The Combination Effect Of Histone Deacetylase Inhibitors And Cisplatin On Oral Squamous Cell Carcinoma Cell Lines

BackgroundPlatinum-based chemotherapy drug, for example, cisplatin, has been used as the first -line single agent for its powerful therapeutic effects against oral squamous cell carcinoma(OSCC).However, both the resistance to cisplatin and dose-related toxicity remain two of the most crucial issues in the chemotherapy of clinical OSCC treatment. Researches have been seeking a combinative treatment regimen to improve the effect of chemotherapy. In our study, we evaluated the potential combinative effect of histone deacetylase inhibitors (HDACIs) and cisplatin on OSCC cell lines.PurposeTo explore the possible synergistic anticancer efficiency of both HDACIs and cisplatin in OSCC cell line. Molecular mechanisms underlying drug induced apoptosis and activation of apoptosis related proteins in OSCC cell lines are also examined.MethodsBy using MTS methods, Tca8113 and KB cells were firstly treated with HDACIs and cisplatin alone and the dose response for single agent was obtained. Then, western blotting was performed to evaluate the acetylated histone level in Tca81113 and KB cells treated with HDACIs. Subsequently, a subtoxic dose of cisplatin and HDACIs was used in combination to compare their activities against OSCC cancer cells. Cell growth and viability were assessed using MTS and colony formation assay, and apoptosis was measured by flow cytometry and DeadEnd^TM Fluorometric TUNEL System. At last, to further explore the cellular basis of the synergistic response observed in OSCC cell lines, the analysis of selected p53 related apoptosis network was then performed by western blotting.ResultsBoth Tca8113 and KB were sensitive to HDACIs and cisplatin alone. HDACIs could rapidly induce accumulation of acetylated histone in OSCC cell lines. Compared with either HDACIs or cisplatin treated alone, co-administration of subtoxic of both drugs synergistically induces cytotoxicity and apoptosis in both Tca8113 and KB cell lines (P<0.05).The increased drug sensitivity observed with co-treatment of the cells with HDACIs is mediated by p53 induction, increased activation of pro-apoptotic protein BID, released of cytochrome C to cytosol, and increased activation of caspase-3.ConclusionThese founding suggest us that concurrent treatment with HDACIs enhances tumor cell sensitivity to subtoxic doses of cisplatin through p53 intrinsic and extrinsic apoptosis pathway that has close relationship with drug resistance. This may be regarded as a novel strategy for treatment of OSCC.