The Bcl-2 Family Protein Inhibitor, ABT-737, Has Substantial Antimyeloma Activity and Shows Synergistic Effect with Dexamethasone and Melphalan

Clinical Cancer Research - Tập 13 Số 2 - Trang 621-629 - 2007
Suzanne Trudel1, A. Keith Stewart2, Zhihua Li1, Yamin Shu1,3, Sheng Liang1, Young Trieu1, Donna Reece1, Josh Paterson1, Dingyan Wang1,3, Xiao‐Yan Wen1,3
11Department of Medical Oncology and Hematology, Princess Margaret Hospital, University Health Network, and Department of Medicine, University of Toronto;
23Division of Hematology-Oncology, Mayo Clinic, Scottsdale, Arizona
32Division of Cell and Molecular Biology, Toronto General Research Institute, Toronto General Hospital, University Health Network, and McLaughlin Centre for Molecular Medicine, Toronto, Canada; and

Tóm tắt

Abstract Purpose: The aim of this study is to investigate the antimyeloma activity of a novel Bcl-2 family inhibitor, ABT-737, in preclinical treatment of multiple myeloma. Experimental Design: The antimyeloma activity of ABT-737 was evaluated in cultured myeloma cell lines and patient myeloma samples, and in a xenograft mouse myeloma model. Drug combination therapy using ABT-737 with other commonly used myeloma drugs was also investigated. Results: MY5 and JJN3 cell lines exhibited the most sensitivity to ABT-737 with an EC50 of 0.2 and 0.5 μmol/L, respectively, with increased cell apoptosis and elevated activated caspase-3. We identified two distinct groups of myeloma patient samples that were either sensitive or resistant to the drug. Four of 15 patient bone marrow samples (27%) were highly sensitive to ABT-737 at doses of 0.25 and 0.5 μmol/L, which eliminated 80% to 90% of myeloma cells as a result of cellular apoptosis 3 days after drug treatment. ABT-737 showed a synergistic effect when combined with dexamethasone or melphalan in inducing myeloma cell death. Furthermore, the dexamethasone-resistant MM1(Dex)R myeloma cell line was highly sensitive to 0.2 μmol/L ABT-737. As determined by colony assay, little or no detectable toxicity to patient hematologic progenitor cells was observed at 1 μmol/L ABT-737. ABT-737 dose dependently suppressed tumor growth in a xenograft MY5 mouse model. Conclusions: These studies show substantial antimyeloma activity of ABT-737 as a single agent or in combination with dexamethasone or melphalan and suggest a rationale for future clinical trials.

Từ khóa


Tài liệu tham khảo

Chen Q, Ray S, Hussein MA, Srkalovic G, Almasan A. Role of Apo2L/TRAIL and Bcl-2-family proteins in apoptosis of multiple myeloma. Leuk Lymphoma 2003;44:1209–14.

Martinou JC, Desagher S, Antonsson B. Cytochrome c release from mitochondria: all or nothing. Nat Cell Biol 2000;2:E41–3.

Gazitt Y. TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells. Leukemia 1999;13:1817–24.

Mitsiades CS, Treon SP, Mitsiades N, et al. TRAIL/Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma: therapeutic applications. Blood 2001;98:795–804.

Puthier D, Derenne S, Barille S, et al. Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells. Br J Haematol 1999;107:392–5.

Spets H, Stromberg T, Georgii-Hemming P, Siljason J, Nilsson K, Jernberg-Wiklund H. Expression of the bcl-2 family of pro- and anti-apoptotic genes in multiple myeloma and normal plasma cells: regulation during interleukin-6(IL-6)-induced growth and survival. Eur J Haematol 2002;69:76–89.

Anderson KC, Kyle RA, Dalton WS, et al. Multiple myeloma: new insights and therapeutic approaches. Hematology 2000;:147–65.

Wen XY, Stewart AK, Sooknanan RR, et al. Identification of c-myc promoter-binding protein and X-box binding protein 1 as interleukin-6 target genes in human multiple myeloma cells. Int J Oncol 1999;15:173–8.

Oltersdorf T, Elmore SW, Shoemaker AR, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435:677–81.

Cory S, Adams JM. Killing cancer cells by flipping the Bcl-2/Bax switch. Cancer Cell 2005;8:5–6.

Trudel S, Li ZH, Wei E, et al. CHIR-258, a novel, multitargeted tyrosine kinase inhibitor for the potential treatment of t(4;14) multiple myeloma. Blood 2005;105:2941–8.

Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul 1984;22:27–55.

Catley L, Weisberg E, Kiziltepe T, et al. Aggresome induction by proteasome inhibitor bortezomib and {α}-tubulin hyperacetylation by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells. Blood 2006;108:3441–9.

Tu Y, Renner S, Xu F, et al. BCL-X expression in multiple myeloma: possible indicator of chemoresistance. Cancer Res 1998;58:256–62.

Chanan-Khan A. Bcl-2 antisense therapy in hematologic malignancies. Curr Opin Oncol 2004;16:581–5.

van de Donk NW, Kamphuis MM, van Kessel B, Lokhorst HM, Bloem AC. Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels. Blood 2003;102:3354–62.

van de Donk NW, de Weerdt O, Veth G, et al. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 2004;18:1078–84.

Dvorakova K, Payne CM, Landowski TH, Tome ME, Halperin DS, Dorr RT. Imexon activates an intrinsic apoptosis pathway in RPMI8226 myeloma cells. Anticancer Drugs 2002;13:1031–42.

Stewart AK, Li ZH, Wen XY, et al. Studies of the Bcl inhibitor GX15-070 in multiple myeloma demonstrate substantial pre-clinical activity. Blood 2005;106:451a.

Zhai D, Jin C, Satterthwait AC, Reed JC. Comparison of chemical inhibitors of antiapoptotic Bcl-2-family proteins. Cell Death Differ 2006;13:1419–21.

Letai A, Bassik MC, Walensky LD, Sorcinelli MD, Weiler S, Korsmeyer SJ. Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell 2002;2:183–92.

Certo M, Del Gaizo Moore V, Nishino M, et al. Mitochondria primed by death signals determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 2006;9:351–65.

Pollett JB, Trudel S, Stern D, Li ZH, Stewart AK. Overexpression of the myeloma-associated oncogene fibroblast growth factor receptor 3 confers dexamethasone resistance. Blood 2002;100:3819–21.

Gazitt Y, Rothenberg ML, Hilsenbeck SG, Fey V, Thomas C, Montegomrey W. Bcl-2 overexpression is associated with resistance to paclitaxel, but not gemcitabine, in multiple myeloma cells. Int J Oncol 1998;13:839–48.

Kurosawa Y, Pillay S, Greenstein S, Ghias K, Krett NL, Rosen ST. Gene Expression related to glucocorticoid-induced apoptosis in dexamethasone-treated multiple myeloma cells (MM.1S). Blood 2001;98:369.

Gomez-Bougie P, Oliver L, Le Gouill S, Bataille R, Amiot M. Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. Oncogene 2005;24:8076–9.

Gomez-Bougie P, Bataille R, Amiot M. The imbalance between Bim and Mcl-1 expression controls the survival of human myeloma cells. Eur J Immunol 2004;34:3156–64.

Hideshima T, Richardson P, Chauhan D, et al. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Res 2001;61:3071–6.

Hideshima T, Chauhan D, Hayashi T, et al. Proteasome inhibitor PS-341 abrogates IL-6 triggered signaling cascades via caspase-dependent downregulation of gp130 in multiple myeloma. Oncogene 2003;22:8386–93.

Thông tin
Thông tin xuất bản

Clinical Cancer Research

Tập 13 Số 2

621-629

Thông tin tác giả