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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.

AbstractBACKGROUND:
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.
AuthorsE 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
JournalBritish journal of cancer (Br J Cancer) Vol. 104 Issue 2 Pg. 281-9 (Jan 18 2011) ISSN: 1532-1827 [Electronic] England
PMID21179037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 4-acetoxy-5-(1-(naphthyl))naphtho(2,3-b)pyrrolo(2,1-d)(1,4)oxazepine
  • Oxazepines
  • Pyrroles
  • Receptors, Death Domain
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
Topics
  • Apoptosis (drug effects)
  • Cell Line, Tumor
  • Down-Regulation (drug effects)
  • Humans
  • Microscopy, Fluorescence
  • Microtubules (drug effects)
  • Multiple Myeloma (pathology)
  • Oxazepines (pharmacology)
  • Pyrroles (pharmacology)
  • Receptors, Death Domain (metabolism)
  • TNF-Related Apoptosis-Inducing Ligand (physiology)
  • Up-Regulation (drug effects)

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