Journal
PHARMACEUTICAL BIOLOGY
Volume 50, Issue 1, Pages 25-29Publisher
TAYLOR & FRANCIS LTD
DOI: 10.3109/13880209.2011.626784
Keywords
Anticancer activity; bortezomib; glidobactin A; multiple myeloma; natural products; neuroblastoma; plant pathogen Pseudomonas syringae pv. syringae; pediatric cancer; synthetic analogues; syrbactins
Funding
- Hawaii Community Foundation (HCF) [10ADVC-47862]
- College of Pharmacy
- University of California Cancer Research Coordinating Committee
- UC-MEXUS
- CONACYT
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Context: The bacterium Pseudomonas syringae pv. syringae (Pss) is a pathogen of many plant species and causes, for example, brown spot disease in bean plants (Phaseolus vulgaris). Pss excretes the syringolins, natural product molecules that act as a virulence factors and inhibit the proteasome of the host plants. Objective: Proteasome inhibitors belong to an important class of anticancer agents and bortezomib (Velcade (R)) has been Food and Drug Administration-approved for the treatment of multiple myeloma (MM) and mantle cell lymphoma. Syringolins represent a new class of proteasome inhibitors and the present work was undertaken to design a potent syringolin-inspired analogue (TIR-203) for anticancer drug development. Materials and methods: TIR-203 was tested against human MM and neuroblastoma (NB) cells. Cancer cells were treated with TIR-203 at various concentrations (0-10 mu M) and the cell viability was measured using the MTS assay. To determine the effects on proteasomal activities, the cell culture-based proteasome inhibition assay was used. Syringolin A (SylA) and bortezomib were included as controls. Results: TIR-203 inhibited the cell proliferation of MM and NB cells in a dose-dependent manner at significantly lower concentrations than SylA. In MM cells, TIR-203 effectively inhibited the chymotrypsin-like (CT-L), caspase-like (C-L), and trypsin-like (T-L) activities of the proteasome. In NB cells, TIR-203 inhibited the CT-L and C-L activities, but not the T-L activity. Discussion and conclusions: The newly designed proteasome inhibitor TIR-203 is more potent than the natural product SylA and strongly inhibits the cell viability and proteasomal activity of MM and NB cells.
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