Back to Search Start Over

PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells.

Authors :
Maginn, E. N.
Browne, P. V.
Hayden, P.
Vandenberghe, E.
MacDonagh, B.
Evans, P.
Goodyer, M.
Tewari, P.
Campiani, G.
Butini, S.
Williams, D. C.
Zisterer, D. M.
Lawler, M. P.
McElligott, A. M.
Source :
British Journal of Cancer; 1/18/2011, Vol. 104 Issue 2, p281-289, 9p, 6 Graphs
Publication Year :
2011

Abstract

<bold>Background: </bold>In recent years, much progress has been made in the treatment of multiple myeloma. However, a major limitation of existing chemotherapeutic drugs is the eventual emergence of resistance; hence, the development of novel agents with new mechanisms of action is pertinent. Here, we describe the activity and mechanism of action of pyrrolo-1,5-benzoxazepine-15 (PBOX-15), a novel microtubule-targeting agent, in multiple myeloma cells.<bold>Methods: </bold>The anti-myeloma activity of PBOX-15 was assessed using NCI-H929, KMS11, RPMI8226, and U266 cell lines, and primary myeloma cells. Cell cycle distribution, apoptosis, cytochrome c release, and mitochondrial inner membrane depolarisation were analysed by flow cytometry; gene expression analysis was carried out using TaqMan Low Density Arrays; and expression of caspase-8 and Bcl-2 family of proteins was assessed by western blot analysis.<bold>Results: </bold>Pyrrolo-1,5-benzoxazepine-15 induced apoptosis in ex vivo myeloma cells and in myeloma cell lines. Death receptor genes were upregulated in both NCI-H929 and U266 cell lines, which displayed the highest and lowest apoptotic responses, respectively, following treatment with PBOX-15. The largest increase was detected for the death receptor 5 (DR5) gene, and cotreatment of both cell lines with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the DR5 ligand, potentiated the apoptotic response. In NCI-H929 cells, PBOX-15-induced apoptosis was shown to be caspase-8 dependent, with independent activation of extrinsic and intrinsic apoptotic pathways. A caspase-8-dependent decrease in expression of Bim(EL) preceded downregulation of other Bcl-2 proteins (Bid, Bcl-2, Mcl-1) in PBOX-15-treated NCI-H929 cells.<bold>Conclusion: </bold>PBOX-15 induces apoptosis and potentiates TRAIL-induced cell death in multiple myeloma cells. Thus, PBOX-15 represents a promising agent, with a distinct mechanism of action, for the treatment of this malignancy. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00070920
Volume :
104
Issue :
2
Database :
Complementary Index
Journal :
British Journal of Cancer
Publication Type :
Academic Journal
Accession number :
57395759
Full Text :
https://doi.org/10.1038/sj.bjc.6606035