21. DiDonato JA, Hayakawa M, Rothwarf DM, Zandi E, Karin M (1997) A cytokineresponsive IkappaB kinase that activates the transcription factor NF- kappaB. Nature 388: 548–554. 22. Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, et al. (2001) The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 61: 3071–3076. 23. Hideshima T, Ikeda H, Chauhan D, Okawa Y, Raje N, et al. (2009) Bortezomib induces canonical nuclear factor-kappaB activation in multiple myeloma cells. Blood 114: 1046–1052. 24. Lounnas N, Frelin C, Gonthier N, Colosetti P, Sirvent A, et al. (2009) NF- kappaB inhibition triggers death of imatinib-sensitive and imatinib-resistant chronic myeloid leukemia cells including T315I Bcr-Abl mutants. Int J Cancer 125: 308–317. 25. Sors A, Jean-Louis F, Begue E, Parmentier L, Dubertret L, et al. (2008) Inhibition of IkappaB kinase subunit 2 in cutaneous T-cell lymphoma down- regulates nuclear factor-kappaB constitutive activation, induces cell death, and potentiates the apoptotic response to antineoplastic chemotherapeutic agents. Clin Cancer Res 14: 901–911. 26. Griessinger E, Frelin C, Cuburu N, Imbert V, Dageville C, et al. (2008) Preclinical targeting of NF-kappaB and FLT3 pathways in AML cells. Leukemia 22: 1466–1469. 27. Romagnoli M, Desplanques G, Maiga S, Legouill S, Dreano M, et al. (2007) Canonical nuclear factor kappaB pathway inhibition blocks myeloma cell growth and induces apoptosis in strong synergy with TRAIL. Clin Cancer Res 13: 6010–6018. 28. Jordheim LP, Plesa A, Dreano M, Cros-Perrial E, Keime C, et al. (2011) Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868. Cancer Chemotherapy and Pharmacology;in press, doi: 10.1007/s00280-010-1458-y. 29. Jordheim LP, Cros E, Gouy MH, Galmarini CM, Peyrottes S, et al. (2004) Characterization of a gemcitabine-resistant murine leukemic cell line: reversion of in vitro resistance by a mononucleotide prodrug. Clin Cancer Res 10: 5614–5621. 30. Sahara N, Takeshita A, Ono T, Sugimoto Y, Kobayashi M, et al. (2006) Role for interleukin-6 and insulin-like growth factor-I via PI3-K/Akt pathway in the proliferation of CD562 and CD56+ multiple myeloma cells. Exp Hematol 34: 736–744. 31. Raje N, Kumar S, Hideshima T, Ishitsuka K, Chauhan D, et al. (2004) Combination of the mTOR inhibitor rapamycin and CC-5013 has synergistic activity in multiple myeloma. Blood 104: 4188–4193. 32. Hideshima T, Chauhan D, Richardson P, Mitsiades C, Mitsiades N, et al. (2002) NFkappa B as a therapeutic target in multiple myeloma. J Biol Chem 277: 16639–16647. 33. Birmann BM, Tamimi RM, Giovannucci E, Rosner B, Hunter DJ, et al. (2009) Insulinlike growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev 18: 282–288. 34. Franchimont N, Gangji V, Durant D, Canalis E (1997) Interleukin-6 with its soluble receptor enhances the expression of insulin-like growth factor-I in osteoblasts. Endocrinology 138: 5248–5255. Anti-IGF-1R Potentiate the Effect of AS602868 35. Guo YQ, Chen SL (2006) [The significance of IGF-1, VEGF, IL-6 in multiple myeloma progression]. Zhonghua Xue Ye Xue Za Zhi 27: 231–234. 36. Hideshima T, Podar K, Chauhan D, Anderson KC (2005) Cytokines and signal transduction. Best Pract Res Clin Haematol 18: 509–524. 37. Jelinek DF (1999) Mechanisms of myeloma cell growth control. Hematol Oncol Clin North Am 13: 1145–1157. 38. Sprynski AC, Hose D, Caillot L, Reme T, Shaughnessy JD, Jr., et al. (2009) The role of IGF-1 as a major growth factor for myeloma cell lines and the prognostic relevance of the expression of its receptor. Blood 113: 4614–4626. 39. Jourdan M, De Vos J, Mechti N, Klein B (2000) Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. Cell Death Differ 7: 1244–1252. 40. Jelinek DF, Witzig TE, Arendt BK (1997) A role for insulin-like growth factor in the regulation of IL-6-responsive human myeloma cell line growth. J Immunol 159: 487–496. 41. Heron-Milhavet L, LeRoith D (2002) Insulin-like growth factor I induces MDM2- dependent degradation of p53 via the p38 MAPK pathway in response to DNA damage. J Biol Chem 277: 15600–15606. 42. Qiang YW, Kopantzev E, Rudikoff S (2002) Insulinlike growth factor-I signalling in multiple myeloma: downstream elements, functional correlates, and pathway crosstalk. Blood 99: 4138–4146. 43. Warshamana-Greene GS, Litz J, Buchdunger E, Hofmann F, Garcia- Echeverria C, et al. (2004) The insulin-like growth factor-I (IGF-I) receptor kinase inhibitor NVPADW742, in combination with STI571, delineates a spectrum of dependence of small cell lung cancer on IGF-I and stem cell factor signalling. Mol Cancer Ther 3: 527–535. 44. Burtrum D, Zhu Z, Lu D, Anderson DM, Prewett M, et al. (2003) A fully human monoclonal antibody to the insulin-like growth factor I receptor blocks liganddependent signalling and inhibits human tumor growth in vivo. Cancer Res 63: 8912–8921. 45. Bohula EA, Playford MP, Macaulay VM (2003) Targeting the type 1 insulin-like growth factor receptor as anti-cancer treatment. Anticancer Drugs 14: 669–682. 46. Blum G, Gazit A, Levitzki A (2003) Development of new insulin-like growth factor-1 receptor kinase inhibitors using catechol mimics. J Biol Chem 278: 40442–40454. 47. Warshamana-Greene GS, Litz J, Buchdunger E, Garcia-Echeverria C, Hofmann F, et al. (2005) The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, sensitizes small cell lung cancer cell lines to the effects of chemotherapy. Clin Cancer Res 11: 1563–1571. 48. Ni H, Ergin M, Huang Q, Qin JZ, Amin HM, et al. (2001) Analysis of expression of nuclear factor kappa B (NF-kappa B) in multiple myeloma: downregulation of NFkappa B induces apoptosis. Br J Haematol 115: 279–286. 49. Chauhan D, Hideshima T, Mitsiades C, Richardson P, Anderson KC (2005) Proteasome inhibitor therapy in multiple myeloma. Mol Cancer Ther 4: 686–692. 50. Sunwoo JB, Chen Z, Dong G, Yeh N, Crowl Bancroft C, et al. (2001) Novel proteasome inhibitor PS-341 inhibits activation of nuclear factor-kappa B, cell survival, tumor growth, and angiogenesis in squamous cell carcinoma. Clin Cancer Res 7: 1419–1428. PLoS ONE | www.plosone.org 9 July 2011 | Volume 6 | Issue 7 | e22641