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 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methylation, histone modifications, and nucleosomal occupancy collaborate to cause silencing of tumor-related genes in cancer. The development of drugs that target these processes is therefore important for cancer therapy. Inhibitors of DNA methylation and histone deacetylation have been approved by the Food and Drug Administration for treatment of hematologic malignancies. However, drugs that target other mechanisms still need to be developed. Recently, 3-deazaneplanocin A (DZNep) was reported to selectively inhibit trimethylation of lysine 27 on histone H3 (H3K27me3) and lysine 20 on histone H4 (H4K20me3) as well as reactivate silenced genes in cancer cells. This finding opens the door to the pharmacologic inhibition of histone methylation. We therefore wanted to further study the mechanism of action of DZNep in cancer cells. Western blot analysis shows that DZNep globally inhibits histone methylation and is not selective. Two other drugs, sinefungin and adenosine dialdehyde, have similar effects as DZNep on H3K27me3. Intriguingly, chromatin immunoprecipitation of various histone modifications and microarray analysis show that DZNep acts through a different pathway than 5-aza-2'-deoxycytidine, a DNA methyltransferase inhibitor. These observations give us interesting insight into how chromatin structure affects gene expression. We also determined the kinetics of gene activation to understand if the induced changes were somatically heritable. We found that upon removal of DZNep, gene expression is reduced to its original state. This suggests that there is a homeostatic mechanism that returns the histone modifications to their "ground state" after DZNep treatment. Our data show the strong need for further development of histone methylation inhibitors.
Mol Cancer Ther 2009 Jun
PMID:DZNep is a global histone methylation inhibitor that reactivates developmental genes not silenced by DNA methylation. 1950 60

Colorectal cancer (CRC) is the third most common form of cancer and the second cause of cancer-related death in the Western world, leading to 655,000 deaths worldwide per year (Jemal et al. in CA Cancer J Clin 56:106-130, 2006). Despite the emergence of new targeted agents and the use of various therapeutic combinations, none of the treatment options available is curative in patients with advanced cancer. A growing body of evidence is increasingly supporting the idea that human cancers can be considered as a stem cell disease. According to the cancer stem cell model, malignancies originate from a small fraction of cancer cells that show self-renewal and pluripotency and are capable of initiating and sustaining tumor growth (Boman and Wicha in J Clin Oncol 26:2795-2799, 2008). The cancer-initiating cells or "cancer stem cells" were first identified in hematologic malignancies and most recently in several solid tumors, including CRC. The hypothesis of stem cell-driven tumorigenesis in colon cancer raises questions as to whether current treatments are able to efficiently target the tumorigenic cell population that is responsible for tumor growth and maintenance. This review will focus on the different aspects of stem cell biology in the context of CRC, which might help to understand the mechanisms that give rise to tumor development and resistance to therapy. First, we will briefly revise the knowledge available on normal intestinal stem cells and recent advances in understanding crypt biology, which have led to new theory on the origins of colon adenomas and cancers. Then, we will summarize the evidence and current status on colon cancer stem cells, focusing on their relevance and promises for the treatment of colorectal carcinoma.
J Mol Med (Berl) 2009 Nov
PMID:Colon cancer stem cells. 1972 38

Multiple myeloma is the second most common hematological malignancy in the United States. The disease is characterized by an accumulation of clonal plasma cells. Clinically, patients present with anemia, lytic bone lesions, hypercalcaemia, or renal impairment. The genome of the malignant plasma cells is extremely unstable and is typically aneuploid and characterized by a complex combination of structure and numerical abnormalities. The basis of the genomic instability underlying myeloma is unclear. In this regard, centrosome amplification is present in about a third of myeloma and may represent a mechanism leading to genomic instability in myeloma. Centrosome amplification is associated with high-risk features and poor prognosis. Understanding the underlying etiology of centrosome amplification in myeloma may lead to new therapeutic avenues.
Environ Mol Mutagen 2009 Oct
PMID:Centrosomes and myeloma; aneuploidy and proliferation. 1973 37

Analysis of centrosome number and structure has become one means of assessing the potential for aberrant chromosome segregation and aneuploidy in tumor cells. Centrosome amplification directly causes multipolar catastrophic mitoses in mouse embryonic fibroblasts (MEFs) deficient for the tumor suppressor genes Brca1 or Trp53. We observed supernumerary centrosomes in cell lines established from aneuploid, but not from diploid, colorectal carcinomas; however, multipolar mitoses were never observed. This discrepancy prompted us to thoroughly characterize the centrosome abnormalities in these and other cancer cell lines with respect to both structure and function. The most striking result was that supernumerary centrosomes in aneuploid colorectal cancer cell lines were unable to nucleate microtubules, despite the presence of gamma-tubulin, pericentrin, PLK1, and AURKA. Analysis by scanning electron microscopy revealed that these supernumerary structures are devoid of centrioles, a result significantly different from observations in aneuploid pancreatic cancer cell lines and in Trp53 or Brca1 deficient MEFs. Thus, multipolar mitoses are dependent upon the ability of extra gamma-tubulin containing structures to nucleate microtubules, and this correlated with the presence of centrioles. The assessment of centrosome function with respect to chromosome segregation must therefore take into consideration the presence of centrioles and the capacity to nucleate microtubules. The patterns and mechanisms of chromosomal aberrations in hematologic malignancies and solid tumors are fundamentally different. The former is characterized by specific chromosome translocations, whose consequence is the activation of oncogenes. Most carcinomas, however, reveal variations in the nuclear DNA content. The observed genomic imbalances and gross variations in chromosome number can result from unequal chromosome segregation during mitotic cell division. It is therefore fundamental to elucidate mechanisms involved in distribution of the genome to daughter cells. Prior to cell division, the centrosome organizes microtubules and the mitotic spindle. Deciphering the consequences of alterations in centrosome number, structure, and function is an important step towards understanding how a diploid genome is maintained. Although extra centrosomes have now been observed in carcinomas and were correlated with aneuploidy, a careful functional investigation of these structures and their role in generating chromosome imbalances may lead to the identification of distinct mechanistic pathways of genomic instability. Understanding these pathways will also be important in determining whether they are potential molecular targets of therapeutic intervention.
Environ Mol Mutagen 2009 Oct
PMID:Nucleation capacity and presence of centrioles define a distinct category of centrosome abnormalities that induces multipolar mitoses in cancer cells. 1976 32

The insulin-like growth factor-I receptor (IGF-IR) signaling pathway is activated in various tumors, and inhibition of IGF-IR kinase provides a therapeutic opportunity in these patients. GSK1838705A is a small-molecule kinase inhibitor that inhibits IGF-IR and the insulin receptor with IC(50)s of 2.0 and 1.6 nmol/L, respectively. GSK1838705A blocks the in vitro proliferation of cell lines derived from solid and hematologic malignancies, including multiple myeloma and Ewing's sarcoma, and retards the growth of human tumor xenografts in vivo. Despite the inhibitory effect of GSK1838705A on insulin receptor, minimal effects on glucose homeostasis were observed at efficacious doses. GSK1838705A also inhibits the anaplastic lymphoma kinase (ALK), which drives the aberrant growth of anaplastic large-cell lymphomas, some neuroblastomas, and a subset of non-small cell lung cancers. GSK1838705A inhibits ALK, with an IC(50) of 0.5 nmol/L, and causes complete regression of ALK-dependent tumors in vivo at well-tolerated doses. GSK1838705A is therefore a promising antitumor agent for therapeutic use in human cancers.
Mol Cancer Ther 2009 Oct
PMID:GSK1838705A inhibits the insulin-like growth factor-1 receptor and anaplastic lymphoma kinase and shows antitumor activity in experimental models of human cancers. 1982 1

The topoisomerase-I (topo-I) inhibitor topotecan, derivative of camptothecin, is the only registered drug for relapsed small cell lung cancer (SCLC). The histone deacetylase inhibitor vorinostat has shown preclinical and clinical antitumor activities in hematologic malignancies and solid tumors, including SCLC, and has recently been approved for the treatment of cutaneous T-cell lymphomas. In this study, we analyzed the antitumor effect of vorinostat combined with topotecan or camptothecin in topo-I inhibitor-sensitive H209 and inhibitor-resistant H526 SCLC cells. Simultaneous or sequential exposure (24 h delay) to either agent resulted in strong synergistic cytotoxic effect in both cell lines, as shown by calculating combination index, and confirmed by growth in soft agar. Combination treatments increased S-phase cell cycle arrest paralleled by apoptosis as measured by hypodiploid peak formation, Annexin V binding, DNA fragmentation, and mitochondria destruction. The apoptotic process was triggered by a caspase-dependent mechanism and can be ascribed to the phosphorylation of H2AX, a reporter of DNA double-strand breaks. These effects were paralleled by an increase of topo-I/DNA covalent complexes induced by combination treatment and suggest a potentiation by vorinostat of topotecan-induced DNA damage. Finally, oxidative injury played a significant functional role in the observed enhanced lethality because coadministration of the antioxidant N-acetyl-l-cysteine blocked reactive oxygen species generation, apoptosis, and mitochondria destruction induced by the vorinostat/topotecan combination. To our knowledge, this is the first demonstration of a synergistic antitumor effect between topotecan and vorinostat in SCLC. Because no well-established treatment is available for recurrent SCLC patients, our results indicate that this drug combination should be explored clinically.
Mol Cancer Ther 2009 Nov
PMID:Synergistic antitumor effect between vorinostat and topotecan in small cell lung cancer cells is mediated by generation of reactive oxygen species and DNA damage-induced apoptosis. 1988 47

Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia (FA). FANCC is one of the most commonly mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. Here, we studied the role of Fancc in telomere length regulation in mice. Deletion of Fancc (Fancc(-/-)) did not affect telomerase activity, telomere length or telomeric end-capping in a mouse strain possessing intrinsically long telomeres. However, ablation of Fancc did exacerbate telomere attrition when murine bone marrow cells experienced high cell turnover after serial transplantation. When Fancc(-/-) mice were crossed into a telomerase reverse transcriptase heterozygous or null background (Tert(+/-) or Tert(-/-)) with short telomeres, Fancc deficiency led to an increase in the incidence of telomere sister chromatid exchange. In contrast, these phenotypes were not observed in Tert mutant mice with long telomeres. Our data indicate that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres.
Hum Mol Genet 2010 Mar 01
PMID:FANCC suppresses short telomere-initiated telomere sister chromatid exchange. 2002 86

Standard therapeutic approaches of cytotoxics and radiation in cancer are not only highly toxic, but also of limited efficacy in treatment of a significant number of cancer patients. The molecular analysis of the cancer genomes have shown a remarkable complexity and pointed to key genomic and epigenomic alterations in cancer. These discoveries are paving the way for targeted therapy approaches. However, although there are a large number of potential targets, only a few can regulate key cellular functions and intersect multiple signaling networks. The Aurora kinase family members (A, B, and C) are a collection of highly related and conserved serine-threonine kinases that fulfill these criteria, being key regulators of mitosis and multiple signaling pathways. Alterations in Aurora kinase signaling are associated with mitotic errors and have been closely linked to chromosomal aneuploidy in cancer cells. Several studies have shown amplification and/or overexpression of Aurora kinase A and B in hematologic malignancies and solid tumors. Over the past several years, Aurora kinases have become attractive targets. Several ongoing clinical trials and bench-based research are assessing the unique therapeutic potential of Aurora-based targeted therapy.
Mol Cancer Ther 2010 Feb
PMID:Aurora kinase inhibitors--rising stars in cancer therapeutics? 2012 50

Clinical trials have shown activity of the isotype-selective histone deacetylase (HDAC) inhibitor MGCD0103 in different hematologic malignancies. There are data to support the use of HDAC inhibitors in association with other cancer therapies. To propose a rational combination therapy, it is necessary to depict the molecular basis behind the cytotoxic effect of MGCD0103. In this study, we found that MGCD0103 was substantially more toxic in neoplastic B cells relative to normal cells, and we described the death pathways activated by MGCD0103 in B-cell chronic lymphocytic leukemia (CLL) cells from 32 patients. MGCD0103 decreased the expression of Mcl-1 and induced translocation of Bax to the mitochondria, mitochondrial depolarization, and release of cytochrome c in the cytosol. Caspase processing in the presence of the caspase inhibitor Q-VD-OPh and time course experiments showed that caspase-9 was the apical caspase. Thus, MGCD0103 induced the intrinsic pathway of apoptosis in CLL cells. Moreover, MGCD0103 treatment resulted in the activation of a caspase cascade downstream of caspase-9, caspase-dependent amplification of mitochondrial depolarization, activation of calpain, and Bax cleavage. We propose a model whereby the intrinsic pathway of apoptosis triggered by MGCD0103 in CLL is associated with a mitochondrial death amplification loop.
Mol Cancer Ther 2010 May
PMID:The histone deacetylase inhibitor MGCD0103 induces apoptosis in B-cell chronic lymphocytic leukemia cells through a mitochondria-mediated caspase activation cascade. 2040 47

Multiple myeloma (MM) is the second most common hematological malignancy, with an overall survival of 4-6 years. It is always preceded by a premalignant stage called monoclonal gammopathy of unknown significance (MGUS). Importantly, at this time we lack reliable predictors to determine who will progress from MGUS to MM, and who will remain stable. The bone marrow microenvironment plays a key role in myelomagenesis (growth, survival and migration of malignant plasma cells). In the present review, we summarize and discuss our current understanding of the bone marrow microenvironment and its compartments in relation to myelomagenesis. Although it remains to be proven, we believe that an improved characterization of the cellular constituents, the extracellular matrix components and the soluble factors of the bone marrow could open up novel avenues to better understand underlying mechanisms of the transformation from MGUS to MM. Ultimately, this will lead to the development of early treatment of high-risk precursor disease aimed to delay/prevent MM.
Expert Rev Mol Diagn 2010 May
PMID:Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis. 2046 1


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