Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

Menon, Vijay; Peterson, Erica J.; Valerie, Kristoffer; Farrell, Nicholas; Povirk, Lawrence F.

doi:10.1016/j.bcp.2013.10.012

Cited by 22 publications

(13 citation statements)

References 41 publications

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“…Cyclin B1 and Cdc2 are key molecules for G2–M transition during the cell cycle. Cyclin B1 is essential for the initiation of mitosis and suppression of Cyclin B1 could lead to cells block and eventual cell apoptosis [ 24 ]. Similarly, after the down-regulation of Cdc25A, cell cycle progression was inhibited [ 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo

Chen

Sun

et al. 2015

Bioscience Reports

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NUF2 (NUF2, Ndc80 kinetochore complex component) plays an important role in kinetochore-microtubule attachment. It has been reported that NUF2 is associated with multiple human cancers. However, the functional role of NUF2 in pancreatic cancer remains unclear. In this study, we found that NUF2 expression was stronger in tumour tissues than in normal pancreatic tissues, and its overexpression could be related to poor prognosis. Moreover, NUF2 was highly expressed in several human pancreatic cancer cell lines. We took advantage of lentivirus-mediated siRNA (small interfering RNA) to suppress NUF2 expression in PANC-1 and Sw1990 cell lines aiming to investigate the role of NUF2 in pancreatic cancer. NUF2 silencing by RANi (RNA interference) reduced the proliferation and colony formation ability of pancreatic cancer cells in vitro. Cell cycle analysis showed that NUF2 knockdown induced cell cycle arrest at G0/G1 phase via suppression of Cyclin B1, Cdc2 and Cdc25A. More importantly, NUF2 silencing was able to alleviate in vivo tumourigenesis in pancreatic cancer xenograft nude mice. Collectively, the present study indicates that the siRNA-mediated knockdown against NUF2 may be a promising therapeutic method for the treatment of pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo

Chen

Sun

et al. 2015

Bioscience Reports

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“…To obtain G 0 cell synchronization, cells were seeded at a density of 5 × 10 5 cells per 100 mm dish and allowed to attach for 24 h. The cells were serum-starved in media containing 0.5% FBS for 96 h. Flow cytometry analysis of synchronized cells showed approximately 80% cells arrested in G 0 /G 1 phase. 35 …”

Section: Methodsmentioning

confidence: 99%

Nucleolar Targeting by Platinum: p53-Independent Apoptosis Follows rRNA Inhibition, Cell-Cycle Arrest, and DNA Compaction

Peterson

Menon²,

Gatti

et al. 2014

Mol. Pharmaceutics

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TriplatinNC is a highly positively charged, substitution-inert derivative of the phase II clinical anticancer drug, BBR3464. Such substitution-inert complexes form a distinct subset of polynuclear platinum complexes (PPCs) interacting with DNA and other biomolecules through noncovalent interactions. Rapid cellular entry is facilitated via interaction with cell surface glycosoaminoglycans and is a mechanism unique to PPCs. Nanoscale secondary ion mass spectrometry (nanoSIMS) showed rapid distribution within cytoplasmic and nucleolar compartments, but not the nucleus. In this article, the downstream effects of nucleolar localization are described. In human colon carcinoma cells, HCT116, the production rate of 47S rRNA precursor transcripts was dramatically reduced as an early event after drug treatment. Transcriptional inhibition of rRNA was followed by a robust G1 arrest, and activation of apoptotic proteins caspase-8, -9, and -3 and PARP-1 in a p53-independent manner. Using cell synchronization and flow cytometry, it was determined that cells treated while in G1 arrest immediately, but cells treated in S or G2 successfully complete mitosis. Twenty-four hours after treatment, the majority of cells finally arrest in G1, but nearly one-third contained highly compacted DNA; a distinct biological feature that cannot be associated with mitosis, senescence, or apoptosis. This unique effect mirrored the efficient condensation of tRNA and DNA in cell-free systems. The combination of DNA compaction and apoptosis by TriplatinNC treatment conferred striking activity in platinum-resistant and/or p53 mutant or null cell lines. Taken together, our results support that the biological activity of TriplatinNC reflects reduced metabolic deactivation (substitution-inert compound not reactive to sulfur nucleophiles), high cellular accumulation, and novel consequences of high-affinity noncovalent DNA binding, producing a new profile and a further shift in the structure–activity paradigms for antitumor complexes.

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“…The protocol described by Menon VR et al 52 was used to assess cell cycle distribution. H460 control, H460 shATG5 and shBECN1 cells were seeded in 100-mm tissue culture plates at different densities based on the time points for collection.…”

Section: Facs Analysis For Cell Cycle Distributionmentioning

confidence: 99%

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

Sharma¹

2014

Autophagy

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The standard of care for unresectable lung cancer is chemoradiation. However, therapeutic options are limited and patients are rarely cured. We have previously shown that vitamin D and vitamin D analogs such as EB 1089 can enhance the response to radiation in breast cancer through the promotion of a cytotoxic form of autophagy. In A549 and H460 non-small cell lung cancer (NSCLC) cells, 1,25-D3 (the hormonally active form of vitamin D) and EB 1089 prolonged the growth arrest induced by radiation alone and suppressed proliferative recovery, which translated to a significant reduction in clonogenic survival. In H838 or H358 NSCLC cells, which lack VDR/vitamin D receptor or functional TP53, respectively, 1,25-D3 failed to modify the extent of radiation-induced growth arrest or suppress proliferative recovery post-irradiation. Sensitization to radiation in H1299 NSCLC cells was evident only when TP53 was induced in otherwise tp53-null H1299 NSCLC cells. Sensitization was not associated with increased DNA damage, decreased DNA repair or an increase in apoptosis, necrosis, or senescence. Instead sensitization appeared to be a consequence of the conversion of the cytoprotective autophagy induced by radiation alone to a novel cytostatic form of autophagy by the combination of 1,25-D3 or EB 1089 with radiation. While both pharmacological and genetic suppression of autophagy or inhibition of AMPK phosphorylation sensitized the NSCLC cells to radiation alone, inhibition of the cytostatic autophagy induced by the combination treatment reversed sensitization. Evidence for selectivity was provided by lack of radiosensitization in normal human bronchial cells and cardiomyocytes. Taken together, these studies have identified a unique cytostatic function of autophagy that appears to be mediated by VDR, TP53, and possibly AMPK in the promotion of an enhanced response to radiation by 1,25-D3 and EB 1089 in NSCLC.

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Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

Cited by 22 publications

References 41 publications

siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo

siRNA-mediated knockdown against NUF2 suppresses pancreatic cancer proliferation in vitro and in vivo

Nucleolar Targeting by Platinum: p53-Independent Apoptosis Follows rRNA Inhibition, Cell-Cycle Arrest, and DNA Compaction

A novel cytostatic form of autophagy in sensitization of non-small cell lung cancer cells to radiation by vitamin D and the vitamin D analog, EB 1089

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