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Cancer Chemother Pharmacol. 2008 May;61(6):1045-58. Epub 2007 Aug 10.

Disruption of Golgi processing by 2-phenyl benzimidazole analogs blocks cell proliferation and slows tumor growth.

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  • 1Avanir Pharmaceuticals, 101 Enterprise, Aliso Viejo, CA 92656, USA.

Abstract

PURPOSE:

Cancer chemotherapy continues to be challenged by the emergence of resistant tumors, and one organelle entwined in the development of drug resistance is the Golgi apparatus. Recently, we discovered a group of 2-(substituted phenyl)-benzimidazole (2-PB) compounds that displace resident Golgi proteins from the juxtanuclear region resulting in their degradation. These compounds are also potent anti-proliferative agents, which together with their action on the Golgi made a compelling case for testing them against cancer.

METHODS:

The anti-tumor activity of a group of 2-PB compounds was examined both in vitro and in vivo. The role of the Golgi in the anti-proliferative effect was assessed by comparing the proliferation of individual cell lines with the distribution and total cellular expression of selected resident Golgi proteins.

RESULTS:

The anti-proliferative activity of 2-PB compounds is partially reversible (time- and concentration-dependent), non-cell-cycle-specific, and translates to tumor growth inhibition in vivo. While 2-PB compounds displace resident Golgi proteins from the juxtanuclear region in all cells, those that are resistant to the anti-proliferative effects differ from sensitive cells in that they have the capacity to protect these Golgi proteins from degradation.

CONCLUSIONS:

These results illustrate the utility of targeting the Golgi for cancer drug development. They also reveal a cellular strategy for resisting 2-PB drug effects through protection of displaced Golgi proteins from degradation thus allowing their continued function.

[PubMed - indexed for MEDLINE]
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