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Nickel nanowires induce cell cycle arrest and apoptosis by generation of reactive oxygen species in HeLa cells.

ABSTRACT: Nickel nanowires (Ni NWs) have great potential to be used as a living cell manipulation tool and developed into an anticancer agent. However, their candidacy as biomedical appliances need detailed human cell studies, such as study of the interaction between Ni NWs and tumor cells. The present study investigated the cytotoxicity of Ni NWs in HeLa cells. A dose-dependent inhibition of cell growth was observed by using the MTT assay. We demonstrated that Ni NWs induced oxidative stress by generation of reactive oxygen species (ROS). Apoptosis induction was evidenced by flow cytometry, annexin V binding assay and DAPI staining. DNA flow cytometric analysis indicated that Ni NWs significantly increased the percentages of cells in S phase compared with control cells. This process was accompanied by the loss of mitochondrial membrane potential. These results revealed that Ni NWs induced apoptosis in HeLa cells via ROS generation and cell cycle arrest.

SUBMITTER: Ma C

PROVIDER: S-EPMC5598471 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Nickel nanowires induce cell cycle arrest and apoptosis by generation of reactive oxygen species in HeLa cells.

Ma ChangGuo C Song MengMeng M Zhang Ye Y Yan ManQing M Zhang Min M Bi Hong H

Toxicology reports 20140516

Nickel nanowires (Ni NWs) have great potential to be used as a living cell manipulation tool and developed into an anticancer agent. However, their candidacy as biomedical appliances need detailed human cell studies, such as study of the interaction between Ni NWs and tumor cells. The present study investigated the cytotoxicity of Ni NWs in HeLa cells. A dose-dependent inhibition of cell growth was observed by using the MTT assay. We demonstrated that Ni NWs induced oxidative stress by generatio ...[more]

PMID: 28962232

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Project description:In our previous studies, we have shown that benzyl isothiocyanate (BITC) inhibits the growth of human pancreatic cancer cells by inducing apoptosis. In the present study, we demonstrate the activation of all the three (MAPK) family members [extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinase (JNK) and P38] in response to BITC treatment. Exposure of Capan-2 cells with varying concentrations of BITC for 24 h resulted in the phosphorylation (activation) of ERK at Thr202/Tyr204, JNK at Thr183/Tyr185 and P38 at Thr180/Tyr182, leading to the induction of apoptosis. Similar MAPK activation was also observed in MiaPaCa-2 cells in response to BITC treatment. However, normal human pancreatic ductal epithelial cells did not show the activation of MAPK's and remained unaffected by BITC treatment. To confirm the role of ERK, JNK and P38 in BITC-induced G(2)/M arrest and apoptosis, Capan-2 cells were pre-treated with MAPK-specific inhibitors or MAPK8-short hairpin RNA (shRNA) prior to BITC treatment. Significant protection from BITC-induced G(2)/M arrest was observed in the cells pre-treated with MAPK kinase (MEK-1) but not JNK or P38 inhibitors. On the other hand, BITC-induced apoptosis was almost completely abrogated in the cells pre-treated with MEK-1, JNK or P38 inhibitors. Similarly, MAPK8-shRNA also offered almost complete protection against BITC-induced G(2)/M arrest and apoptosis. Furthermore, we observed that BITC treatment leads to the generation of reactive oxygen species (ROS) in Capan-2 and MiaPaCa-2 cells, which in part was orchestrated by depletion of reduced glutathione (GSH) level. Blocking ROS generation with N-acetyl-L-cysteine (NAC) significantly prevented GSH depletion and activation of ERK and JNK but not P38. Further, NAC or tiron prevented G(2)/M arrest by blocking G(2)/M regulatory proteins and completely protected the cells from BITC-induced apoptosis. Taken together, our results suggest that BITC-mediated G(2)/M arrest is mediated through ERK activation, whereas apoptosis is via ERK, JNK and P38.

Project description:BackgroundThe Securinega-type alkaloids occur in plants belonging to Euphorbiaceae family. One of the most widely distributed alkaloid of this group is securinine, which was identified next to allosecurinine in Phyllanthus glaucus (leafflower). Recently, some Securinega-type alkaloids have paid attention to its antiproliferative potency towards different cancer cells. However, the cytotoxic properties of allosecurinine have not yet been evaluated.MethodsThe cytotoxicity of the extract, alkaloid fraction obtained from P. glaucus, isolated securinine and allosecurinine against HeLa cells was evaluated by real-time xCELLigence system and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected by annexin V and 7-amino-actinomycin (7-AAD) staining and confirmed with fluorescent Hoechst 33342 dye. The assessment of mitochondrial membrane potential (MMP), reactive oxygen species (ROS) generation, the level of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), caspase-3/7 activity and cell cycle analysis were measured by flow cytometry. The enzymatic activity of caspase-9 was assessed by a luminometric assay. The expression of apoptosis associated genes was analyzed by real-time PCR.ResultsThe experimental data revealed that securinine and the alkaloid fraction were significantly potent on HeLa cells growth inhibition with IC50 values of 7.02 ± 0.52 μg/ml (32.3 μM) and 25.46 ± 1.79 μg/ml, respectively. The activity of allosecurinine and Phyllanthus extract were much lower. Furthermore, our study showed that the most active securinine induced apoptosis in a dose-dependent manner in the tested cells, increased the percentage of ROS positive cells and depolarized cells as well as stimulated the activity of ERK1/2, caspase-9 and -3/7. Securinine also induced cell cycle arrest in S phase. Real-time PCR analysis showed high expression of TNFRSF genes in the cells stimulated with securinine.ConclusionsSecurinine induces apoptosis and activates cell cycle checkpoints in HeLa cells which is associated with oxidative stress. The results indicate that the mitochondrial pathway is involved in the programmed cell death.

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Nickel nanowires induce cell cycle arrest and apoptosis by generation of reactive oxygen species in HeLa cells.

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Nickel nanowires induce cell cycle arrest and apoptosis by generation of reactive oxygen species in HeLa cells.

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