Hashitani Susumu, Urade Masahiro, Nishimura Norihiko, Maeda Tsunenari, Takaoka Kazuki, Noguchi Kazuma, Sakurai Kazunari
Department of Oral and Maxillofacial Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.
Int J Oncol. 2003 Sep;23(3):665-72.
Colorectal carcinomas are well known to highly express COX-2 and their growth is markedly inhibited by COX-2 inhibitors, but little is known about head and neck carcinomas. In this study, we investigated the effect of a selective COX-2 inhibitor, celecoxib, on growth and apoptosis induction of four human head and neck carcinoma cell lines, SCC25, KB, HSG and HSY, in comparison with frequently used COX inhibitor sulindac. Also, we examined whether celecoxib augments the sensitivity of these cell lines to anticancer drugs such as doxorubicin (DOX), vincristine (VCR), cisplatin (CDDP), bleomycin (BLM) and 5-fluorouracil (5-FU). The growth of all cultured cell lines particularly SCC25 and HSG was inhibited by celecoxib and sulindac in a dose-dependent manner. The IC50 of celecoxib was ten times lower than that of sulindac. SCC25 produced ample PGE2 whereas KB, HSG and HSY produced a small amount of PGE2. The PGE2 production and COX-2 expression were inhibited more efficiently by celecoxib than by sulindac. Exogenous addition of PGE2 resulted in an increased cell growth of SCC25 even under the celecoxib-treated condition, but not of HSG. These results suggested that PGE2 is involved in the growth of SCC25 but not of HSG. The ability of celecoxib to induce apoptosis is greater than that of sulindac. Treatment of SCC25 and HSG with non-cytotoxic 1 micro M or less cytotoxic 5 micro M of celecoxib enhanced the sensitivity of both cell lines to anticancer drugs, particularly in DOX, VCR and BLM two to ten times as demonstrated by lowering of IC50s. The enhanced rate was almost parallel to the degree of apoptosis induction. These findings indicated that a selective COX-2 inhibitor celecoxib inhibits cell proliferation, induces apoptosis and augments sensitivity to anticancer drugs in human head and neck carcinoma cells. Therefore, celecoxib would be useful as biological modulator in treatment of head and neck cancer.
众所周知，结肠直肠癌高表达COX - 2，其生长受到COX - 2抑制剂的显著抑制，但对头颈部癌的了解却很少。在本研究中，我们研究了选择性COX - 2抑制剂塞来昔布对四种人头颈部癌细胞系SCC25、KB、HSG和HSY的生长及凋亡诱导的影响，并与常用的COX抑制剂舒林酸进行了比较。此外，我们还检测了塞来昔布是否能增强这些细胞系对阿霉素（DOX）、长春新碱（VCR）、顺铂（CDDP）、博来霉素（BLM）和5 - 氟尿嘧啶（5 - FU）等抗癌药物的敏感性。塞来昔布和舒林酸均以剂量依赖性方式抑制所有培养细胞系的生长，尤其是SCC25和HSG。塞来昔布的IC50比舒林酸低十倍。SCC25产生大量前列腺素E2（PGE2），而KB、HSG和HSY产生少量PGE2。塞来昔布比舒林酸更有效地抑制PGE2的产生和COX - 2的表达。即使在塞来昔布处理的条件下，外源性添加PGE2也会导致SCC25细胞生长增加，但HSG细胞不会。这些结果表明PGE2参与SCC25的生长，但不参与HSG的生长。塞来昔布诱导凋亡的能力大于舒林酸。用非细胞毒性的1μM或细胞毒性较小的5μM塞来昔布处理SCC25和HSG，增强了这两种细胞系对抗癌药物的敏感性，特别是对DOX、VCR和BLM，IC50降低表明敏感性提高了两到十倍。增强率几乎与凋亡诱导程度平行。这些发现表明，选择性COX - 2抑制剂塞来昔布可抑制人头颈部癌细胞的增殖、诱导凋亡并增强其对抗癌药物的敏感性。因此，塞来昔布可作为头颈部癌治疗中的生物调节剂。
