Targeting the Cell Cycle: A New Approach to Cancer Therapy

Abstract

The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.

Cell cycle arrest and mechanism of apoptosis induction in H400 oral cancer cells in response to Damnacanthal and Nordamnacanthal isolated from Morinda citrifolia

“…Suppression of the cell cycle is a desirable target for cancer therapy with cytotoxic agents (Schwartz and Shah 2005). The cell cycle is organised through a number of checkpoints scanning genomic integrity as well as confirming that DNA replication continues in a coordinated fashion (Machida et al 2005).…”

Marine sponge‐derived smenospongine preferentially eliminates breast cancer stem‐like cells via p38/AMPKα pathways

“…The cell cycle arrest serves as a survival mechanism that allows time and opportunity for the repair of DNA. Once DNA repair is failed, the apoptotic cascade will be activated and finally cause cell death 37. In breast CSC‐like cells, we found that Sme caused DNA damage, cell cycle arrest, and apoptosis.…”

Apoptotic effects of non-edible parts of Punica granatum on human multiple myeloma cells

“…The checkpoints that control G 1 /S and G 2 /M transitions act as an inspection mechanism for the persistence of the cell cycle [41]. Thus, when an improper action is detected at the cell cycle checkpoints, such as uncompleted DNA replication or a mismatch that cannot be repaired by the cell, apoptotic cascade would be activated that eventually leads to the death of the cell, representing one of the ideal strategies for cancer therapy [42]. Interestingly, we found that G 2 /M phase arrest of the U266 cells was observed at the highest stem concentration followed by 250 μg/ml leaves extracts (Fig.…”