title: Ornithine decarboxylase attenuates leukemic chemotherapy drugs-induced cell apoptosis and arrest in human promyelocytic HL-60 cells.
abstract: 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-alpha 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 (Deltapsi 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 Deltapsi 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.
authors.affiliation: Department of Life Sciences, National Chung-Hsing University, Taichung, Taiwan, ROC.
authors.forename: Pei-Chen
authors.initials: PC
authors.lastname: Hsu
authors.forename: Hui-Chih
authors.initials: HC
authors.lastname: Hung
authors.forename: Ya-Fan
authors.initials: YF
authors.lastname: Liao
authors.forename: Chu-Chen
authors.initials: CC
authors.lastname: Liu
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsay
authors.forename: Guang-Yaw
authors.initials: GY
authors.lastname: Liu
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D002945:Cisplatin / Q000037:antagonists & inhibitors; D005047:Etoposide / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009955:Ornithine Decarboxylase / Q000378:metabolism*; D017239:Paclitaxel / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011700:Putrescine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D005047:Etoposide; D020169:Caspases; D009955:Ornithine Decarboxylase; D005978:Glutathione; D017239:Paclitaxel; D002945:Cisplatin; D011700:Putrescine; D000111:Acetylcysteine