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1.
Curr Cancer Drug Targets ; 12(4): 356-71, 2012 May.
Article in English | MEDLINE | ID: mdl-22385513

ABSTRACT

Although several drugs have been designed in the last few years to target specific key pathways and functions in colorectal cancer (CRC), the backbone of CRC treatment is still made up of compounds which rely on DNA damage to accomplish their role. DNA damage response (DDR) and checkpoint pathways are intertwined signaling networks that arrest cell cycle, recognize and repair genetic mistakes which arise during DNA replication and transcription, as well as through the exposure to chemical and physical agents that interact with nucleic acids. The good but highly variable activity of DNA damaging agents in the treatment of CRC suggests that intrinsic alterations in DDR pathways and cell cycle checkpoints may contribute differentially to the way cancer cells react to DNA damage. In the present review, our aim is to depict the recent advances in understanding the molecular basis of the activity of DNA damaging agents used for the treatment of CRC. We focus on the known and potential drug targets that are part of these complex and intertwined pathways. We describe the potential role of the checkpoints in CRC, and how their pharmacological manipulation could lead to chemopotentiation or synergism with currently used drugs. Novel therapeutic agents playing a role in DDR and checkpoint inhibition are assessed. We discuss the possible rationale for combining PARP inhibition with DNA damaging agents, and we address the link between DDR and EGFR pathways in CRC.


Subject(s)
Cell Cycle Checkpoints/genetics , Colorectal Neoplasms/genetics , DNA Damage/genetics , DNA Repair/genetics , Animals , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , ErbB Receptors/antagonists & inhibitors , Female , Humans , Male , Mice , Molecular Targeted Therapy , Poly(ADP-ribose) Polymerase Inhibitors , Treatment Outcome
2.
Oncogene ; 31(4): 403-18, 2012 Jan 26.
Article in English | MEDLINE | ID: mdl-21765476

ABSTRACT

CHEK2 encodes a serine/threonine kinase (Chk2) activated by ATM in response to DNA double-strand breaks. On the one hand, CHEK2 has been described as a tumor suppressor with proapoptotic, cell-cycle checkpoint and mitotic functions. On the other hand, Chk2 is also commonly activated (phosphorylated at T68) in cancers and precancerous lesions. Here, we report an extensive characterization of CHEK2 across the panel of 60 established cancer cell lines from the NCI Anticancer Screen (the NCI-60) using genomic and proteomic analyses, including exon-specific mRNA expression, DNA copy-number variation (CNV) by aCGH, exome sequencing, as well as western blot analyses for total and activated (pT68-Chk2) Chk2. We show that the high heterogeneity of Chk2 levels in cancer cells is primarily due to its inactivation (owing to low gene expression, alternative splicing, point mutations, copy-number alterations and premature truncation) or reduction of protein levels. Moreover, we observe that a significant percentage of cancer cells (12% of the NCI-60 and HeLa cells) show high endogenous Chk2 activation, which is always associated with p53 inactivation, and which is accompanied by downregulation of the Fanconi anemia and homologous recombination pathways. We also report the presence of activated Chk2 (pT68-Chk2) along with histone γ-H2AX in centrosomes.


Subject(s)
Gene Expression Regulation, Neoplastic , Gene Silencing , Neoplasms/genetics , Protein Serine-Threonine Kinases/genetics , Ataxia Telangiectasia Mutated Proteins , Cell Cycle Proteins/physiology , Cell Line, Tumor , Checkpoint Kinase 2 , Chromosomal Instability , DNA Damage , DNA-Binding Proteins/physiology , Exons , Fanconi Anemia/genetics , Genomics , Humans , Phosphorylation , Point Mutation , Protein Serine-Threonine Kinases/analysis , Protein Serine-Threonine Kinases/physiology , Proteomics , RNA, Messenger/analysis , Recombination, Genetic , Tumor Suppressor Protein p53/physiology , Tumor Suppressor Proteins/physiology
3.
Mol Cell Biol ; 25(21): 9621-31, 2005 Nov.
Article in English | MEDLINE | ID: mdl-16227610

ABSTRACT

Caspases play important roles in apoptotic cell death and in some other functions, such as cytokine maturation, inflammation, or differentiation. We show here that the 5'-flanking region of the human CASP-2 gene contains three functional response elements for sterol regulatory element binding proteins (SREBPs), proteins that mediate the transcriptional activation of genes involved in cholesterol, triacylglycerol, and fatty acid synthesis. Exposure of several human cell lines to statins, lipid-lowering drugs that drive SREBP proteolytic activation, induced the CASP-2 gene to an extent similar to that for known targets of SREBP proteins. Adenoviral vector-mediated transfer of active SREBP-2 also induced expression of the CASP-2 gene and the caspase-2 protein and increased the cholesterol and triacylglycerol cellular content. These rises in lipids were strongly impaired following small interfering RNA-mediated silencing of the CASP-2 gene. Taken together, our results identify the human CASP-2 gene as a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels.


Subject(s)
Cysteine Endopeptidases/physiology , Sterol Regulatory Element Binding Protein 2/physiology , 5' Flanking Region , Binding Sites , Caspase 2 , Cell Line, Tumor , Cholesterol/biosynthesis , Cysteine Endopeptidases/biosynthesis , Cysteine Endopeptidases/genetics , Gene Expression Regulation , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , RNA, Small Interfering/genetics , Response Elements , Sterol Regulatory Element Binding Protein 2/genetics , Triglycerides/biosynthesis
5.
Therapie ; 57(6): 524-9, 2002.
Article in French | MEDLINE | ID: mdl-12666259

ABSTRACT

It was shown in 1999 thalidomide could induce a therapeutic response in patients with refractory multiple myeloma. Between March 2000 and January 2002, we treated 21 patients with refractory multiple myeloma with thalidomide (Thalidomide) at initial dose of 400 mg a day. Response rate (Intergroupe Francophone du Myélome criteria) was 33 percent and median progression-free survival estimated to 15 months. All patients suffered from drowsiness and constipation requiring lowest doses. Five patients developed a sensitive neuropathy. Eight refractory patients were treated by a combination of their prior maximally tolerated dose of thalidomide and monthly dexamethasone (Soludécadron) alone (n = 4) or associated to cyclophosphamide (Endoxan) and étoposide (Etopophos) (n = 4). Six patients on 8 were responders. Our results suggest that the combination thalidomide/dexamethasone should be compared to thalidomide alone in a prospective, randomized study in patients with refractory multiple myeloma.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Dexamethasone/therapeutic use , Immunosuppressive Agents/therapeutic use , Multiple Myeloma/drug therapy , Thalidomide/therapeutic use , Adult , Aged , Anti-Inflammatory Agents/administration & dosage , Antineoplastic Agents/therapeutic use , Dexamethasone/administration & dosage , Drug Resistance, Neoplasm , Drug Therapy, Combination , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , Middle Aged , Survival Analysis , Thalidomide/administration & dosage
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