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Journal of Hematology & Oncology

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Open Access 01-12-2015 | Research Article

The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo

Authors: Min-Wu Chao, Mei-Jung Lai, Jing-Ping Liou, Ya-Ling Chang, Jing-Chi Wang, Shiow-Lin Pan, Che-Ming Teng

Published in: Journal of Hematology & Oncology | Issue 1/2015

Abstract

Background

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.

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Title: The synergic effect of vincristine and vorinostat in leukemia in vitro and in vivo
Authors: Min-Wu Chao
Mei-Jung Lai
Jing-Ping Liou
Ya-Ling Chang
Jing-Chi Wang
Shiow-Lin Pan
Che-Ming Teng
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Journal of Hematology & Oncology / Issue 1/2015
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-015-0176-7

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Abstract

Background

Methods

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