Microtubules in Apoptosis Induction: Are They Necessary?

International audienc

RESTORATION BY BIOTIN OF THE INVITRO MICROTUBULE FORMATION INHIBITED BY UREMIC TOXINS

Tubulin is an intracellular protein whose in vivo polymerization leads to the formation of microtubules (MT). MT are an essential component of axons of nerve cells. This reaction is the limiting factor in the growth of axons. Uremic neuropathy is characterized in part by an axonal degeneration. A chromatographic fraction from uremic plasma (2-5 fraction) inhibits in vitro the tubulin polymerization and thus MT formation and therefore may be implicated in the occurrence of uremic neuropathy. In vitro, biotin counteracts the inhibitory effect of 2-5 fraction on MT formation. This effect could be a partial explanation of the possible clinical improvement brought on by biotin in uremic neuropathy

Patupilone-Induced Apoptosis Is Mediated by Mitochondrial Reactive Oxygen Species through Bim Relocalization to Mitochondria

International audienceAmong the new microtubule-targeted agents, the epothilone family of molecules has shown promising anticancer potential, and clinical trials are currently underway for patupilone (epothilone B) in various cancer indications. In this study, we characterized novel aspects of patupilone's cellular action that may underlie its potent cytotoxicity in human neuroblastoma cells. Patupilone induced mitochondrial membrane potential collapse, mitochondrial morphological changes, and cytochrome c release, leading to apoptosis. Within the first 2 h, patupilone increased the generation of reactive oxygen species (ROS; i.e., superoxides and hydrogen peroxide, 33+/-6 and 51+/-3% increase, respectively), specifically from mitochondria. ROS scavengers and mitochondrial DNA depletion [rho(-) cells] significantly protected cells against patupilone cytotoxicity, indicating that ROS generation is a key event in the initial phase of apoptosis. Although the Bim expression level was not modified by patupilone, this proapoptotic protein accumulated in the mitochondrial compartment (2.4-fold increase at IC70) after only a 6-h treatment. In contrast, Bax and Bcl-2 mitochondrial levels were not changed during treatment. It is noteworthy that ROS inhibition prevented Bim relocalization to mitochondria and mitochondrial membrane changes induced by patupilone. Altogether, our data reveal that patupilone-mediated ROS production by mitochondria initiates the intrinsic signaling cascade by inducing Bim accumulation in mitochondria. These results might explain the superior activity of patupilone in tumor cells compared with paclitaxel that is, until now, the clinical reference among microtubule-stabilizing agents. Furthermore, our data highlight the importance of mitochondria that simultaneously assume the role of activator and integrator of apoptotic signals triggered by patupilone

EB1-dependent long survival of glioblastoma cancer stem-like cell tumor-bearing mice after daily oral treatment with the novel Tumor Checkpoint Controller BAL101553

30th EORTC-NCI-AACR Symposium, Dublin, IRELAND, NOV 13-16, 201

Organic Nanoparticles as Anticancer and Theranostic Devices

International audienc

EB1-dependent long survival of glioblastoma cancer stem-like cell tumor-bearing mice after daily oral treatment with the novel Tumor Checkpoint Controller BAL101553

30th EORTC-NCI-AACR Symposium, Dublin, IRELAND, NOV 13-16, 201