Two 4N cell-cycle arrests contribute to cisplatin-resistance.
Two 4N cell-cycle arrests contribute to cisplatin-resistance.
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DOI：
10.1371/journal.pone.0059848
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Maki CG
中科院分区：
文献类型：
--
作者：
Shen H;Perez RE;Davaadelger B;Maki CG
顺铂是一种铂类药物，用于治疗多种原发性人类癌症。然而，顺铂的治疗效果常常受到内在或获得性耐药性的限制。因此，一个重要的目标是确定导致癌症顺铂耐药的机制，然后利用这些信息更有效地靶向耐药细胞。 HCT116 细胞系的顺铂抗性克隆在顺铂处理后经历了长时间的 G2 停滞，而敏感克隆则没有。星形孢菌素类似物 UCN-01 消除了这种 G2 停滞并使耐药克隆对顺铂敏感。在稍后的时间点，4N 停滞的细胞呈现四倍体 G1 状态，其特征是 4N 细胞中细胞周期蛋白 A、细胞周期蛋白 B 和 CDC2 的耗尽以及 p53 和 p21 的表达增加。 siRNA 介导的 p21 敲低消除了四倍体 G1 停滞并诱导依赖于 p53 的杀伤。结果确定了两种可导致顺铂耐药的可靶向 4N 阻滞：首先是 UCN-01 可以靶向的延长 G2 阻滞，其次是 p21 siRNA 可以靶向的四倍体 G1 阻滞。
Cisplatin is a platinum-based drug that is used for the treatment of a wide-variety of primary human cancers. However, the therapeutic efficacy of cisplatin is often limited by intrinsic or acquired drug resistance. An important goal, therefore, is to identify mechanisms that lead to cisplatin resistance in cancer, and then use this information to more effectively target resistant cells. Cisplatin-resistant clones of the HCT116 cell line underwent a prolonged G2 arrest after cisplatin treatment while sensitive clones did not. The staurosporine analog UCN-01 abrogated this G2 arrest and sensitized the resistant clones to cisplatin. At later time points, 4N arrested cells assumed a tetraploid G1 state that was characterized by depletion of Cyclin A, Cyclin B, and CDC2, and increased expression of p53 and p21, in 4N cells. siRNA-mediated knockdown of p21 abrogated the tetraploid G1 arrest and induced killing that was dependent on p53. The results identify two targetable 4N arrests that can contribute to cisplatin resistance: First, a prolonged G2 arrest that can be targeted by UCN-01, and second, a tetraploid G1 arrest that can be targeted by siRNA against p21.
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影响因子：
8
作者：
Sato, S;Fujita, N;Tsuruo, T
通讯作者：
Tsuruo, T
影响因子：
4.7
作者：
He G;Kuang J;Khokhar AR;Siddik ZH
通讯作者：
Siddik ZH
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
56.9
作者：
Bunz, F;Dutriaux, A;Vogelstein, B
通讯作者：
Vogelstein, B
CHK1的抑制通过p53依赖性途径杀死四倍体肿瘤细胞。
影响因子：
3.7
作者：
Vitale, Ilio;Galluzzi, Lorenzo;Vivet, Sonia;Nanty, Lisa;Dessen, Philippe;Senovilla, Laura;Olaussen, Ken A.;Lazar, Vladimir;Prudhomme, Michelle;Golsteyn, Roy M.;Castedo, Maria;Kroemer, Guido
通讯作者：
Kroemer, Guido