Efficacy of Tubulin Polymerization Inhibitor in Myelodysplastic Syndrome
Tubulin belongs to protein superfamily of globular proteins. Monomer tubulin can polymerize into microtubules, which are highly dynamic and play a critical role in mitosis during cell division. Therefore, microtubule dynamics is an important target for the developing anti-cancer drugs.  Inhibition of tubulin polymerization or depolymerization has been utilized and shown efficacy in many types of solid tumors. A novel small molecule PTC596 directly binds tubulin and inhibits microtubule polymerization and has been shown to downregulates MCL-1 and induces p53-independent apoptosis in acute myeloid leukemia cells. We herein investigated the efficacy of PTC028, another novel microtubule polymerization inhibitor for myelodysplastic syndrome (MDS). PTC028 induced growth suppression and apoptosis of MDS cell lines. The efficacy of PTC028 in primary MDS samples was also confirmed by cell proliferation assays. PTC028 synergized with hypomethylating agents, such as decitabine and azacitidine, to inhibit the growth and induce apoptosis of MDS cells. Mechanistically, a treatment with PTC028 induced G2/M arrest followed by apoptotic cell death. Finally, we assessed the efficacy of PTC028 in a xenograft mouse model of MDS using an MDS cell line, MDS-L and AkaBLI bioluminescence imaging system system, which is composed of AkaLumine-HCl and Akaluc. PTC028 prolonged the survival of mice in xenograft models. In summary, our data reveal a possible chemotherapeutic strategy for MDS by disruption of microtubule dynamics as a single agent and in combination with hypomethylating agents.