Accumulated cytotoxicity of CDK inhibitor dinaciclib with first-line chemotherapy drugs in salivary adenoid cystic carcinoma cells
Accumulated cytotoxicity of CDK inhibitor dinaciclib with first-line chemotherapy drugs in salivary adenoid cystic carcinoma cells
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DOI：
10.1007/s10266-019-00451-5
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发表时间：
2019-09
期刊：
影响因子：
2.5
通讯作者：
Laijun Xu;Lingzhi Li;Jun Zhang;W. Cai;Shouliang Zhao;Shangfeng Liu
中科院分区：
文献类型：
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作者：
Laijun Xu;Lingzhi Li;Jun Zhang;W. Cai;Shouliang Zhao;Shangfeng Liu
腺样囊性癌是涎腺最常见的恶性肿瘤之一。其治疗失败的部分原因是化疗药物的局限性及其不良反应。本研究的目的是确定一种新型的CDK抑制剂迪纳西利与一线化疗药物在ACC中潜在的相加抗癌作用。应用免疫组织化学方法检测17例ACC石蜡包埋标本中磷酸化CDK2(p-CDK2)蛋白的表达。采用细胞计数试剂盒(CCK-8)、克隆形成试验和流式细胞仪检测地奈西利与其他一线化疗药物合用或不合用对ACC-2细胞增殖和凋亡的影响。Western印迹法检测蛋白质的表达。有趣的是，我们发现p-CDK2蛋白在涎腺腺样囊性癌组织中的胞浆和胞核均有表达，高于正常唾液组织，提示靶向CDK2的药物可能是治疗这类肿瘤的潜在策略。正如预期的那样，CDK抑制剂diaciclib显著诱导ACC-2细胞凋亡。此外，它还使细胞对化疗药物如顺铂、培美曲塞和依托泊苷(VP-16)增敏，这种作用可能通过抑制CDK2活性而诱导细胞周期停滞。因此，CDK抑制剂地奈西利与一线化疗药物联合治疗涎腺ACC可能是一种很有前途的治疗策略。
Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignant tumors. Its treatment failure is partly due to the limitations of chemotherapeutic agents and their adverse effects. The objective of this study was to determine the potential additive anti-cancer effect of a novel CDK inhibitor dinaciclib with first-line chemotherapy drugs in ACC. Protein expression of phosphorylated CDK2 (p-CDK2) in paraffin-embedded tissue specimens of ACC from 17 patients was investigated by immunohistochemistry (IHC). Cell Counting Kit (CCK-8), clone formation assay, and flow cytometry were used to test the proliferation and apoptosis of ACC-2 cells treated with dinaciclib with or without other first-line chemotherapy drugs. Protein expression was also determined by Western blot. Interestingly, we discovered that p-CDK2 protein was expressed in both cytoplasmic and nucleus in salivary ACC tissues, which was higher than that in normal salivary tissues, indicating that agents targeting CDK2 may be potential therapeutic strategies against this type of tumor. As expected, CDK inhibitor dinaciclib significantly induced ACC-2 cells apoptosis. Moreover, it sensitized cells to the chemotherapeutic agents such as cisplatin, pemetrexed, and etoposide (VP-16), and this effect by dinaciclib may induce cell cycle arrest via abrogating CDK2 activity. Therefore, combinational therapy of CDK inhibitor dinaciclib with first-line chemotherapy drugs may be a promising strategy in the treatment of salivary ACC.