Abstract
BackgroundCombination 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.MethodsCell 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.ResultsCell 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.ConclusionThese 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0176-7) contains supplementary material, which is available to authorized users.
Highlights
Combination therapy is a key strategy for minimizing drug resistance, a common problem in cancer therapy
Cells treated with 500 nM Suberoylanilide hydroxamic acid (SAHA) and various concentrations of vincristine (0.3 to 3 nM) significantly inhibited cell survival compared to each treatment alone (Fig. 1c)
Vincristine in combination with SAHA induced mitotic arrest by stimulating cyclin B1, aurora B, phospho-Cdc2 (Thr161), and phospho-PLK1 expression, and suppressing Cdc25c and phospho-Cdc2 (Tyr15) levels. The magnitude of these changes was more obvious than those observed with vincristine treatment alone (Fig. 3c). These findings demonstrate that SAHA enhanced vincristineinduced M phase arrest and that the combination therapy induced microtubule dynamics instability and mitotic activation
Summary
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. Drugs that inhibit microtubule dynamics have been used clinically in cancer treatment for more than 20 years [3]. These agents can be divided into two major types: microtubule-destabilizing agents, such as vincristine, and microtubule-stabilizing agents, such as. Chao et al Journal of Hematology & Oncology (2015) 8:82 paclitaxel [4] At lower concentrations, both types affect only microtubule dynamics, inducing abnormal mitotic spindle formation and causing cell arrest in the M phase and, subsequently, cell apoptosis [5]. The current trends in tubulin-binding agent development are to change the dosage to improve solubility or a combination of these agents with other anticancer drugs to reduce toxicity and enhance activity [6]
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