Segal-Bendirdjian E, Jacquemin-Sablon A
Unité de physicochimie et pharmacologie des macromolécules biologiques (URA147), Villejuif, France.
Bull Cancer. 1996 May;83(5):371-8.
It has been recently reported that a number of anticancer drugs, including cisplatin, may exert their toxicity by inducing apoptosis. In order to investigate whether an alteration in the mechanisms involved in the process of apoptosis could contribute to cellular resistance, induction of apoptosis was studied in a cisplatin-resistant cell line (L1210/DDP) derived from a L1210 murine leukemia cell line (L1210/0). We first established that the mutant cell line resisted 5-azacytidine, a drug to which it was never exposed and which is known to have a very different mechanism of action from that of cisplatin. We then showed that these cells did not exhibit any DNA fragmentation or morphological changes typical of apoptosis, when exposed to toxic concentrations of either cisplatin or 5-azacytidine. The failure of these cells to undergo typical apoptosis upon cisplatin or 5-azacytidine exposure was correlated with the lack of a nuclear endonuclease activity present in wild type cell nuclei. However, staurosporine, a potent protein kinase C inhibitor, which exerted the same toxicity on both cell lines, induced the internucleosomal DNA fragmentation and morphological features of apoptosis in both of them. This indicates that a functional pathway for apoptosis is preserved in the resistant cells. The induction of this pathway can be correlated with the presence of a cytoplamic endonuclease activity whose specificity seems different from that operating in L1210/0 cells. In conclusion, our data indicate that the mechanisms which control activation of apoptosis in L1210/0 cells differ from those which operate in L1210/DDP cells. One of the differences concerns the nature and the subcellular localization of the endonuclease activity possibly involved in the internucleosomal DNA cleavage.
最近有报道称，包括顺铂在内的多种抗癌药物可能通过诱导细胞凋亡发挥其毒性作用。为了研究凋亡过程中相关机制的改变是否会导致细胞耐药，我们对源自L1210小鼠白血病细胞系（L1210/0）的顺铂耐药细胞系（L1210/DDP）中的凋亡诱导情况进行了研究。我们首先确定该突变细胞系对5-氮杂胞苷具有抗性，5-氮杂胞苷是一种它从未接触过的药物，且已知其作用机制与顺铂截然不同。然后我们发现，当暴露于毒性浓度的顺铂或5-氮杂胞苷时，这些细胞未表现出任何典型的凋亡DNA片段化或形态学变化。这些细胞在顺铂或5-氮杂胞苷暴露后未能发生典型凋亡，这与野生型细胞核中存在的核内切酶活性缺失有关。然而，星形孢菌素是一种有效的蛋白激酶C抑制剂，它对两种细胞系都具有相同的毒性，可诱导它们出现核小体间DNA片段化和凋亡的形态学特征。这表明耐药细胞中存在一条功能性的凋亡途径。该途径的诱导可能与一种细胞质内切酶活性的存在有关，其特异性似乎与L1210/0细胞中起作用的酶不同。总之，我们的数据表明，L1210/0细胞中控制凋亡激活的机制与L1210/DDP细胞中起作用的机制不同。其中一个差异涉及可能参与核小体间DNA切割的内切酶活性的性质和亚细胞定位。
