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.

Abstract

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.

• Authors: Jennifer Neumann, Melanie Boerries, Rebecca Köhler, Marco Giaisi, Peter H Krammer, Hauke Busch, Min Li-Weber
• Journal: International journal of cancer (Int J Cancer) Vol. 134 Issue 8 Pg. 1991-2002 (Apr 15 2014) ISSN: 1097-0215 [Electronic] United States
• PMID: 24150948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 UICC.

Chemical References

• Antineoplastic Agents
• Benzofurans
• Plant Extracts
• RNA, Small Interfering
• rocaglamide
• Protein Kinases
• Checkpoint Kinase 2
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins
• CHEK1 protein, human
• Checkpoint Kinase 1
• CDC25A protein, human
• cdc25 Phosphatases

Topics

• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins (drug effects, metabolism)
• Benzofurans (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Checkpoint Kinase 1
• Checkpoint Kinase 2 (genetics, metabolism)
• DNA Damage (drug effects)
• HCT116 Cells
• HT29 Cells
• Hep G2 Cells
• Humans
• Jurkat Cells
• Leukemia (drug therapy)
• MCF-7 Cells
• Phosphorylation (drug effects)
• Plant Extracts (pharmacology)
• Protein Biosynthesis (drug effects)
• Protein Kinases (genetics, metabolism)
• RNA Interference
• RNA, Small Interfering
• S Phase Cell Cycle Checkpoints (drug effects)
• T-Lymphocytes (drug effects)
• cdc25 Phosphatases (biosynthesis, genetics, metabolism)