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/ATRChk1/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.In normal cells, the cell division cycle is tightly controlled. Cancer cells are characterized by deregulation in the cell division cycle, which is associated with increased DNA replication and elevated cellular proliferation. 1-3 Therefore, targeting the cancer cell cycle machinery has been considered to be a rational strategy for cancer treatment. 4 Cell division is governed by cyclin dependent kinases (CDKs) that are tightly regulated by cyclins and CDK inhibitors (CDKIs). Tumor-associated cell cycle defects often show alterations in CDK expression or/and activity. 2 Typically, CDK4 and CDK6 that are crucial for G1 checkpoint control are often over-expressed in many malignancies. 2,3 Evidence shows that deregulation of CDK4 and CDK6 activity is associated with a wide variety of tumors. 2 Moreover, elevated expressions of the cell division cycle 25 (Cdc25) phosphatases, in particular, the isoform Cdc25A, which is essential for cell cycle transitions of G1-S and S-G2, has been shown in different cancers and their over-expression often correlates with more aggressive disease and poor prognosis. 1,5 Recently, genetic studies indicate that CDK2, CDK4 and CDK6 are not essential for the mammalian cell cycle. Instead, they are only required for the proliferation of specific cell types. 2 Thus, targeting the activities of CDK2, CDK4 and CDK6 may be a promising approach for cancer treatment.Rocaglamides (Roc; 5 Flavaglines), derived from the traditional Chinese medicinal plant Aglaia, are a group of naturally occurring herbal chemicals. A number of Roc compounds have been shown to possess potent inhibitory effects on tumor growth in vitro and in vivo in animal models with IC 50 concentrations at the n...

Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species

“…Interestingly, this effect appears to be due to DNA replication stress-mediated activation of the ATM/ATR pathway and not inhibition of translation. 89 Additionally, the levels of certain microRNA species were found to be affected by silvestrol ( 2 ) in acute myeloid leukemia cells via an unknown mechanism. 62 As microRNAs have been shown to be involved in the regulation of key cell functions as well as the development of malignancy, this finding introduces an entirely new area of investigation into the reasons for the diverse biological effects of cyclopenta[ b ]benzofurans.…”

Activation and Inhibition of ATM by Phytochemicals: Awakening and Sleeping the Guardian Angel Naturally

“…Using in vitro assays, it was shown that degradation of CDC25A-triggered G1 arrest through the ATM/ATR-CHEK1/2 checkpoint pathway in several malignant cell lines but not for normal T lymphocytes (Neumann et al 2014). Rocaglamide was reported to sensitize the TRAIL-resistant hepatocellular carcinoma Huh7 cells to TRAIL-mediated apoptosis by downregulation of cellular FADD-like IL-1b-converting enzyme like inhibitory protein and caspase 8 activation (Luan et al 2015).…”

“…Accordingly, we aim to discuss a list of phytonutrients reported to be involved in the induction of cell cycle arrest. Following certain natural agents, normal ATM function commonly triggers G1 arrest (Costantino et al 2013;Neumann et al 2014) via p53. ATM is also involved in inducing S phase (Tyagi et al 2005) and G2/M phase arrest (Guo et al 2014b;Tyagi et al 2014b).…”

Anti-proliferative effect of Moringa oleifera Lam (Moringaceae) leaf extract on human colon cancer HCT116 cell line

“…Cancer is one of the leading diseases that results in hundreds of thousand deaths among Thais [1][2][3]. Many of the naturally derived anti-cancer drugs successfully became current drugs such as placitaxel, vincristine, and vinblastine.…”