GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner
GTP depletion synergizes the anti-proliferative activity of chemotherapeutic agents in a cell type-dependent manner
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DOI：
10.1016/j.bbrc.2011.09.091
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发表时间：
2011-10-22
影响因子：
3.1
通讯作者：
Tsai, Robert Y. L.
中科院分区：
文献类型：
--
作者：
Lin, Tao;Meng, Lingjun;Tsai, Robert Y. L.
霉酚酸通过阻断鸟嘌呤核苷酸的合成来耗尽细胞内的GTP。GTP广泛用于DNA/RNA合成和信号分子。在这里，我们有了一个令人惊讶的发现，即甲孕酮的抗增殖活性与特定的化疗药物以细胞类型依赖的方式协同作用。在MDA-MB-231细胞中，甲孕酮与5-FU有极强的协同作用，但与阿霉素或依托泊苷无协同作用。与致瘤性较低的乳腺癌细胞相比，5-FU和MPA之间的协同作用对高致瘤性的乳腺肿瘤细胞最有效，而在我们测试的非乳腺癌细胞类型中不起作用，PC3细胞除外。相反，在口腔鳞癌的SCC-25细胞中，甲孕酮与紫杉醇的协同作用最强，但与5-FU的协同作用不明显。从机制上讲，甲孕酮对5-FU的协同作用可以通过抑制RNA聚合酶-I的活性来实现，并且需要核干素的表达。这项工作揭示了甲孕酮和抗增殖剂之间的协同作用是由细胞类型依赖因素决定的。(C)2011 Elsevier Inc.保留所有权利。
Mycophenolic acid (MPA) depletes intracellular GTP by blocking de novo guanine nucleotide synthesis. GTP is used ubiquitously for DNA/RNA synthesis and as a signaling molecule. Here, we made a surprising discovery that the anti-proliferative activity of MPA acts synergistically with specific chemotherapeutic agents in a cell type-dependent manner. In MDA-MB-231 cells, MPA shows an extremely potent synergy with 5-FU but not with doxorubicin or etoposide. The synergy between 5-FU and MPA works most effectively against the highly tumorigenic mammary tumor cells compared to the less tumorigenic ones, and does not work in the non-breast cancer cell types that we tested, with the exception of PC3 cells. On the contrary, MPA shows the highest synergy with paclitaxel but not with 5-FU in SCC-25 cells, derived from oral squamous cell carcinomas. Mechanistically, the synergistic effect of MPA on 5-FU in MDA-MB-231 cells can be recapitulated by inhibiting the RNA polymerase-I activity and requires the expression of nucleostemin. This work reveals that the synergy between MPA and anti-proliferative agents is determined by cell type-dependent factors. (C) 2011 Elsevier Inc. All rights reserved.