Targeting the cell cycle for cancer therapy

Carnero, Amancio

doi:10.1038/sj.bjc.6600458

Cited by 137 publications

(111 citation statements)

References 52 publications

(44 reference statements)

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“…A number of laboratories are currently evaluating the possibility of targeting cell cycle regulators as a new strategy in cancer therapy (33,34). Indeed, cell-cycle deregulation is a hallmark of tumor cells, and a number of neoplasias show abnormal expression or mutation of key regulators (35).…”

Section: Discussionmentioning

confidence: 99%

A Novel Synthetic Inhibitor of CDC25 Phosphatases

et al. 2004

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CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro. It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G 1 -S, in S phase and at the G 2 -M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G 1 phase. Selectivity of this inhibitor is demonstrated: (a) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and (b) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice.BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.

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Section: Discussionmentioning

confidence: 99%

A Novel Synthetic Inhibitor of CDC25 Phosphatases

et al. 2004

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“…Understanding the regulation and progression of the cell cycle is a critical component in combating a wide variety of human diseases, the most prominent being cancer (1,2). Our current understanding of phenotypic changes during cell cycle progression is based on well-defined observations using classic flow cytometry, microscopy, and early forms of automated imaging, but few reports followed cellular subpopulations as they progressed through the cell cycle (3 -5).…”

Section: Introductionmentioning

confidence: 99%

High-content imaging characterization of cell cycle therapeutics through in vitro and in vivo subpopulation analysis

Low

Huang²,

Blosser³

et al. 2008

Molecular Cancer Therapeutics

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Although the cycling of eukaryotic cells has long been a primary focus for cancer therapeutics, recent advances in imaging and data analysis allow even further definition of cellular events as they occur in individual cells and cellular subpopulations in response to treatment. High-content imaging (HCI) has been an effective tool to elucidate cellular responses to a variety of agents; however, these data were most frequently observed as averages of the entire captured population, unnecessarily decreasing the resolution of each assay. Here, we dissect the eukaryotic cell cycle into individual cellular subpopulations using HCI in conjunction with unsupervised K-means clustering. We generate distinct phenotypic fingerprints for each major cell cycle and mitotic compartment and use those fingerprints to screen a library of 310 commercially available chemotherapeutic agents. We determine that the cell cycle arrest phenotypes caused by these agents are similar to, although distinct from, those found in untreated cells and that these distinctions frequently suggest the mechanism of action. We then show via subpopulation analysis that these arrest phenotypes are similar in both mouse models and in culture. HCI analysis of cell cycle using data obtained from individual cells under a broad range of research conditions and grouped into cellular subpopulations represents a powerful method to discern both cellular events and treatment effects. In particular, this technique allows for a more accurate means of assessing compound selectivity and leads to more meaningful comparisons between so-called targeted therapeutics.

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“…There are at least three different mechanisms responsible for uncontrolled cellular proliferation: (1) untimely upregulation of cyclin expression, the regulatory subunits of CDKs, (2) increased activity of CDK-activating kinases (CAKs) and/or phosphatase cdc25, and (3) inactivation of CDK inhibitors (CKIs). For example, while overexpression of cyclin D1 and cyclin A has been implicated in the pathogenesis of various cancers, such as breast cancer and hepatocellular carcinoma, activating mutations in the Cdc25 gene are involved in the development of head and neck cancer (Carnero, 2002). Also, inactivating mutations in CKIs are common characteristics of leukemia, lymphomas, and breast cancer (Carnero, 2002).…”

mentioning

confidence: 99%

“…Neoplasias commonly result from defects in the regulatory pathways controlling cell-cycle progression (Weinberg, 1995;Carnero, 2002). The majority of neoplastic transformations involve alterations in the mechanisms regulating cyclin-dependent kinase (CDK) activity.…”

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confidence: 99%

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

et al. 2004

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Chondrosarcomas represent the second most frequent class of primary skeletal malignancies. This tumor type is highly resistant to radiation therapy and currently available chemotherapies, thereby limiting treatment choice to surgical resection. Identifying the mechanisms responsible for chondrosarcoma cell proliferation is therefore crucial for the development of new treatment strategies. Here, we demonstrate a significant reduction in rat chondrosarcoma cell proliferation following treatment with pharmacological inhibitors (SB202190 and PD169316) of p38 mitogen-activated protein (MAP) kinases. In an attempt to dissect possible mechanisms, we investigated the effect of p38 inhibition on promoter activity of cell-cycle genes. Surprisingly, p38 inhibition resulted in upregulation of the activities of all three D-type cyclin promoters. In addition, p38 inhibitors induced increased transcription of the cell-cycle inhibitor p21 waf1/cip1 . As expected, promoter activity of the cyclin A gene, which lies downstream of D-type cyclins and p21 in cell-cycle progression, was strongly reduced by p38 inhibitors. These effects were independent of a cyclic AMP response element and conferred by the proximal 150 nucleotides of the cyclin A promoter. Decreased transcription was accompanied by greatly reduced cyclin A protein levels upon p38 inhibition. These observations indicate complex regulation of chondrosarcoma cell-cycle progression by p38 signaling, and suggest that components of p38 MAP kinase pathways may be effective targets in the treatment of these tumors.

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Targeting the cell cycle for cancer therapy

Cited by 137 publications

References 52 publications

A Novel Synthetic Inhibitor of CDC25 Phosphatases

A Novel Synthetic Inhibitor of CDC25 Phosphatases

High-content imaging characterization of cell cycle therapeutics through in vitro and in vivo subpopulation analysis

p38 MAP kinase signaling is necessary for rat chondrosarcoma cell proliferation

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