Sakagami Hiroshi, Okudaira Noriyuki, Masuda Yoshiko, Amano Osamu, Yokose Satoshi, Kanda Yumiko, Suguro Madoka, Natori Takenori, Oizumi Hiroshi, Oizumi Takaaki
Division of Pharmacology, Meikai University School of Dentistry, Sakado, Japan
Meikai Pharmaco-Medical Laboratory (MPL), Meikai University School of Dentistry, Sakado, Japan.
Anticancer Res. 2017 Mar;37(3):1023-1029. doi: 10.21873/anticanres.11412.
BACKGROUND/AIM: We have previously reported that doxorubicin (DXR) showed much higher cytotoxicity against human oral squamous cell carcinoma cell lines compared to normal human mesenchymal normal oral cells (gingival fibroblast, periodontal ligament fibroblast, pulp cell), yielding high tumor-specificity. However, we unexpectedly found that doxorubicin showed potent cytotoxicity against human normal oral keratinocytes and primary gingival epithelial cells. In the present study, we investigated the reproducibility, underlining mechanisms and generality of this unexpected finding.
Viable cell number was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method, fine cell structure by transmission electron microscopy and apoptosis induction by western blot analysis.
Doxorubicin induced keratinocyte toxicity, regardless of cell density and concentration of FBS in the culture medium. Doxorubicin induced apoptosis (characterized by the loss of cell surface microvilli, chromatin condensation, nuclear fragmentation and caspase-3 activation) in keratinocytes. A total of 11 anticancer drugs showed similar keratinocyte toxicity. Alkaline extract of the leaves of Sasa senanensis Rehder partially alleviated the DXR-induced keratinocyte cytotoxicity by promoting cell growth.
The present study suggested that oral keratinocyte toxicity is a novel adverse effect of most anticancer agents.
背景/目的：我们之前报道过，与正常人间质口腔细胞（牙龈成纤维细胞、牙周膜成纤维细胞、牙髓细胞）相比，阿霉素（DXR）对人口腔鳞状细胞癌细胞系显示出更高的细胞毒性，具有较高的肿瘤特异性。然而，我们意外地发现阿霉素对人正常口腔角质形成细胞和原代牙龈上皮细胞显示出强大的细胞毒性。在本研究中，我们调查了这一意外发现的可重复性、潜在机制及普遍性。
通过3-（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐法测定活细胞数量，通过透射电子显微镜观察细胞精细结构，并通过蛋白质印迹分析诱导凋亡情况。
无论细胞密度和培养基中胎牛血清的浓度如何，阿霉素均可诱导角质形成细胞毒性。阿霉素可诱导角质形成细胞凋亡（表现为细胞表面微绒毛丧失、染色质凝聚、核碎裂和半胱天冬酶-3激活）。共有11种抗癌药物显示出类似的角质形成细胞毒性。青篱竹（Sasa senanensis Rehder）叶的碱性提取物通过促进细胞生长部分减轻了阿霉素诱导的角质形成细胞毒性。
本研究表明，口腔角质形成细胞毒性是大多数抗癌药物的一种新的不良反应。
