Human caspases are a group of eleven endoproteases, caspases 1–10 and caspase 14, controlling cell regulatory networks of inflammation and cell death.
A crucial element of apoptotic cell death is caspase-3, a cysteine protease that catalyzes a number of key endocellular proteins. 5-fluorouracil is an effective pharmaceutical agent reported to initiate apoptotic processes against a number of malignancies such as colorectal, oral, breast, head and neck, gastric and cervical carcinomas. Therefore, a fundamental target of conventional chemotherapy is the activation of endocellular signaling mechanisms involved in cell death pathways, in particular, those mediating apoptosis.
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Conclusions: These findings may be useful for facilitating future high throughput screening of different chemotherapeutic drugs with a cytotoxic principle based on free radical production.Ĭancer cells have the ability to prevent programmed cell death by disorganizing tissue homeostasis, the balance between cell proliferation and cell death. Our findings suggest that changes in superoxide concentration could be detected with the biosensor in a non-invasive and rapid manner, thus allowing a reliable estimation of oxidative damage due to cell apoptosis. Results: The results of this study indicate that 5-FU differentially affects superoxide production and caspase-3 activation when applied in cytotoxic concentrations against HeLa cells, while superoxide accumulation is in accordance with mitochondrial superoxide levels. The cytotoxic effects of 5-fluorouracil on HeLa cells were assessed by the MTT proliferation assay, whereas oxidative damage and induction of apoptosis were measured fluorometrically by the mitochondria-targeted MitoSOX™ Red and caspase-3 activation assays, respectively.
Methods: A cell-based bioelectric biosensor was used to detect alterations in superoxide levels in the culture medium of HeLa cervical cancer cells after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). Silvestrol appears to be well tolerated in animals.Background: In vitro cell culture monitoring can be used as an indicator of cellular oxidative stress for the assessment of different chemotherapy agents. We propose that silvestrol mediates its effects by preferentially inhibiting translation of malignancy-related mRNAs. Conclusions/Significance Our results indicate that silvestrol is a potent anti-cancer compound in vivo that exerts its activity by affecting survival pathways as well as angiogenesis. We demonstrate that targeting translation by silvestrol results in preferential inhibition of weakly initiating mRNAs. We show that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis. We find that silvestrol impairs the ribosome recruitment step of translation initiation by affecting the composition of the eukaryotic initiation factor (eIF) 4F complex. Methodology/Principal Findings Among a number of flavagline family members tested herein, we find that silvestrol is the more potent translation inhibitor among these. One flavagline, silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model. They have been shown to modulate the activity of eIF4A, the DEAD-box RNA helicase subunit of the eukaryotic initiation factor (eIF) 4F complex, a complex that stimulates ribosome recruitment during translation initiation. Abstract : Background Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and in vivo and inhibit translation initiation.
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