The natural anticancer compound rocaglamide selectively inhibits the G1‐S‐phase transition in cancer cells through the ATM/ATR‐mediated Chk1/2 cell cycle checkpoints

• Published in: International journal of cancer 2014-04, Vol.134 (8), p.1991-2002
• Main Authors: Neumann, Jennifer, Boerries, Melanie, Köhler, Rebecca, Giaisi, Marco, Krammer, Peter H., Busch, Hauke, Li‐Weber, Min
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Ataxia Telangiectasia Mutated Proteins - drug effects; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM; ATR; Benzofurans - pharmacology; Biological and medical sciences; Cancer; cdc25 Phosphatases - biosynthesis; cdc25 Phosphatases - genetics; cdc25 Phosphatases - metabolism; Cdc25A; Cell cycle; Cell Line, Tumor; Cell Proliferation - drug effects; Checkpoint Kinase 1; Checkpoint Kinase 2 - genetics; Checkpoint Kinase 2 - metabolism; Chk1; Chk2; DNA Damage - drug effects; HCT116 Cells; Hep G2 Cells; HT29 Cells; Humans; Jurkat Cells; Leukemia - drug therapy; Lymphocytes; MCF-7 Cells; Medical research; Medical sciences; Phosphorylation - drug effects; Plant Extracts - pharmacology; Protein Biosynthesis - drug effects; Protein Kinases - genetics; Protein Kinases - metabolism; RNA Interference; RNA, Small Interfering; S Phase Cell Cycle Checkpoints - drug effects; T-Lymphocytes - drug effects; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28521

Targeting the cancer cell cycle machinery is an important strategy for cancer treatment. Cdc25A is an essential regulator of cycle progression and checkpoint response. Over‐expression of Cdc25A occurs often in human cancers. In this study, we show that Rocaglamide‐A (Roc‐A), a natural anticancer compound isolated from the medicinal plant Aglaia, induces a rapid phosphorylation of Cdc25A and its subsequent degradation and, thereby, blocks cell cycle progression of tumor cells at the G1‐S phase. Roc‐A has previously been shown to inhibit tumor proliferation by blocking protein synthesis. In this study, we demonstrate that besides the translation inhibition Roc‐A can induce a rapid degradation of Cdc25A by activation of the ATM/ATR‐Chk1/Chk2 checkpoint pathway. However, Roc‐A has no influence on cell cycle progression in proliferating normal T lymphocytes. Investigation of the molecular basis of tumor selectivity of Roc‐A by a time‐resolved microarray analysis of leukemic vs. proliferating normal T lymphocytes revealed that Roc‐A activates different sets of genes in tumor cells compared with normal cells. In particular, Roc‐A selectively stimulates a set of genes responsive to DNA replication stress in leukemic but not in normal T lymphocytes. These findings further support the development of Rocaglamide for antitumor therapy. What's new? Rocaglamides (Rocs) are a group of plant‐derived compounds that are known to preferentially kill malignant hematologic cells, while sparing normal cells. In this study, the authors identified a novel molecular mechanism by which Roc‐A inhibits leukemic cell growth, via the ATM/ATR‐Chk1/Chk2 cell‐cycle checkpoint pathway. Meanwhile, cell‐cycle progression in normal proliferating T cells was unaffected. These findings support further development of rocaglamides as an anti‐tumor therapy, potentially with lower toxicity than standard chemotherapeutic drugs.