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: Jennifer Neumann, Yi Yang, Rebecca Köhler, Marco Giaisi, Mathias Witzens-Harig, Dong Liu, Peter H Krammer, Wenhan Lin, Min Li-Weber
• Journal: International journal of cancer (Int J Cancer) Vol. 137 Issue 11 Pg. 2739-48 (Dec 01 2015) ISSN: 1097-0215 [Electronic] United States
• PMID: 26061604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.

Chemical References

• Antineoplastic Agents
• Diterpenes
• Reactive Oxygen Species
• Tumor Suppressor Proteins
• Protein Kinases
• Checkpoint Kinase 2
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• CHEK2 protein, human
• Checkpoint Kinase 1
• Chek1 protein, mouse

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Checkpoint Kinase 1
• Checkpoint Kinase 2 (metabolism)
• DNA Damage (drug effects)
• Diterpenes (pharmacology)
• G2 Phase (drug effects)
• Humans
• Jurkat Cells
• Leukemia, T-Cell (drug therapy, metabolism)
• Mice
• Protein Kinases (metabolism)
• Reactive Oxygen Species (metabolism)
• Rhizophoraceae (chemistry)
• S Phase (drug effects)
• Tumor Suppressor Proteins (metabolism)