Disruption of Golgi processing by 2-phenyl benzimidazole analogs blocks cell proliferation and slows tumor growth.
OBJECTIVE
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.
Lio
Shirley Cruz
SC
Avanir Pharmaceuticals, 101 Enterprise, Aliso Viejo, CA 92656, USA.
Johnson
Jessica
J
Chatterjee
Arka
A
Ludwig
Jeffrey W
JW
Millis
Diane
D
Banie
Homayon
H
Sircar
Jagadish C
JC
Sinha
Anjana
A
Richards
Mark L
ML
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D005455:Fluorescent Antibody Technique; D006056:Golgi Apparatus / Q000187:drug effects* / Q000378:metabolism*; D007073:Immunoglobulin E; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007073:Immunoglobulin E; C117755:2-phenylbenzimidazole