In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465 - PubMed (original) (raw)

doi: 10.1111/j.1365-2141.2009.07891.x. Epub 2009 Sep 14.

Douglas W McMillin, Jake Delmore, Nicholas Mitsiades, Patrick Hayden, Steffen Klippel, Teru Hideshima, Dharminder Chauhan, Nikhil C Munshi, Carolyn A Buser, John Pollard, Paul G Richardson, Kenneth C Anderson, Constantine S Mitsiades

Affiliations

In vitro anti-myeloma activity of the Aurora kinase inhibitor VE-465

Joseph M Negri et al. Br J Haematol. 2009 Dec.

Abstract

This study characterized the preclinical anti-myeloma activity of VE465, a low molecular weight pan-Aurora kinase inhibitor. After 96-h drug exposure, several multiple myeloma (MM) cell lines were more sensitive to VE465 compared to non-malignant cells. The anti-MM activity of VE465 was maintained in the presence of interleukin-6 and, interestingly, enhanced by co-culture with stromal cells. However, primary MM cells were less responsive than cell lines. Combinations with dexamethasone (Dex), doxorubicin (Doxo) and bortezomib showed no antagonism. Our study highlights the potential role of the tumour microenvironment in modulating the activity of this drug class.

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Figures

Figure 1

Figure 1. In vitro anti-myeloma activity of VE465

Viability following treatment with VE465 on MM cell lines (N=3 replicates per condition) (A), and primary CD138+ plasma cells selected from bone marrow aspirates (N=6 replicates per condition) (B). Cell death commitment assay of MM.1S cells following treatment with VE465 (N=2 replicates per condition) (C). Cell Cycle Analysis of MM.1S cells treated with VE465 (single analysis per condition) (D). Data of panels A, B, and C, are presented as % viability compared to untreated controls.

Figure 1

Figure 1. In vitro anti-myeloma activity of VE465

Viability following treatment with VE465 on MM cell lines (N=3 replicates per condition) (A), and primary CD138+ plasma cells selected from bone marrow aspirates (N=6 replicates per condition) (B). Cell death commitment assay of MM.1S cells following treatment with VE465 (N=2 replicates per condition) (C). Cell Cycle Analysis of MM.1S cells treated with VE465 (single analysis per condition) (D). Data of panels A, B, and C, are presented as % viability compared to untreated controls.

Figure 1

Figure 1. In vitro anti-myeloma activity of VE465

Viability following treatment with VE465 on MM cell lines (N=3 replicates per condition) (A), and primary CD138+ plasma cells selected from bone marrow aspirates (N=6 replicates per condition) (B). Cell death commitment assay of MM.1S cells following treatment with VE465 (N=2 replicates per condition) (C). Cell Cycle Analysis of MM.1S cells treated with VE465 (single analysis per condition) (D). Data of panels A, B, and C, are presented as % viability compared to untreated controls.

Figure 1

Figure 1. In vitro anti-myeloma activity of VE465

Viability following treatment with VE465 on MM cell lines (N=3 replicates per condition) (A), and primary CD138+ plasma cells selected from bone marrow aspirates (N=6 replicates per condition) (B). Cell death commitment assay of MM.1S cells following treatment with VE465 (N=2 replicates per condition) (C). Cell Cycle Analysis of MM.1S cells treated with VE465 (single analysis per condition) (D). Data of panels A, B, and C, are presented as % viability compared to untreated controls.

Figure 2

Figure 2. VE465 overcomes protective effects of the bone marrow milieu

Viability of MM cell lines treated with VE465 in the presence or absence of the bone-marrow stromal cell line HS-5 (N=5 replicates per condition) (A), or the presence or absence of exogenous IL-6 (10 ng/ml; N=3 replicates per condition) (B). Data are presented as % viability compared to untreated controls. DEX, dexamethasone

Figure 2

Figure 2. VE465 overcomes protective effects of the bone marrow milieu

Viability of MM cell lines treated with VE465 in the presence or absence of the bone-marrow stromal cell line HS-5 (N=5 replicates per condition) (A), or the presence or absence of exogenous IL-6 (10 ng/ml; N=3 replicates per condition) (B). Data are presented as % viability compared to untreated controls. DEX, dexamethasone

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