Cell cycle target validation: approaches and successes (original) (raw)
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A Preclinical Model to Evaluate Cell Cycle Inhibitors with Therapeutic Activity
2005
Deregulation of the G1-S transition of the cell cycle is a common feature of human cancer. Tumor-associated alter- ations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27Kip1), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development.
Cell Cycle as a Target of Antineoplastic Drugs
Current Pharmaceutical Design, 2010
The cell cycle consists of a number of complex biochemical pathways that ensure that the start of a particular event depends on the successful and right end of previous steps in the pathway. An important role is played by cyclin/cyclin-dependent kinase (cdk) complexes which are critical regulators of cell cycle progression and RNA transcription. To ensure proper progression through each phase, cells have developed a series of orchestrated checkpoints that govern the different cellular kinases required for distinct cell cycle events. In particular, several cell cycle protein kinases, including members of the Aurora family and the Polo-like kinases, play critical roles in mitotic entry and chromosome segregation that ensure the correct formation of daughter cells. Tumour cell proliferation is frequently associated to both genetic and epigenetic mechanisms commonly affecting the expression of cell cycle regulatory proteins or causing an incompetent checkpoint control, resulting in aberrant responses to cellular damage. These alterations result not only in proliferative advantages but also in an increased susceptibility to the accumulation of additional genetic alterations that contribute to tumour progression and acquisition of more aggressive phenotypes. In the last years, the identification of anticancer drugs directed against critical cell cycle regulators has received particular attention. Specifically, several preclinical and clinical trials are addressing cdks or cell cycle protein kinase inhibitors. Starting from a description of cell cycle, this review summarizes the most recent studies on drugs targeting cell cycle regulators that are being used in cancer therapy.
Milestones in cell division To cycle or not to cycle: a critical decision in cancer
Nature Reviews Cancer, 2001
NATURE REVIEWS | CANCER VOLUME 1 | DECEMBER 2001 | 2 2 3 R E V I E W S whereas CDK2 is required to complete G1 and initiate S phase. CDK4 and CDK6 form active complexes with the D-type cyclins (cyclins D1, D2 and D3). These kinases are highly related and, so far, have resisted functional differentiation, except for their distinct pattern of activation 5-6 . Characterization of mice that are defective for the genes encoding these CDKs should provide information regarding their distinct roles in vivo 7-8 . CDK2 is sequentially activated by the E-type cyclins --cyclin E1 and E2 -during the G1/S transition, and the A-type cyclins -cyclin A1 and A2during S phase 4 . The role of CDK3 is still obscure, mainly due to its low expression levels. Moreover, this enzyme is truncated, and presumably inactive, in several strains of inbred mice, indicating that it is dispensable for the cell cycle 9 . CDK regulators. By controlling the level of CDK activity, CDK regulators can also control cell-cycle commitment (ONLINE TABLE 1). They include activators, mainly the cyclins, and inhibitors, generically known as CKIs (CDK kinase inhibitors; see below). CDKs are also regulated by phosphorylation (reviewed in REFS 3,10,11): they must be
Cell cycle control and cancer chemotherapy
Journal of Cellular Biochemistry, 1994
As detailed information accumulates about how cell cycle events are regulated, we can expect new opportunities for application to cancer therapy. The altered expression of oncogenes and tumor suppressor genes that commonly occurs in human cancers may impair the ability of the cells to respond to metabolic perturbations or stress. Impaired cell cycle regulation would make cells vulnerable to pharmacologic intervention by drug regimens tailored to the defects existing in particular tumors. Recent findings that may become applicable to therapy are reviewed, and the possible form of new therapeutic stratagems is considered.
Cell homeostasis is regulated by proliferation, growth arrest and apoptosis. Negative growth rate controls such as growth arrest and apoptosis are vital pathways governing aberrant development in the contribution to malignancy. Apoptosis provides the mechanism by which damaged or superfluous cells are effectively removed from the cell pool. As the cell progresses from one phase to another it is tightly regulated by a number of controls. Defects of these surveillance checkpoints may lead to an accumulation of DNA abnormalities and subsequent pathological disorders. This review considers an overview of the intricate and complex regulation of the cell cycle with potential therapeutic targets. The roles of key players are highlighted in an attempt to provide an insight into the ever increasing body of evidence of interplay and pathways of cell progression, arrest and death with deregulation leading to initiation of tumourigenesis.
Cancer Research, 2005
Deregulation of the G 1 -S transition of the cell cycle is a common feature of human cancer. Tumor-associated alterations in this process frequently affect cyclin-dependent kinases (Cdk), their regulators (cyclins, INK4 inhibitors, or p27 Kip1 ), and their substrates (retinoblastoma protein). Although these proteins are generally thought to act in a linear pathway, mutations in different components frequently cooperate in tumor development. Using gene-targeted mouse models, we report in this article that Cdk4 resistance to INK4 inhibitors, due to the Cdk4 R24C mutation, strongly cooperates with p27 Kip1 deficiency in tumor development. No such cooperation is observed between Cdk4 R24C and p18 INK4c absence, suggesting that the only function of p18 INK4c is inhibiting Cdk4 in this model. Cdk4 R/ / /R knock in mice, which express the Cdk4 R24C mutant protein, develop pituitary tumors with complete penetrance and short latency in a p27 Kip1À/À À/À or p27 Kip1+/À +/À background. We have investigated whether this tumor model could be useful to assess the therapeutic activity of cell cycle inhibitors. We show here that exposure to flavopiridol, a wide-spectrum Cdk inhibitor, significantly delays tumor progression and leads to tumorfree survival in a significant percentage of treated mice. These data suggest that genetically engineered tumor models involving key cell cycle regulators are a valuable tool to evaluate drugs with potential therapeutic benefit in human cancer. (Cancer Res 2005; 65(9): 3846-52)
The Influence of Cell Cycle Regulation on Chemotherapy
International Journal of Molecular Sciences, 2021
Cell cycle regulation is orchestrated by a complex network of interactions between proteins, enzymes, cytokines, and cell cycle signaling pathways, and is vital for cell proliferation, growth, and repair. The occurrence, development, and metastasis of tumors are closely related to the cell cycle. Cell cycle regulation can be synergistic with chemotherapy in two aspects: inhibition or promotion. The sensitivity of tumor cells to chemotherapeutic drugs can be improved with the cooperation of cell cycle regulation strategies. This review presented the mechanism of the commonly used chemotherapeutic drugs and the effect of the cell cycle on tumorigenesis and development, and the interaction between chemotherapy and cell cycle regulation in cancer treatment was briefly introduced. The current collaborative strategies of chemotherapy and cell cycle regulation are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of combination strategies for ca...