G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy.
G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy.
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DOI：
10.1016/j.radonc.2012.04.021
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发表时间：
2012-08
期刊：
影响因子：
--
通讯作者：
Fan W
中科院分区：
文献类型：
--
作者：
Sui M;Zhang H;Di X;Chang J;Shen Y;Fan W
我们之前证明，辐射可以将肿瘤细胞阻滞在 G2 期，从而阻止抗微管药物的细胞毒性，并导致这两种方式之间的拮抗相互作用。在此，我们测试了G2废除剂是否会减弱上述拮抗相互作用并提高放射线和抗微管药物联合治疗的疗效。对乳腺癌BCap37和表皮样癌KB细胞系单独或组合施用放射线、UCN-01（G2废除剂的模型药物）、紫杉醇或长春新碱。通过一系列细胞毒性、细胞凋亡、细胞周期、形态学和生化测定来分析单一和联合治疗的抗肿瘤活性。 UCN-01显着增强放射、抗有丝分裂药物及其联合治疗的体外细胞毒性。进一步的研究表明，UCN-01 减弱了辐射诱导的 G2 期停滞，并随后抑制了辐射对药物诱导的有丝分裂停滞和细胞凋亡的抑制作用。这是第一份证明 G2 检查点废除可抑制放射线对抗微管药物的抑制作用的报告，这可能与癌症联合治疗有关。考虑到 G2 废除剂正在接受广泛的癌症治疗评估，我们的研究结果为此类有前景的化合物提供了有价值的信息。
We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs. Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptosis, cell cycle, morphological and biochemical assays. UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis. This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.
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