RICOLINOSTAT INDUCES MICROTUBULE ACETYLATION AND NEURITE REGENERATION IN CELLULAR MODELS OF CHEMOTHERAPY-INDUCED NEUROPATHY

Chemotherapy leaded to the increase of life expectancy of cancer patients but it has long-term consequences that may worsen patients' quality of life inducing healthcare system burden. Indeed, more than 50% of treated cancer patients develop chemotherapy-induced peripheral neuropathy (CIPN), a omplication that may persist six months after the completion of antineoplastic treatment. CIPN is a primarily sensory neuropathy characterized by the eduction of peripheral nerve fibres, which may be accompanied by pain, autonomic disturbances, and motor deficit. The better comprehension of its molecular pathogenesis could drive disease modifying strategies that might prompt fibres regeneration and ameliorate patients' life. To unravel the athogenic mechanisms of seemingly unrelated antineoplastic agents (Bortezomib, Carfilzomib, Cisplatin and Paclitaxel) we used in vitro models of CIPN nd we looked at the possible impact on microtubule cytoskeleton. We started with the definition of treatment-paradigm and with a broader investigation of 3D architecture of microtubule network and its post-translational modifications indifferentiated F11 cells. We further challenged cells with ricolinostat (ACY-1215), a first-in-line inhibitor of HDAC6, and test its ability in rescue the possible microtubule defects and in inducing neurites regrowth. Then, we refined and deepened the analyses in murine DRG neurons. Our preliminary findings revealed that chemotherapy drugs acting on different cellular targets seem to converge their action on microtubule damage. Indeed, we observed a disequilibrium of tubulin posttranslational odifications that are associated to microtubule subsets with a different stability and well known regulators of microtubuledependent functions. Confocal microscopy showed alterations of the 3D organization of the microtubule network at the growth cones; the morphologies we identified are reminiscent of axonal degeneration. In agreement, in the presence of antineoplastic agents we observed an increase in the formation of axonal varicosities, vocative of the block of axonal transport, and the shortening of neurites length. Ricolinostat treatment induced the enrichment of acetylated microtubules, a subset resilient to mechanical breakdown, which allowed microtubuleregrowth and neurites regeneration as well. Here we showed that microtubule system seems to be a common target of unrelated chemotherapy agents, even of those known to impact on different cellular components, and that microtubule dysfunctions can be a central theme in CIPN. Furthermore, we showed that ricolinostat-induced microtubule acetylation is associated to neurite regeneration. These findings could drive innovative strategies of intervention in which ricolinostat administration can modulate microtubule system and induce neuroprotective effects in chemotherapytreated patients.