1. PBOX-15, a novel microtubule targeting agent, induces apoptosis, upregulates death receptors, and potentiates TRAIL-mediated apoptosis in multiple myeloma cells.
- Author
-
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., and McElligott, A. M.
- Subjects
- *
MULTIPLE myeloma , *APOPTOSIS , *CYTOCHROME c , *MITOCHONDRIAL membranes , *CYTOMETRY , *DEATH receptors , *AZEPINES , *BIOCHEMISTRY , *RESEARCH , *HETEROCYCLIC compounds , *MICROSCOPY , *RESEARCH methodology , *CELL receptors , *MEDICAL cooperation , *EVALUATION research , *PHENOMENOLOGY , *COMPARATIVE studies , *CELL lines , *CARRIER proteins , *CYTOPLASM - Abstract
Background: 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.Methods: 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.Results: 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.Conclusion: 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]- Published
- 2011
- Full Text
- View/download PDF