The role of tamoxifen in combination with cisplatin on oral squamous cell carcinoma cell lines
Introduction
General treatment modalities of oral squamous cell carcinoma (OSCC) are surgery, radiotherapy and chemotherapy. A number of chemotherapeutic agents have been used to treat OSCC [1]. However, the survival rate of the patients has not been improved by the treatment with current chemotherapeutic agents substantially. For the improvement of clinical outcome, it is necessary to verify the molecular mechanisms of chemotherapeutic agents and to apply the combination of chemotherapeutic agents that induce synergistic anti-tumor activity.
Cis-platinum(II)-diamine dichloride (cisplatin) is one of the most active chemotherapeutic agents that have been used for the treatment of a various malignant tumors including OSCC [2]. However, the rapid development of resistance is a major limitation of its use as a single agent. Cisplatin combined with other agents was more effective than cisplatin alone and cisplatin has been used for the treatment of several types of malignancy in combination with tamoxifen (TAM) [3], [4].
TAM, which is a triphenylethylene derivative, non-steroidal selective estrogen receptor modulator (SERM), has been extensively used in the preventive therapy or adjuvant therapy of breast carcinoma for more than 30 years. It was believed that TAM act primarily through binding to the estrogen receptor (ER) in ER positive breast carcinoma cells. TAM can bind to the ER competitively with estrogen and block binding between estrogen and ER. TAM is also able to inhibit proliferation of ER negative breast carcinoma. These inhibitory effects are independent of ER. In addition to ER negative breast carcinoma, the effect of TAM was evaluated in some malignant tumors including malignant melanoma, pancreatic carcinoma and renal cell carcinoma. The targets of TAM action in ER independent pathway include inhibition of protein kinase C (PKC) activity and calmodulin-dependent cAMP phosphodiesterase (CDP) which is crucial for cellular proliferation and stimulation of transforming growth factor β1 (TGF-β1) secretion [5]. TAM induced cell cycle arrest and blocked telomerase activity, resulting in apoptosis of tumor cells [6].
It was acclaimed that TAM could also act as a chemosensitizer of several types of solid tumors to cisplatin without increasing its side effects [7]. Combination TAM and cisplatin have been tested in clinical trials for melanoma [8], prostate [9], bladder [10], and non-small cell lung cancer [11]. However, the mechanisms for the sensitizing effect of TAM in these tumors were not fully discovered.
Although there were many trials to apply TAM in various malignant tumors, there have been only a few attempts to evaluate the effect of TAM in oral cancer. The purpose of this study was to evaluate the effect of TAM when used in combination with cisplatin on OSCC. For this, the relation between ER expression level and the cytotoxic effect of TAM, the apoptotic effect of the combination therapy of TAM with cisplatin and molecular mechanisms of apoptotic effect of TAM were investigated using OSCC cell lines.
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Cell lines and cell culture
Three OSCC cell lines, A253 (submandibular gland squamous cell carcinoma), HSC-3 (tongue squamous cell carcinoma) and KB (oral mucosa squamous cell carcinoma) were used. The ER positive human breast cancer cell line, MCF-7, was served as positive control. All cell lines were obtained from Korean Cell Line Bank (KCLB, Seoul). Each cell lines were maintained in RPMI-1640 medium (JBI, USA) supplemented with 10% heat-inactivated fetal bovine serum (FBS, Gibco, Grand Island, NY), 100 μl/ml
Evaluation of cytotoxic effect of TAM and cisplatin in OSCC cell lines
For the evaluation of cytotoxic effect of TAM and cisplatin on OSCC cell lines, A253, HSC-3 and KB were treated with TAM (1–10 μM), cisplatin (0.1–10 μg/ml), or in combination for 24, 48 and 72 h. Percent cell survival was measured by MTT assay. Cytotoxic effect of TAM increased in a dose- and time-dependent manner in all cell lines (Fig. 1A and B). After 24 h, cytotoxicity of TAM (5 μM) was significantly higher in MCF-7 than in OSCC cell lines (P<0.05). However, those effects were not so
Discussion
The broad spectrum of anticancer activity of cisplatin is reflected by their current role as the backbone of chemotherapeutic regimens in a variety of solid tumors, including OSCC. But development of resistance is major problem of clinical application. In relation to the development of cisplatin resistance, several mechanisms have been identified at the molecular level, including enhanced activation of cellular detoxification systems, decreased drug accumulation, increased drug efflux and
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