Restriction of cisplatin induction of acute apoptosis to a subpopulation of cells in a three-dimensional carcinoma culture model
Restriction of cisplatin induction of acute apoptosis to a subpopulation of cells in a three-dimensional carcinoma culture model
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DOI：
10.1002/ijc.24627
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发表时间：
2009-11-15
影响因子：
6.4
通讯作者：
Linder, Stig
中科院分区：
文献类型：
--
作者：
Fayad, Walid;Brnjic, Slavica;Linder, Stig
顺铂是临床上用于治疗上皮恶性肿瘤的重要化学治疗剂。高浓度（20-100 μ M）的顺铂已被用于在许多研究中诱导细胞凋亡的癌细胞生长在单层培养超过24-48小时。这些条件可能不相关的三维肿瘤组织在体内和肿瘤反应的重要性是有争议的。我们在这里研究了顺铂对三维结肠癌体外模型（多细胞球体）的影响。顺铂在40 μ M的剂量诱导活性caspase-3优先在周围30 μ m，细胞层的球状体，主要是在后期阶段（72-96小时）。p53对顺铂的反应也主要局限于外周细胞层。尽管使用了高浓度的顺铂，但球状体中的显著部分的细胞在处理中存活。高比例的存活细胞对β-半乳糖苷酶染色呈阳性，β-半乳糖苷酶是早衰的标志物。顺铂处理的细胞生长停滞显示出比未处理的增殖细胞更高的自发细胞死亡率。我们建议，急性细胞凋亡是次要的意义的癌细胞顺铂治疗的整体反应。(C)2009年UICC
Cisplatin is a clinically important chemotherapeutical agent used to treat epithelial malignancies. High concentrations (20-100 mu M) of cisplatin have been used in numerous studies to induce apoptosis of carcinoma tells grown in monolayer culture over 24-48 hr. These conditions may not be relevant to 3-D tumor tissue in vivo and the importance of apoptosis for tumor response is controversial. We here studied the effects of cisplatin on a 3-D colon carcinoma in vitro model (multicellular spheroids). Cisplatin at a dose of 40 mu M induced active caspase-3 preferentially in the peripheral 30 mu m, cell layer of spheroids, mainly during late stages (72-96 hr). The p53 response to cisplatin was also largely confined to peripheral cell layers. Despite the use of a high cisplatin concentration, a significant fraction of the cells in the spheroids survived treatment. A high proportion of surviving cells stained positive for beta-galactosidase, a marker of premature senescence. Cells growth-arrested by cisplatin treatment showed a higher spontaneous cell death rate than untreated proliferating cells. We propose that acute apoptosis is of minor significance for the overall response of carcinoma cells to cisplatin treatment. (C) 2009 UICC