Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells

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• 作者：Pei-Chen Hsu ; Hui-Chih Hung ; Ya-Fan Liao ; Chu-Chen Liu ; Gregory J. Tsay ; Guang-Yaw Liu
• 关键词：Ornithine decarboxylase ; Cancer chemotherapeutic drug ; Apoptosis ; Cell cycle
• 刊名：Leukemia Research
• 出版年：2008
• 出版时间：October 2008
• 年：2008
• 卷：32
• 期：10
• 页码：1530-1540
• 全文大小：1079 K

文摘

Ornithine decarboxylase (ODC), the rate-limiting enzyme of the polyamine biosynthetic pathway, plays an important role in cell cycle, tumor promotion and anti-apoptosis. In our previous studies, overexpression of ODC prevented apoptosis induced by tumor necrosis factor- and methotrexate. We further investigated the apoptotic mechanisms of the cancer chemotherapeutic drugs, including etoposide (VP-16), paclitaxel (TAX) and cisplatin (CDDP), and the influences of ODC on apoptosis and cell cycle. Our results showed that the investigated drugs induced caspase-dependent apoptosis, the generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (Δψ_m) in HL-60 cells, all of which were reversed by putrescine, glutathione or N-acetyl-l-cysteine. Overexpression of ODC prevented the cancer chemotherapeutic drugs-induced apoptosis, ROS generation and the disruption of Δψ_m. After drug administrations, the decline of Bcl-2, cytochrome c release and caspases’ activation were inhibited by ODC overexpression. In cell cycle, ODC overexpressed cells seemed to overcome the G1 arrest and G2/M arrest, caused by VP-16 and TAX, respectively, and kept on the cell cycle rolling. Overexpression of ODC increased the expression of Cyclin A, D, E and Cdk4 and the enzyme activity of Cdk1 and Cdk2 after the treatment of VP-16 and TAX, respectively. In conclusions, the cancer chemotherapeutic drugs-induced apoptosis is through ROS-related, mitochondria-mediated and caspase-dependent pathways. With higher ODC activity, cells are resistant to the cancer chemotherapeutic drugs-induced apoptosis and keep on the cell cycle rolling with the significant interference in G1/S arrest caused by VP-16 and G2/M arrest by TAX.