5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

Matuo, Renata; Sousa, Fabrício G.; Escargueil, Alexandre E.; Grivicich, Ivana; Garcia-Santos, Daniel; Chies, José Artur Bogo; Saffi, Jenifer; Larsen, Annette K.; Henriques, João Antônio Pêgas

doi:10.1002/jat.1411

Cited by 62 publications

(46 citation statements)

References 35 publications

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“…Cell cycle analysis was performed with Guava Software. [19]. After treatment, cells were harvested, centrifuged and resuspended in 20 lL of PBS buffer.…”

Section: Methodsmentioning

confidence: 99%

Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

Jorge

Oliveira

Filippi-Chiela

et al. 2014

Basic Clin Pharma Tox

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The diphenyl ditelluride (DPDT) is a prototype for the development of new biologically active molecules. In previous studies, DPDT showed an elevated cytotoxicity in Chinese hamster fibroblast (V79) cells but the mechanisms for reduction of cell viability still remain unknown. DPDT showed mutagenic properties by induction of frameshift mutations in bacterium Salmonella typhimurium and yeast Saccharomyces cerevisiae. This organotelluride also induced DNA strand breaks in V79 cells. In this work, we investigated the mechanism of DPDT cytotoxicity by evaluating the effects of this compound on cell cycle progression, apoptosis induction and topoisomerase I inhibition. Significant decrease of V79 cell viability after DPDT treatment was revealed by MTT assay. Morphological analysis showed induction of apoptosis and necrosis by DPDT in V79 cells. An increase of caspase 3/7 activity confirmed apoptosis induction. The cell cycle analysis showed an increase in the percentage of V79 cells in S phase and sub-G1 phase. The yeast strain deficient in topoisomerase I (Topo I) showed higher tolerance to DPDT compared with the isogenic wild-type strain, suggesting that the interaction with this enzyme could be involved in DPDT toxicity. The sensitivity to DPDT found in top3Δ strain indicates that yeast topoisomerase 3 (Top3p) could participate in the repair of DNA lesions induced by the DPDT. We also demonstrated that DPDT inhibits human DNA topoisomerase I (Topo I) activity by DNA relaxation assay. Therefore, our results suggest that the DPDT-induced cell cycle arrest and reduction in cell viability could be attributed to interaction with topoisomerase I enzyme.

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“…Cell cycle analysis was performed with Guava Software. [19]. After treatment, cells were harvested, centrifuged and resuspended in 20 lL of PBS buffer.…”

Section: Methodsmentioning

confidence: 99%

Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

Jorge

Oliveira

Filippi-Chiela

et al. 2014

Basic Clin Pharma Tox

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“…Importantly, silencing NFBD1 enhances the radiosensitivity of human NPC CNE1 cells and results in tumor growth inhibition [26]. Given that DNA is the primary target of CDDP and 5-FU [27][28][29][30], previous studies strongly indicate a close relationship between NFBD1 expression and CDDP or 5-FU resistance.…”

Section: Introductionmentioning

confidence: 97%

Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells

et al. 2016

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Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer that is prevalent among people of southern Chinese ancestry in southern China and Southeast Asia. Radiotherapy and cisplatin (CDDP)-based chemotherapy are the main treatment options. Unfortunately, disease response to concurrent chemoradiotherapy varies among patients with NPC, and many cases are resistant to CDDP and radiotherapy. NFBD1 functions in cell cycle checkpoint activation and DNA repair following DNA damage. In this study, we identified the NFBD1 as a tractable molecular target to chemosensitize NPC cells. NFBD1 expression in NPC CNE1 cell lines was depleted using lentivirus-mediated short hairpin RNA, and the elevated sensitivity of these NFBD1-inhibited NPC cells to therapeutic reagent CDDP and 5-fluorouracil (5-FU) was evaluated using MTS assays. Flow cytometry analysis also showed that NFBD1 knockdown led to an obvious induction of apoptosis in CDDP- or 5-FU-treated CNE1 cells. Furthermore, we implicated the involvement of NFBD1 in Rad51 and DNA-PKcs foci formation following CDDP or 5-FU chemotherapy. In conclusion, NFBD1 knockdown improves the chemosensitivity of NPC cells by inhibiting cell growth and promoting apoptosis through the impairment of DNA damage repair, suggesting NFBD1 as a novel therapeutic target for NPC.

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“…In support of this principle are data demonstrating a marked difference between 5-FU and its metabolite fluorodeoxyuridine monophosphate in their effect on the cell cycle progression in colon cancer, and the cell's ability to generate DNA double-strand breaks, monitored by conversion of H2AX into its active form gH2AX. 6 In addition, it seems that a cancer cell's efficacy to remove and repair DNA sites where uracil have been incorporated highly dictates its sensitivity to 5-FU. 7 Once initiated, apoptosis is executed by caspases and several upstream regulatory factors, which direct their proteolytic activity, have been defined as either tumor suppressors or oncogenes.…”

mentioning

confidence: 99%

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

et al. 2012

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5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53-dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca 2 þ ) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca 2 þ through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca 2 þ -chelator BAPTA (1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FUinduced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53 À / À cells confirmed the importance of a Ca 2 þ -CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes.

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5‐Fluorouracil and its active metabolite FdUMP cause DNA damage in human SW620 colon adenocarcinoma cell line

Cited by 62 publications

References 35 publications

Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

Knockdown of NFBD1/MDC1 enhances chemosensitivity to cisplatin or 5-fluorouracil in nasopharyngeal carcinoma CNE1 cells

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

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