Syringolin B-inspired proteasome inhibitor analogue TIR-203 exhibits enhanced biological activity in multiple myeloma and neuroblastoma

Abstract

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^®) 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 µM) 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.

Keywords::

• Anticancer activity
• bortezomib
• glidobactin A
• multiple myeloma
• natural products
• neuroblastoma
• plant pathogen Pseudomonas syringae pv. syringae
• pediatric cancer
• synthetic analogues
• syrbactins

Acknowledgments

We are grateful to Prof. Dr. Markus Kaiser (University of Duisburg-Essen, Essen, Germany) for providing SylA as well as Prof. Dr. Nancy L. Krett (Northwestern University, Chicago, IL, USA) and Prof. Dr. Jason Shohet (Texas Children’s Hospital, Houston, TX, USA) for providing multiple myeloma cell line MM.1R and neuroblastoma cell line MYCN2, respectively. Prof. Dr. Dana-Lynn Koomoa (University of Hawaii College of Pharmacy, Hilo, HI, USA) is thanked for her expert technical advice.

Declaration of interest

This work was supported by the Robert C. Perry Fund of the Hawaii Community Foundation (HCF grant # 10ADVC-47862), the Hawaii Business and Acceleration Mentors (HiBEAM) and internal funds from the College of Pharmacy (Prof. Dr. André Bachmann). Further support was provided by the University of California Cancer Research Coordinating Committee (Prof. Dr. Michael Pirrung) and postdoctoral fellowships from UC-MEXUS and CONACYT (Dr. Tannya Ibarra-Rivera).