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PBOX-15, a Novel Microtubule Targeting Agent, Induces Apoptosis, Upregulates Death Receptors, and Potentiates TRAIL-mediated Apoptosis in Multiple Myeloma Cells

PBOX-15, a Novel Microtubule Targeting Agent, Induces Apoptosis, Upregulates Death Receptors, and Potentiates TRAIL-mediated Apoptosis in Multiple Myeloma Cells

E N Maginn, P V Browne, P Hayden, E Vandenberghe, B MacDonagh, P Evans, M Goodyer, P Tewari, G Campiani, S Butini, D C Williams, D M Zisterer, M P Lawler, A M McElligott

Br J Cancer. 2011 Jan 18;104(2):281-9.

PMID: 21179037

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP354759107	PBOX-15		354759-10-7	Price

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