Identification of Aneuploidy-Selective Antiproliferation Compounds

Tang, Yun‐Chi; Williams, Bret R.; Siegel, Jake J.; Amon, Angelika

doi:10.1016/j.cell.2011.01.017

Cited by 312 publications

(382 citation statements)

References 57 publications

(70 reference statements)

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“…Aneuploidic cells can be selectively targeted by energy and proteotoxic stress-inducing compounds (e.g. AICAR, 17-AAG and chloroquine), but their clinical usefulness in cancer therapy is yet to be determined [59]. Interestingly, platinum based agents are also thought to effectively kill cancer cells with CIN [60].…”

Section: Cytogenetic Alterationsmentioning

confidence: 99%

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

2016

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Olfactory neuroblastoma (ONB, Esthesioneuroblastoma) is an infrequent neoplasm of the head and neck area derived from olfactory neuroepithelium. Despite relatively good prognosis a subset of patients shows recurrence, progression and/or metastatic disease, which requires additional treatment. However, neither prognostic nor predictive factors are well specified. Thus, we performed a literature search for the currently available data on disturbances in molecular pathways, cytogenetic changes and results gained by next generation sequencing (NGS) approaches in ONB in order to gain an overview of genetic alterations which might be useful for treating patients with ONB. We present briefly ONB molecular pathogenesis and propose potential therapeutic targets and prognostic factors. Possible therapeutic targets in ONB include: receptor tyrosine kinases (c-kit, PDGFR-b, TrkB; EGFR); somatostatin receptor; FGF-FGFR1 signaling; Sonic hedgehog pathway; apoptosis-related pathways (Bcl-2, TRAIL) and neoangiogenesis (VEGF; KDR). Furthermore, we compare high- and low-grade ONB, and describe its frequent mimicker: sinonasal neuroendocrine carcinoma. ONB is often a therapeutic challenge, so our goal should be the implementation of acquired knowledge into clinical practice, especially at pretreated, recurrent and metastatic stages. Moreover, the multicenter molecular studies are needed to increase the amount of available data.

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Section: Cytogenetic Alterationsmentioning

confidence: 99%

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

2016

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“…Centriole biogenesis and maintenance of correct centrosome numbers in proliferating cells critically depend on the exact levels of the key duplication factors Plk4 (Bettencourt‐Dias et al , 2005; Habedanck et al , 2005), Sas‐6 (Leidel et al , 2005; Strnad et al , 2007), and STIL (Tang et al , 2011b; Arquint et al , 2012; Vulprecht et al , 2012). To fully understand the regulation of centriole duplication, it will thus be important to obtain quantitative data on the abundance of these proteins under physiological conditions.…”

Section: Introductionmentioning

confidence: 99%

Quantitative analysis of human centrosome architecture by targeted proteomics and fluorescence imaging

et al. 2016

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Centrioles are essential for the formation of centrosomes and cilia. While numerical and/or structural centrosomes aberrations are implicated in cancer, mutations in centriolar and centrosomal proteins are genetically linked to ciliopathies, microcephaly, and dwarfism. The evolutionarily conserved mechanisms underlying centrosome biogenesis are centered on a set of key proteins, including Plk4, Sas‐6, and STIL, whose exact levels are critical to ensure accurate reproduction of centrioles during cell cycle progression. However, neither the intracellular levels of centrosomal proteins nor their stoichiometry within centrosomes is presently known. Here, we have used two complementary approaches, targeted proteomics and EGFP‐tagging of centrosomal proteins at endogenous loci, to measure protein abundance in cultured human cells and purified centrosomes. Our results provide a first assessment of the absolute and relative amounts of major components of the human centrosome. Specifically, they predict that human centriolar cartwheels comprise up to 16 stacked hubs and 1 molecule of STIL for every dimer of Sas‐6. This type of quantitative information will help guide future studies of the molecular basis of centrosome assembly and function.

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“…95 A recent study has shown that small molecules synergize with proteotoxic and energy stress efficiently and specifically antagonize the proliferation of aneuploid cells. 96 All together, these studies suggest that CIN or aneuploidy may be detrimental for cell proliferation and lead to a proliferative stress, resulting in cell cycle arrest or apoptosis (see figure). In those cases where CIN or aneuploidy results in proliferative advantages, tumor cells may be specifically sensitive to SAC abrogation (which may induce lethal levels of instability) or specific compounds targeting the energetic and proteotoxic stress pathways.…”

Section: Targeting Mitotic Exitmentioning

confidence: 99%

Killing cells by targeting mitosis

2012

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Cell cycle deregulation is a common feature of human cancer. Tumor cells accumulate mutations that result in unscheduled proliferation, genomic instability and chromosomal instability. Several therapeutic strategies have been proposed for targeting the cell division cycle in cancer. Whereas inhibiting the initial phases of the cell cycle is likely to generate viable quiescent cells, targeting mitosis offers several possibilities for killing cancer cells. Microtubule poisons have proved efficacy in the clinic against a broad range of malignancies, and novel targeted strategies are now evaluating the inhibition of critical activities, such as cyclin-dependent kinase 1, Aurora or Polo kinases or spindle kinesins. Abrogation of the mitotic checkpoint or targeting the energetic or proteotoxic stress of aneuploid or chromosomally instable cells may also provide further benefits by inducing lethal levels of instability. Although cancer cells may display different responses to these treatments, recent data suggest that targeting mitotic exit by inhibiting the anaphase-promoting complex generates metaphase cells that invariably die in mitosis.As the efficacy of cell-cycle targeting approaches has been limited so far, further understanding of the molecular pathways modulating mitotic cell death will be required to move forward these new proposals to the clinic.

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Identification of Aneuploidy-Selective Antiproliferation Compounds

Cited by 312 publications

References 57 publications

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Genetic and molecular alterations in olfactory neuroblastoma: implications for pathogenesis, prognosis and treatment

Quantitative analysis of human centrosome architecture by targeted proteomics and fluorescence imaging

Killing cells by targeting mitosis

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