Rhazinilam mimics the cellular effects of taxol by different mechanisms of action.
We have investigated the effects of the microtubule poison rhazinilam on microtubule assembly in vivo and in vitro. In mammalian cells, rhazinilam mimics the effects of taxol and leads to microtubule bundles, multiple asters, and microtubule cold stability. In vitro, rhazinilam protected preassembled microtubules from cold-induced disassembly, but not from calcium ion-induced disassembly. Moreover, both at 0 degrees C and at 37 degrees C, rhazinilam induced the formation of anomalous tubulin assemblies (spirals). This process was prevented by maytansine and vinblastine, but not by colchicine. Preferential saturable and stoichiometric binding of radioactive rhazinilam to tubulin in spirals was observed with a dissociation constant of 5 microM. This binding was abolished in the presence of vinblastine and maytansine. In contrast, specific binding of radioactive rhazinilam to tubulin assembled in microtubules was undetectable. These results demonstrate that rhazinilam alters microtubule stability differently than taxol, and that the overall similar effects of rhazinilam and taxol on the cellular cytoskeleton are the consequence of two distinct mechanisms of action at the molecular level.
CNRS, Laboratoire de Pharmacologie et de Toxicologie Fondamentales, Toulouse, France.
B
B
David
T
T
Sévenet
M
M
Morgat
G
G
Guénard
A
A
Moisand
Y
Y
Tollon
O
O
Thoison
M
M
Wright
D000470:Alkaloids / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006160:Guanosine Triphosphate / Q000378:metabolism; D007212:Indolizines; D007769:Lactams; D007614:Macropodidae; D008453:Maytansine / Q000494:pharmacology; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000187:drug effects / Q000378:metabolism; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D008938:Mitosis / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D013696:Temperature; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D000470:Alkaloids; D007212:Indolizines; D007769:Lactams; D008869:Microtubule-Associated Proteins; D014404:Tubulin; D008453:Maytansine; C009170:rhazinilam; D014747:Vinblastine; D006160:Guanosine Triphosphate; D017239:Paclitaxel; D002118:Calcium