Cell cycle control as a basis for cancer chemoprevention through dietary agents

Abstract

The development of cancer is associated with disorders in the regulation of the cell cycle. The purpose of this review is to briefly summarize the known sequence of events that regulate cell cycle progression with an emphasis on the checkpoints and the mechanisms cell employ to insure DNA stability in the face of genotoxic stress. Key transitions in the cell cycle are regulated by the activities of various protein kinase complexes composed of cyclin and cyclin-dependent kinases (CDK) molecules. The cyclins are CDK binding partners which are required for kinase activity and their protein levels are intimately linked to the cell cycle stage. CDK activity can be regulated by other mechanisms, such as phosphorylation events, that may contribute to deregulation of cell cycle and the development of cancer. While fruits and vegetables are recommended for prevention of cancer, their active ingredients and mechanisms of action are less well understood. Here, we briefly present evidence that dietary agents identified from fruits and vegetables can act to modulate the effects of deregulated cell cycle checkpoints, and that this may contribute to the prevention of cancer. The agents include apigenin (celery, parsley), curcumin (turmeric), (-)-epigallocatechin-3-gallate (green tea), resveratrol (red grape, peanuts and berries), genistein (soybean), and silymarin (milk thistle). The teachings of Hippocrates are still true "let food be thy medicine and medicine be thy food".

Figure-1

A schematic diagram illustrating cell cycle checkpoint pathways that are involved in the cell response to DNA damage. When cells incur DNA damage before entering into S phase, it is governed primarily by ATR. The ATR-activated p53 further activates p21 and leads to arrest of cells at the G1 phase. The ATM-activated check point kinase-1 (Chk1) arrests cells at the S phase by ubiquitin-dependent degradation of Cdc25A which inactivates the cdk2-cyclin E/A complex. In G2 arrest, Chk1 and Chk2 phosphorylate the dual specificity phosphatase Cdc25C, which creates a binding site for the 14-3-3 proteins. The 14-3-3/Cdc25C protein complexes are sequestered in the cytoplasm, thereby preventing Cdc25C from activating the Cdk1-Cdc2-Cyclin B1 complex and blocks entry into mitosis. The checkpoints are indicated by a stop sign.

Figure-3

A simplified schematic representation of the various cell cycle phases, and the different cyclins and their kinases that control progression through the cycle. At the core of this control is the cyclin dependent kinase (Cdk) family of serine/threonine kinases, which regulate cell cycle progression through phosphorylation of proteins that function at specific phase of the cell cycle. Different Cdks act at different phases of the cell cycle and their activity is dependent on association with a member of the cyclin family of regulatory sub-units. Different dietary agents, such as EGCG, GSPs, silymarin, apigenin, resveratrol, genistein and curcumin act at different checkpoints as illustrated in the Figure. Some of them act on multiple checkpoints or targets. The arrows indicate activation and blocked signs indicate inhibitory effects.

Figure 4

Molecular targets of cell cycle regulation in cancer cells in vitro and in vivo by dietary agents. Upward arrows (↑) indicate enhancement, and downward arrows (↓) indicate a reduction in the levels, or inhibition of the activity of the target molecules.