|
|
Blood, 15 June 2007, Vol. 109, No. 12, pp. 5430-5438.
Prepublished online as a Blood First Edition Paper on March 13, 2007; DOI 10.1182/blood-2006-10-047951.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma
Suzanne Trudel1,
Zhi Hua Li1,
Jennifer Rauw1,
Rodger E. Tiedemann2,
Xiao Yan Wen1, and
A. Keith Stewart1,2
1 Hematology-Oncology, Princess Margaret Hospital, Toronto, ON;
2 Hematology-Oncology, Mayo Clinic College of Medicine, Scottsdale, AZ
Bcl family members Bcl-2, Bcl-xL, and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC50 of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-xL. Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070–induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow–derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
P. Hersey, L. Bastholt, V. Chiarion-Sileni, G. Cinat, R. Dummer, A. M. M. Eggermont, E. Espinosa, A. Hauschild, I. Quirt, C. Robert, et al.
Small molecules and targeted therapies in distant metastatic disease
Ann. Onc.,
August 1, 2009;
20(suppl_6):
vi35 - vi40.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. W. Ma and A. A. Adjei
Novel Agents on the Horizon for Cancer Therapy
CA Cancer J Clin,
March 1, 2009;
59(2):
111 - 137.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. H. Kang and C. P. Reynolds
Bcl-2 Inhibitors: Targeting Mitochondrial Apoptotic Pathways in Cancer Therapy
Clin. Cancer Res.,
February 15, 2009;
15(4):
1126 - 1132.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. O'Brien, D. F. Claxton, M. Crump, S. Faderl, T. Kipps, M. J. Keating, J. Viallet, and B. D. Cheson
Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia
Blood,
January 8, 2009;
113(2):
299 - 305.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Huang, K. Okumura, and F. A. Sinicrope
BH3 Mimetic Obatoclax Enhances TRAIL-Mediated Apoptosis in Human Pancreatic Cancer Cells
Clin. Cancer Res.,
January 1, 2009;
15(1):
150 - 159.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Krug and M. C. Pietanza
Emerging Therapies in Small Cell Lung Cancer
ASCO Educational Book,
January 1, 2009;
2009(1):
455 - 460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Schimmer, S. O'Brien, H. Kantarjian, J. Brandwein, B. D. Cheson, M. D. Minden, K. Yee, F. Ravandi, F. Giles, A. Schuh, et al.
A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies
Clin. Cancer Res.,
December 15, 2008;
14(24):
8295 - 8301.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Sinicrope, R. L. Rego, K. Okumura, N. R. Foster, M. J. O'Connell, D. J. Sargent, and H. E. Windschitl
Prognostic Impact of Bim, Puma, and Noxa Expression in Human Colon Carcinomas
Clin. Cancer Res.,
September 15, 2008;
14(18):
5810 - 5818.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. F. Tumilasci, S. Oliere, T. L.-A. Nguyen, A. Shamy, J. Bell, and J. Hiscott
Targeting the Apoptotic Pathway with BCL-2 Inhibitors Sensitizes Primary Chronic Lymphocytic Leukemia Cells to Vesicular Stomatitis Virus-Induced Oncolysis
J. Virol.,
September 1, 2008;
82(17):
8487 - 8499.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. P. Martin, A. Miller, L. Emad, M. Rahmani, T. Walker, C. Mitchell, M. P. Hagan, M. A. Park, A. Yacoub, P. B. Fisher, et al.
Lapatinib Resistance in HCT116 Cells Is Mediated by Elevated MCL-1 Expression and Decreased BAK Activation and Not by ERBB Receptor Kinase Mutation
Mol. Pharmacol.,
September 1, 2008;
74(3):
807 - 822.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. L. Mott, S. F. Bronk, R. A. Mesa, S. H. Kaufmann, and G. J. Gores
BH3-only protein mimetic obatoclax sensitizes cholangiocarcinoma cells to Apo2L/TRAIL-induced apoptosis
Mol. Cancer Ther.,
August 1, 2008;
7(8):
2339 - 2347.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Mao, S.-b. Liang, R. Hurren, M. Gronda, S. Chow, G. W. Xu, X. Wang, R. B. Zavareh, N. Jamal, H. Messner, et al.
Cyproheptadine displays preclinical activity in myeloma and leukemia
Blood,
August 1, 2008;
112(3):
760 - 769.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. A. Sinicrope, R. L. Rego, N. R. Foster, S. N. Thibodeau, S. R. Alberts, H. E. Windschitl, and D. J. Sargent
Proapoptotic Bad and Bid Protein Expression Predict Survival in Stages II and III Colon Cancers
Clin. Cancer Res.,
July 1, 2008;
14(13):
4128 - 4133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Nguyen, R. C. Marcellus, A. Roulston, M. Watson, L. Serfass, S. R. Murthy Madiraju, D. Goulet, J. Viallet, L. Belec, X. Billot, et al.
Small molecule obatoclax (GX15-070) antagonizes MCL-1 and overcomes MCL-1-mediated resistance to apoptosis
PNAS,
December 4, 2007;
104(49):
19512 - 19517.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
