title: Mangrove dolabrane-type of diterpenes tagalsins suppresses tumor growth via ROS-mediated apoptosis and ATM/ATR-Chk1/Chk2-regulated cell cycle arrest.
abstract: Natural compounds are an important source for drug development. With an increasing cancer rate worldwide there is an urgent quest for new anti-cancer drugs. In this study, we show that a group of dolabrane-type of diterpenes, collectively named tagalsins, isolated from the Chinese mangrove genus Ceriops has potent cytotoxicity on a panel of hematologic cancer cells. Investigation of the molecular mechanisms by which tagalsins kill malignant cells revealed that it induces a ROS-mediated damage of DNA. This event leads to apoptosis induction and blockage of cell cycle progression at S-G2 phase via activation of the ATM/ATR-Chk1/Chk2 check point pathway. We further show that tagalsins suppress growth of human T-cell leukemia xenografts in vivo. Tagalsins show only minor toxicity on healthy cells and are well tolerated by mice. Our study shows a therapeutic potential of tagalsins for the treatment of hematologic malignancies and a new source of anticancer drugs.
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Neumann
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Köhler
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Giaisi
authors.affiliation: Medizinische Klinik V Hämatologie, Onkologie und Rheumatologie, University of Heidelberg, Im Neuenheimer Feld 410, Heidelberg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Witzens-Harig
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, People's Republic of China.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Lin
authors.affiliation: Tumorimmunology Program (D030), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Min
authors.initials: M
authors.lastname: Li-Weber
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D064447:Checkpoint Kinase 2 / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004224:Diterpenes / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043982:Rhizophoraceae / Q000737:chemistry; D016196:S Phase / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004224:Diterpenes; D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse
keywords: ATM; ATR; Cdc25A; Chk1; Chk2; apoptosis; cancer