Kiyomiya Ken-Ichi, Kurebe Masaru, Nakagawa Hiroshi, Matsuo Saburou
Laboratory of Toxicology, Graduate School of Veterinary Medicine, Osaka Prefecture University, Sakai 599-8531, Japan.
Int J Oncol. 2002 Jun;20(6):1205-9.
To elucidate the involvement of proteasome inhibition in apoptosis induced by anthracycline anticancer agents, we investigated the interaction between the proteasome and anthracycline anticancer agents, and the function of the proteasome in apoptosis. Exposure of L1210 mouse lymphocytic leukemia cells to adriamycin (ADM) or 4'-O-tetrahydropyranyladriamycin (THP) resulted in apoptosis in a dose-dependent manner: 5 microM ADM and 0.5 microM THP induced apoptosis efficiently, but the effects of 10 microM ADM and 5 microM THP were markedly decreased or completely absent. Carbobenzoxy-leucyl-leucyl-leucinal (Z-LLLal), a specific proteasome inhibitor, also induced dose-dependent apoptosis of the cells. The inhibitory effect of THP on chymotrypsin-like protease activity of proteasomes purified from the cytosol of L1210 cells was stronger than that of ADM. Both of these agents showed reversible non-competitive inhibitory effects. The intracellular content of ubiquitinated protein increased in ADM-, THP- or Z-LLLal-treated L1210 cells during apoptosis. These results suggested that anthracycline anticancer agents induce apoptosis by interacting, at least in part, with proteasomes.
为阐明蛋白酶体抑制在蒽环类抗癌药物诱导的细胞凋亡中的作用，我们研究了蛋白酶体与蒽环类抗癌药物之间的相互作用，以及蛋白酶体在细胞凋亡中的功能。将L1210小鼠淋巴细胞白血病细胞暴露于阿霉素（ADM）或4'-O-四氢吡喃基阿霉素（THP）会导致剂量依赖性细胞凋亡：5μM ADM和0.5μM THP能有效诱导细胞凋亡，但10μM ADM和5μM THP的作用明显减弱或完全消失。特异性蛋白酶体抑制剂苄氧羰基-亮氨酰-亮氨酰-亮氨酸醛（Z-LLLal）也能诱导细胞的剂量依赖性凋亡。THP对从L1210细胞胞质溶胶中纯化的蛋白酶体类胰凝乳蛋白酶活性的抑制作用强于ADM。这两种药物均表现出可逆的非竞争性抑制作用。在凋亡过程中，经ADM、THP或Z-LLLal处理的L1210细胞中泛素化蛋白的细胞内含量增加。这些结果表明，蒽环类抗癌药物至少部分通过与蛋白酶体相互作用来诱导细胞凋亡。
