H., Pelluru, D., Fulciniti, M., Prabhala, H.K., Nanjappa, P., Song, W., Pai, C., Amin, S., Tai, Y.T., Richardson, P.G., Ghobrial, I.M., Treon, S.P., Daley, J.F., Anderson, K.C., Kutok, J.L. & Munshi, N.C. (2010) Elevated IL-17 produced by TH17 cells promotes myeloma cell growth and inhibits immune function in multiple myeloma. Blood, 115, 5385-5392.
39. Raje, N., Kumar, S., Hideshima, T., Ishitsuka, K., Chauhan, D., Mitsiades, C., Podar, K., Le Gouill, S., Richardson, P., Munshi, N.C., Stirling, D.I., Antin, J.H. & Anderson, K.C. (2004) Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood, 104, 4188-4193.
40. Roffe, S., Hagai, Y., Pines, M. & Halevy, O. (2010) Halofuginone inhibits Smad3 phosphorylation via the PI3K/Akt and MAPK/ERK pathways in muscle cells: effect on myotube fusion. Experimental Cell Research, 316, 1061-1069.
41. Saha, M.N., Jiang, H., Mukai, A. & Chang, H. (2010a) RITA inhibits multiple myeloma cell growth through induction of p53-mediated caspase-dependent apoptosis and synergistically enhances nutlin-induced cytotoxic responses. Molecular Cancer Therapeutics, 9, 3041-3051.
42. Saha, M.N., Jiang, H. & Chang, H. (2010b) Molecular mechanisms of nutlin-induced apoptosis in multiple myeloma: evidence for p53-transcription-dependent and -independent pathways. Cancer Biology & Therapy, 10, 567-578.
43. Saha, M.N., Jiang, H., Jayakar, J., Reece, D., Branch, D.R. & Chang, H. (2010c) MDM2 antagonist nutlin plus proteasome inhibitor velcade combination displays a synergistic anti-myeloma activity. Cancer Biology & Therapy, 9, 936-944.
44. Sheffer, Y., Leon, O., Pinthus, J.H., Nagler, A., Mor, Y., Genin, O., Iluz, M., Kawada, N., Yoshizato, K. & Pines, M. (2007) Inhibition of fibroblast to myofibroblast transition by halofuginone contributes to the chemotherapy-mediated antitumoral effect. Molecular Cancer Therapeutics, 6, 570-577.
45. Sluss, H.K., Barrett, T., Derijard, B. & Davis, R.J. (1994) Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Molecular and Cellular Biology, 14, 8376-8384.
46. Spector, I., Honig, H., Kawada, N., Nagler, A., Genin, O. & Pines, M. (2010) Inhibition of pancreatic stellate cell activation by halofuginone prevents pancreatic xenograft tumor development. Pancreas, 39, 1008-1015.
47. Stuhmer, T., Chatterjee, M., Hildebrandt, M., Herrmann, P., Gollasch, H., Gerecke, C., Theurich, S., Cigliano, L., Manz, R.A., Daniel, P.T., Bommert, K., Vassilev, L.T. & Bargou, R.C. (2005) Nongenotoxic activation of the p53 pathway as a therapeutic strategy for multiple myeloma. Blood, 106, 3609-3617.
48. Sundrud, M.S., Koralov, S.B., Feuerer, M., Calado, D.P., Kozhaya, A.E., Rhule-Smith, A., Lefebvre, R.E., Unutmaz, D., Mazitschek, R., Waldner, H., Whitman, M., Keller, T. & Rao, A. (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science, 324, 1334-1338.
49. Tacheau, C., Michel, L., Farge, D., Mauviel, A. & Verrecchia, F. (2007) Involvement of ERK signaling in halofuginone-driven inhibition of fibroblast ability to contract collagen lattices. European Journal of Pharmacology, 573, 65-69.
50. Tai, Y.T., Fulciniti, M., Hideshima, T., Song, W., Leiba, M., Li, X.F., Rumizen, M., Burger, P., Morrison, A., Podar, K., Chauhan, D., Tassone, P., Richardson, P., Munshi, N.C., Ghobrial, I.M. & Anderson, K.C. (2007) Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. Blood, 110, 1656-1663.
51. Taras, D., Blanc, J.F., Rullier, A., Dugot-Senant, N., Laurendeau, I., Bieche, I., Pines, M. & Rosenbaum, J. (2006) Halofuginone suppresses the lung metastasis of chemically induced hepatocellular carcinoma in rats through MMP inhibition. Neoplasia, 8, 312-318.
52. Wendling, J., Marchand, A., Mauviel, A. & Verrecchia, F. (2003) 5-fluorouracil blocks transforming growth factor-beta-induced alpha 2 type I collagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 activation. Molecular Pharmacology, 64, 707-713.