Sasaki Masahiro, Okamura Masahiko, Ideo Atsushi, Shimada Jun, Suzuki Fumika, Ishihara Mariko, Kikuchi Hirotaka, Kanda Yumiko, Kunii Shiro, Sakagami Hiroshi
Division of Oral Maxillofacial Surgery, Meikai University School of Dentistry, Sakado, Saitama 350-0283, Japan.
Anticancer Res. 2006 Sep-Oct;26(5A):3373-80.
Three antitumor antibiotics, mitomycin C, bleomycin sulfate and peplomycin sulfate, were compared for their tumor-specific cytotoxicity, using human oral squamous cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and NA), human promyelocytic leukemic cell line HL-60 and human normal oral cell types (gingival fibroblast HGF, pulp cell HPC and periodontal ligament fibroblast HPLF). Among these three compounds, mitomycin C showed the highest tumor-specificity, due to its higher cytotoxic activity against human oral tumor cell lines than bleomycin and peplomycin. However, there was considerable variation of drug sensitivity among the six tumor cell lines. Mitomycin C induced internucleosomal DNA fragmentation and caspase-3, -8 and -9 activation in HL-60 cells only after 24 h. On the other hand, mitomycin C induced no clear-cut DNA fragmentation in HCS-2 cells, although it activated caspase-3, -8 and -9 to a slightly higher extent. Western blot analysis demonstrated that mitomycin C did not induce any apparent change in the intracellular concentration of anti-apoptotic protein (Bcl-2) and pro-apoptotic proteins (Bax, Bad). Electron microscopy of mitomycin C-treated HL-60 cells showed intact mitochondria (as regards to integrity and size) and cell surface microvilli, without production of an apoptotic body or autophagosome, at an early stage after treatment. The present study suggests the incomplete induction of apoptosis or the induction of another type of cell death by mitomycin C treatment.
使用人口腔鳞状细胞系（HSC - 2、HSC - 3、HSC - 4、Ca9 - 22和NA）、人早幼粒细胞白血病细胞系HL - 60以及人正常口腔细胞类型（牙龈成纤维细胞HGF、牙髓细胞HPC和牙周膜成纤维细胞HPLF），比较了三种抗肿瘤抗生素丝裂霉素C、硫酸博来霉素和硫酸培洛霉素的肿瘤特异性细胞毒性。在这三种化合物中，丝裂霉素C表现出最高的肿瘤特异性，因为它对人口腔肿瘤细胞系的细胞毒性活性高于博来霉素和培洛霉素。然而，六种肿瘤细胞系之间的药物敏感性存在相当大的差异。丝裂霉素C仅在24小时后才在HL - 60细胞中诱导核小体间DNA片段化以及半胱天冬酶 - 3、 - 8和 - 9的激活。另一方面，丝裂霉素C在HCS - 2细胞中未诱导出明显的DNA片段化，尽管它将半胱天冬酶 - 3、 - 8和 - 9激活到稍高的程度。蛋白质免疫印迹分析表明，丝裂霉素C未诱导抗凋亡蛋白（Bcl - 2）和促凋亡蛋白（Bax、Bad）的细胞内浓度发生任何明显变化。对丝裂霉素C处理的HL - 60细胞进行电子显微镜检查显示，在处理后的早期阶段，线粒体完整（在完整性和大小方面）且细胞表面微绒毛完整，未产生凋亡小体或自噬体。本研究表明丝裂霉素C处理诱导凋亡不完全或诱导了另一种类型的细胞死亡。
