Barac Aleksandra, Mitulovic Goran, Hallström Seth, Zehetmayer Sonja, Grasl Matthaeus Ch, Erovic Boban M
Clinic for Infectious and Tropical Diseases, Clinical Center of Serbia, Belgrade, Serbia.
Medical and Chemical Laboratory Diagnostics, Medical University of Vienna, Vienna, Austria.
Onco Targets Ther. 2017 Jul 19;10:3607-3616. doi: 10.2147/OTT.S131106. eCollection 2017.
Despite significant advances in diagnosis and therapy, the rate of survival of patients with oral cancers still remains poor as an appropriate treatment has not been found yet, due to side effects of chemo/radiotherapy.
This study aimed to identify molecular mechanisms of cell death of oral cancer cells caused by treatment with a nonselective Cox-2 inhibitor in combination with a low-dose chemotherapeutic drug.
Squamous cell carcinoma (SCC) cells SCC9 and SCC25 were subjected to mono- and combination therapy with nimesulide and cisplatin. Fluorescence-activated cell sorting (FACS), immunohistochemistry, high-pressure liquid chromatography (HPLC), microarray gene chips, and isobaric tags for a relative and absolute quantitation (iTRAQ) system were used.
Increased numbers of apoptotic and necrotic SCC9/SCC25 cells were detected after combined exposure. ATP levels and the energy charge of SCC9 cells were significantly decreased after both individual and combined treatment. We detected and quantified a responsible gene, keratin 6a, and 540 relevant proteins. In SCC25 cells, ATP levels significantly decreased only after combination therapy. After combined treatment of SCC9 cells, significant upregulation of Histon-H2A/H2B/H4 was found, with a local discovery false rate of 0.003 for Histon-H2A and 0.0027 for Histon-H2B, respectively.
Compared to the single-drug treatment, combined treatment of the oral cancer cells with nimesulide and cisplatin increases and induces necrosis and apoptosis through different pathways. A significant effect of the cytoplasmic increase was also observed in histones of cell lines SCC9 and SCC25 that were previously treated with combined nimesulide and cisplatin therapy.
尽管在诊断和治疗方面取得了重大进展，但口腔癌患者的生存率仍然很低，因为尚未找到合适的治疗方法，这是由于化疗/放疗的副作用所致。
本研究旨在确定非选择性环氧化酶-2（Cox-2）抑制剂与低剂量化疗药物联合治疗导致口腔癌细胞死亡的分子机制。
对鳞状细胞癌（SCC）细胞SCC9和SCC25进行尼美舒利和顺铂的单一及联合治疗。使用了荧光激活细胞分选（FACS）、免疫组织化学、高压液相色谱（HPLC）、微阵列基因芯片以及相对与绝对定量的等压标记（iTRAQ）系统。
联合暴露后检测到凋亡和坏死的SCC9/SCC25细胞数量增加。单独及联合治疗后，SCC9细胞的三磷酸腺苷（ATP）水平和能量电荷显著降低。我们检测并定量了一个相关基因角蛋白6a和540种相关蛋白质。在SCC25细胞中，仅联合治疗后ATP水平显著降低。SCC9细胞联合治疗后，发现组蛋白-H2A/H2B/H4显著上调，组蛋白-H2A的局部发现错误率分别为0.003，组蛋白-H2B为0.0027。
与单一药物治疗相比，尼美舒利和顺铂联合治疗口腔癌细胞可通过不同途径增加并诱导坏死和凋亡。在先前接受尼美舒利和顺铂联合治疗的SCC9和SCC25细胞系的组蛋白中也观察到细胞质增加的显著影响。
