Abstract

Cisplatin and paclitaxel are commonly used to treat oral cancer, but their use is often limited because of acquired drug resistance. Here, we tested the effects of combined cisplatin and paclitaxel on three parental (YD-8, YD-9, and YD-38) and three cisplatin-resistant (YD-8/CIS, YD-9/CIS, and YD-38/CIS) oral squamous cell carcinoma (OSCC) cell lines using cell proliferation assays and combination index analysis. We detected forkhead box protein M1 (FOXM1) mRNA and protein expression via real-time qPCR and Western blot assays. Cell death of the cisplatin-resistant cell lines in response to these drugs with or without a FOXM1 inhibitor (forkhead domain inhibitory compound 6) was then measured by propidium iodide staining and TdT dUTP nick end labeling (TUNEL) assays. In all six OSCC cell lines, cell growth was more inhibited by paclitaxel alone than combination therapy. Cisplatin-induced overexpression of FOXM1 showed the same trend only in cisplatin-resistant cell lines, indicating that it was associated with inhibition of paclitaxel-related apoptosis. In summary, these results suggest that, in three cisplatin-resistant cell lines, the combination of cisplatin and paclitaxel had an antagonistic effect, likely because cisplatin blocks paclitaxel-induced apoptosis. Cisplatin-induced FOXM1 overexpression may explain the failure of this combination.

Highlights

  • According to the GLOBOCAN 2018 report, oral cancer is estimated to have 354,864 new cases and 177,384 deaths worldwide in a single year [1]

  • We confirmed the effect of cisplatin and paclitaxel on cell growth of three parental cell lines (YD-8, YD-9, and YD-38) and three derived cisplatin-resistant cell lines (YD-8/CIS, YD-9/CIS, and YD-38/CIS) over 24 h and 48 h

  • When paclitaxel was the treatment, cell growth of all six cell lines was significantly suppressed in a dose- and time-dependent manner

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Summary

Introduction

According to the GLOBOCAN 2018 report, oral cancer is estimated to have 354,864 (males 246,420; females 108,444) new cases and 177,384 (males 119,693; females 57,691) deaths worldwide in a single year [1]. Chemotherapy is classically used as a method of treating oral cancer [3]. Cis-diamminedichloridoplatinum (II), is known as an anticancer drug that inhibits the proliferation of cancer cells through the formation of intra-strand crosslinks with the purine bases in DNA [4,5]. It has been widely used to treat various cancers, including oral cancer, in cisplatin-based chemotherapy [6,7,8]. Combining cisplatin with other anticancer drugs may overcome this resistance and provide new treatment strategies for many cancers [4]

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