Abstract
CKD-602 (7-[2-(N-isopropylamino) ethyl]-(20S)-camptothecin, belotecan) is a synthetic water-soluble camptothecin derivative and topoisomerase I inhibitor that has been shown to exert a clinical anticancer effect on various types of tumor. In the present study, the anticancer effects of CKD-602 on the following three human oral squamous cell carcinoma (OSCC) cell lines originating from Korean cancer patients: YD-8 (tongue), YD-9 (buccal mucosa) and YD-38 (lower gingiva) were analyzed. The apoptotic proportion of the cells and cell cycle position were analyzed using flow cytometry. The expression of cell cycle regulatory proteins was detected by western blot analysis. CKD-602 was demonstrated to exert a time- and dose-dependent antiproliferative effect in all cell lines in vitro, however, susceptibility to CKD-602 at 72 h following treatment varied among the three cell lines, with 50% inhibition of cell viability at concentrations of 2.4 μg/ml for YD-8, 0.18 μg/ml for YD-9 and 0.05 μg/ml for YD-38. To investigate the underlying mechanism of the CKD-602 antiproliferative effect, a cell cycle-analysis was conducted in the three OSCC cell lines and CKD-602 treatment was observed to induce G2/M phase arrest. Furthermore, western blot analysis revealed that the expression levels of phospho-cdc2 (Tyr 15), cyclin A2 and cyclin B1 were increased in a time-dependent manner, following the administration of CKD-602. In the fluorescence-activated cell sorting analysis, the number of apoptotic cells was also increased in a dose-dependent manner following CKD-602 treatment of the OSCC cell lines. The results suggest that CKD-602 may inhibit the proliferation of OSCC oral cancer cells derived from samples from Korean patients by apoptosis and by G2/M phase arrest.
Highlights
Squamous cell carcinoma is the most common type of malignant neoplasm of the oral mucosa and accounts for >90% of all intraoral malignant tumors, in Korea [1]
Despite gradual improvements in surgery, radiotherapy and chemotherapy treatments, the prognosis of patients presenting with locally advanced oral squamous cell cancer (OSCC) remains poor, with only a 50% survival rate over five years [2]
The YD cell lines were derived from untreated primary tumors of the tongue (YD‐8), buccal mucosa (YD‐9) and lower gingiva (YD‐38), and the cell lines exhibited genetically different p53 statuses
Summary
Squamous cell carcinoma is the most common type of malignant neoplasm of the oral mucosa and accounts for >90% of all intraoral malignant tumors, in Korea [1]. Despite gradual improvements in surgery, radiotherapy and chemotherapy treatments, the prognosis of patients presenting with locally advanced oral squamous cell cancer (OSCC) remains poor, with only a 50% survival rate over five years [2]. Due to these poor survival rates and the severe functional impairment caused by surgery and radiation, the development of novel therapeutic strategies in the management of patients with advanced OSCC is urgently required. The YD‐8 cell line had a point mutation at codon 273 of exon 8, which is involved in the DNA‐binding site, revealing its significance in p53 transcriptional activation; the GGT (arginine) sequence was replaced with CAT (histidine). Tumors with an inactive mutant p53 are aggressive and are commonly resistant to ionizing radiation and chemotherapy [8]
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