Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma

Suzanne Trudel, Hua Li Zhi, Jennifer Rauw, Rodger E. Tiedemann, Yan Wen Xiao, Alexander Keith Stewart

Research output: Contribution to journalArticle

182 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5430-5438
Number of pages9
JournalBlood
Volume109
Issue number12
DOIs
StatePublished - Jun 15 2007

Fingerprint

Multiple Myeloma
Melphalan
Cytotoxicity
Dexamethasone
Bone
Bone Marrow
Cells
obatoclax
Cell Line
Lymphocytes
Coculture Techniques
Cytochromes c
Inhibitory Concentration 50
Tumors
Interleukin-6
Neoplasms
Cell Survival
Blood
Up-Regulation
Molecules

ASJC Scopus subject areas

  • Hematology

Cite this

Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. / Trudel, Suzanne; Zhi, Hua Li; Rauw, Jennifer; Tiedemann, Rodger E.; Xiao, Yan Wen; Stewart, Alexander Keith.

In: Blood, Vol. 109, No. 12, 15.06.2007, p. 5430-5438.

Research output: Contribution to journalArticle

Trudel, Suzanne ; Zhi, Hua Li ; Rauw, Jennifer ; Tiedemann, Rodger E. ; Xiao, Yan Wen ; Stewart, Alexander Keith. / Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma. In: Blood. 2007 ; Vol. 109, No. 12. pp. 5430-5438.
@article{428d404665be445b94fd6d5b898018f0,
title = "Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma",
abstract = "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.",
author = "Suzanne Trudel and Zhi, {Hua Li} and Jennifer Rauw and Tiedemann, {Rodger E.} and Xiao, {Yan Wen} and Stewart, {Alexander Keith}",
year = "2007",
month = "6",
day = "15",
doi = "10.1182/blood-2006-10-047951",
language = "English (US)",
volume = "109",
pages = "5430--5438",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "12",

}

TY - JOUR

T1 - Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma

AU - Trudel, Suzanne

AU - Zhi, Hua Li

AU - Rauw, Jennifer

AU - Tiedemann, Rodger E.

AU - Xiao, Yan Wen

AU - Stewart, Alexander Keith

PY - 2007/6/15

Y1 - 2007/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34249982915&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34249982915&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-10-047951

DO - 10.1182/blood-2006-10-047951

M3 - Article

C2 - 17332241

AN - SCOPUS:34249982915

VL - 109

SP - 5430

EP - 5438

JO - Blood

JF - Blood

SN - 0006-4971

IS - 12

ER -