Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, PR China.
Oncol Rep. 2012 Sep;28(3):969-76. doi: 10.3892/or.2012.1900. Epub 2012 Jul 5.
Medulloblastoma (MB) is one of the most common malignant brain tumors of childhood and is associated with a poor prognosis. Gap-junctional intercellular communication (GJIC) is an important mode for cell-to-cell communication. Dysfunctional GJIC is exhibited in most cancer cells. There is significant evidence that GJIC is important in at least some prodrug/suicide gene systems by augmenting the bystander effect (BE). GJIC is made up of connexins (Cxs), among which Cx43 is present in most tissues. Bcl-2, an important apoptosis blocker, is closely associated with the sensitivity to anticancer drugs. Our study showed that dibutyryl cyclic adenosine monophosphate (db-cAMP) upregulated the Cx43 expression and GJIC function in Daoy medulloblastoma cells. It directly enhanced the BE using a herpes simplex virus thymidine kinase (HSV‑tk)/ganciclovir (GCV) system, which was blocked by a Cx43 inhibitor. In addition, db-cAMP increased the cytotoxicity of temozolomide and teniposide, possibly by downregulating the Bcl-2 expression and inducing apoptosis. Taken together, we demonstrated the beneficial effect of db-cAMP in treating medulloblastoma depending on the upregulation of BE and chemosensitivity through Cx43 and Bcl-2-mediated pathways.
髓母细胞瘤（MB）是儿童中最常见的恶性脑肿瘤之一，预后不良。缝隙连接细胞间通讯（GJIC）是细胞间通讯的重要方式。大多数癌细胞中存在功能失调的 GJIC。有大量证据表明，GJIC 至少在某些前药/自杀基因系统中通过增强旁观者效应（BE）很重要。GJIC 由连接蛋白（Cxs）组成，其中 Cx43 存在于大多数组织中。Bcl-2 是一种重要的凋亡抑制剂，与抗癌药物的敏感性密切相关。我们的研究表明，二丁酰环腺苷单磷酸（db-cAMP）可上调 Daoy 髓母细胞瘤细胞中的 Cx43 表达和 GJIC 功能。它直接通过单纯疱疹病毒胸苷激酶（HSV-tk）/更昔洛韦（GCV）系统增强 BE，该系统被 Cx43 抑制剂阻断。此外，db-cAMP 增加了替莫唑胺和替尼泊苷的细胞毒性，可能通过下调 Bcl-2 表达并诱导细胞凋亡。综上所述，我们证明了 db-cAMP 通过 Cx43 和 Bcl-2 介导的途径上调 BE 和化疗敏感性来治疗髓母细胞瘤的有益作用。
