CHE-MING TENG2018-09-102018-09-102015http://www.scopus.com/inward/record.url?eid=2-s2.0-84938879952&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/392038Background: Combination therapy is a key strategy for minimizing drug resistance, a common problem in cancer therapy. The microtubule-depolymerizing agent vincristine is widely used in the treatment of acute leukemia. In order to decrease toxicity and chemoresistance of vincristine, this study will investigate the effects of combination vincristine and vorinostat (suberoylanilide hydroxamic acid (SAHA)), a pan-histone deacetylase inhibitor, on human acute T cell lymphoblastic leukemia cells. Methods: Cell viability experiments were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and cell cycle distributions as well as mitochondria membrane potential were analyzed by flow cytometry. In vitro tubulin polymerization assay was used to test tubulin assembly, and immunofluorescence analysis was performed to detect microtubule distribution and morphology. In vivo effect of the combination was evaluated by a MOLT-4 xenograft model. Statistical analysis was assessed by Bonferroni's t test. Results: Cell viability showed that the combination of vincristine and SAHA exhibited greater cytotoxicity with an IC50 value of 0.88 nM, compared to each drug alone, 3.3 and 840 nM. This combination synergically induced G2/M arrest, followed by an increase in cell number at the sub-G1 phase and caspase activation. Moreover, the results of vincristine combined with an HDAC6 inhibitor (tubastatin A), which acetylated α-tubulin, were consistent with the effects of vincristine/SAHA co-treatment, thus suggesting that SAHA may alter microtubule dynamics through HDAC6 inhibition. Conclusion: These findings indicate that the combination of vincristine and SAHA on T cell leukemic cells resulted in a change in microtubule dynamics contributing to M phase arrest followed by induction of the apoptotic pathway. These data suggest that the combination effect of vincristine/SAHA could have an important preclinical basis for future clinical trial testing. ? 2015 Chao et al.HDAC6; Leukemia; SAHA; Vincristine[SDGs]SDG3alpha tubulin; caspase; histone deacetylase 6; vincristine; vorinostat; antineoplastic agent; hydroxamic acid; vincristine; vorinostat; acute lymphoblastic leukemia; animal experiment; animal model; antineoplastic activity; apoptosis; Article; cancer combination chemotherapy; cancer survival; cell count; cell cycle; cell cycle G1 phase; cell structure; cell viability; cellular distribution; controlled study; dose response; drug cytotoxicity; drug dose comparison; drug effect; drug potentiation; enzyme activation; enzyme inhibition; flow cytometry; G2 phase cell cycle checkpoint; human; human cell; IC50; immunofluorescence test; in vitro study; in vivo study; microtubule; mitochondrial membrane potential; mouse; MTT assay; nonhuman; polymerization; cell survival; leukemia; tumor cell line; Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Drug Synergism; Humans; Hydroxamic Acids; Leukemia; Vincristinejournal article10.1186/s13045-015-0176-7