title: Parthenolide-induced apoptosis in multiple myeloma cells involves reactive oxygen species generation and cell sensitivity depends on catalase activity.
abstract: The sesquiterpene lactone, parthenolide (PTL), possesses strong anticancer activity against various cancer cells. We report that PTL strongly induced apoptosis in 4 multiple myeloma (MM) cell lines and primary MM cells (CD38(+) high), but barely induced death in normal lymphocytes (CD38(-/+)low). PTL-mediated apoptosis correlated well with ROS generation and was almost completely inhibited by L-N-acetylcysteine (L-NAC), indicating the crucial role of oxidative stress in the mechanism. Among 4 MM cell lines, there is considerable difference in susceptibility to PTL. KMM-1 and MM1S cells sensitive to PTL possess less catalase activity than the less sensitive KMS-5 and NCI-H929 cells as well as normal lymphocytes. A catalase inhibitor 3-amino-1,2,4-triazole enhanced their PTL-mediated ROS generation and cell death. The siRNA-mediated knockdown of catalase in KMS-5 cells decreased its activity and sensitized them to PTL. Our findings indicate that PTL induced apoptosis in MM cells depends on increased ROS and intracellular catalase activity is a crucial determinant of their sensitivity to PTL.
authors.affiliation: Division of Molecular Oncology and Molecular Diagnosis, Graduate School of Medicine, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Masaaki
authors.initials: M
authors.lastname: Adachi
authors.forename: Rina
authors.initials: R
authors.lastname: Kawamura
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sakamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Hayashi
authors.forename: Tadao
authors.initials: T
authors.lastname: Ishida
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Shinomura
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000473:pathology*; D009861:Onium Compounds / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D004791:Enzyme Inhibitors; D009861:Onium Compounds; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; C002669:parthenolide; C007517:diphenyleneiodonium; D002374:Catalase; D000111:Acetylcysteine