title: Paclitaxel induces apoptosis in leukemia cells through a JNK activation-dependent pathway.
abstract: Paclitaxel (PTX) is a mitotic inhibitor widely used in chemotherapy for many types of cancers, including solid tumors and hematological malignancies. However, the molecular basis of the anti-proliferation activity of PTX is not fully understood. In this paper, we focused on the role of c-Jun N-terminal kinase (JNK) pathways in PTX-induced apoptosis and proliferation inhibition. The effects of PTX were examined in human leukemia cell lines and patients' chronic lymphocytic leukemia (CLL) cells in relation to mitochondrial events, apoptosis, and perturbation of JNK activation using flow cytometry, siRNA, mitochondrial membrane potential determination, and western blotting. Exposure of cells to PTX at concentrations ≥ 10 nM for 18 or 24 h resulted in a significant release of cytochrome c from mitochondria to the cytosol, cleavages of procaspase 3 and poly (ADP-ribose) polymerase (PARP), and JNK activation, leading to apoptosis. The pan-caspase inhibitor BOC-D-FMK blocked the PTX-induced apoptosis but had no effect on cytochrome c release, suggesting that cytochrome c had been released before caspase activation. Moreover, both pharmacological JNK inhibitors SP600125 and JNK siRNA dramatically blocked PTX-induced apoptosis, cytochrome c release, caspase 3, and PARP cleavage. These findings demonstrate that JNK activation plays a critical role in the induction of apoptosis mediated by PTX in human leukemia cell lines and CLL patient-derived primary cancer cells, and this event is upstream of cytochrome c release, caspase 3, and PARP cleavage.
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Z G
authors.initials: ZG
authors.lastname: Peng
authors.affiliation: Department of Surgery, Beijing Xuanwu Hospital, Capital Medical University, Xuanwu District, Beijing, China.
authors.forename: D C
authors.initials: DC
authors.lastname: Liu
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Y B
authors.initials: YB
authors.lastname: Yao
authors.affiliation: Department of Functional Genomics, National Human Genome Center of China, BDA, Beijing, China.
authors.forename: X L
authors.initials: XL
authors.lastname: Feng
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: Y L
authors.initials: YL
authors.lastname: Tang
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, China.
authors.forename: X X
authors.initials: XX
authors.lastname: Wang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel