Azuma Y, Onishi Y, Mizuno Y, Kizaki H
Department of Biochemistry, Tokyo Dental College, Chiba, Japan.
Immunopharmacology. 1993 Nov-Dec;26(3):235-40. doi: 10.1016/0162-3109(93)90039-s.
Previous studies demonstrated that arabinosylcytosine (ara-C) induced internucleosomal DNA fragmentation and cell death in mouse thymocytes and that those were inhibited by 1-(5-iso-quinoline-sulfonyl)-2-methylpiperazine hydrochloride, an inhibitor of protein kinases. In the present study, we examined the relationship between the DNA fragmentation induced by ara-C and that by agents which activate intracellular signaling and induce apoptosis in mouse thymocytes. 12-O-tetradecanoyl 13-acetate, a phorbol ester capable of activating protein kinase C or A23187, a calcium ionophore, had no effect on ara-C induced DNA fragmentation. However, ara-C induced DNA fragmentation was synergistically enhanced by cAMP and cAMP receptor agonists. Ara-C inhibited the incorporation of choline into the acid soluble and lipid fractions, and cAMP enhanced this inhibition, suggesting that ara-C metabolites interfere with membrane phospholipid metabolism, partly evoking a certain cellular signaling for apoptosis and interacting with cAMP-evoked signaling.
先前的研究表明，阿糖胞苷（ara-C）可诱导小鼠胸腺细胞发生核小体间DNA片段化和细胞死亡，且这些过程会被蛋白激酶抑制剂盐酸1-(5-异喹啉磺酰基)-2-甲基哌嗪所抑制。在本研究中，我们检测了ara-C诱导的DNA片段化与激活细胞内信号传导并诱导小鼠胸腺细胞凋亡的试剂所诱导的DNA片段化之间的关系。能够激活蛋白激酶C的佛波酯12-O-十四烷酰佛波醇-13-乙酸酯或钙离子载体A23187对ara-C诱导的DNA片段化没有影响。然而，cAMP和cAMP受体激动剂可协同增强ara-C诱导的DNA片段化。ara-C抑制胆碱掺入酸溶性和脂质部分，而cAMP增强了这种抑制作用，这表明ara-C代谢产物干扰膜磷脂代谢，部分引发了某种细胞凋亡信号传导并与cAMP引发的信号传导相互作用。
