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D suggests existence of a therapeutic window for this bone-targeting compound
A recent in vitro study on colon cancer cells has proposed Ca2+-release-mediated p53-dependent and ndependent pathways of KP46-mediated programmed cell death induction. When in p53+/+ cells p53-induced upregulation of reactive oxygen species (ROS) was proposed as central mode-of action downstream of intracellular Ca2+-release, in p53-mutated or -deleted cells FAS-related extrinsic apoptosis was postulated [31].Kubista et al. Journal of Experimental Clinical Cancer Study (2017) 36:Page 9 ofViability (-fold handle)HOS1.1.0.CI value1001.0.0.0.0 100Obatoclax (nM)Obatoclax (nM)U-2 OSViability (-fold control)1.1.0.CI value1.0.0.0 1000.0 100Obatoclax (nM)Obatoclax (nM)1.MG-Viability (-fold control)1.0.CI value1001.0.0.0.0 100Obatoclax (nM)Obatoclax (nM)1.SAOS-Viability (-fold handle)1.0.CI value1001.0.0.0.0 100Obatoclax (nM)Obatoclax (nM)Fig. 4 The anti-apoptotic bcl-2 loved ones and autophagy inhibitor obatoclax enhances the activity of KP46 within the majority in the tested OS cell models. The two compounds have been either applied alone or in combination in the indicated concentrations for 72 h continuous drug exposure. Cell viability was determined by an MTT-based survival assay. Dose-response curves in the left are when compared with the respective mixture indices (CI) calculated by CalcuSyn Decernotinib JAK Software program in the correct panelsAccordingly, a p53-dependent cell death mechanism via KP46 accumulation in mitochondria and deregulation of mitochondrial dynamics and bioenergetics was recommended recently for human colon cancer cells [13]. Depletion on the intracellular labile iron pool by KP46 PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/26100631 initiated p53dependent BNIP3L activation and in turn mitophagic cell death [13]. On the other hand, in a preceding study we were unable to detect any proof for an influence of the p53 status on the basic sensitivity of an extended panel PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/27864321 of lung and colon cancer cells against KP46 treatment [17].Accordingly, from the here investigated OS cell lines only U-2 OS harbors an intact p53 response whilst the other 3 cell models are p53 mutated or null [32, 33]. Having said that, U-2 OS was characterized by the lowest sensitivity against KP46 arguing against a significant sensitizing part of wild-type p53 against this gallium-containing metal compound. Consequently, though p53-mediated anxiety or harm recognition could influence around the mode of KP46-induced cell death, it truly is of course not a basic determinant of cancer cell sensitivity to KP46.Kubista et al. Journal of Experimental Clinical Cancer Research (2017) 36:Web page 10 ofFig. five KP46 therapy induces autophagy and synergizes with downstream autophagy inhibitors.D suggests existence of a therapeutic window for this bone-targeting compound at the very least in the cellular level. Interestingly, cisplatin exhibited the lowest IC50 values inside the non-malignant HLF cell model nicely in agreement using the massive adverse effects by this clinically utilized anticancer metal drug. The molecular mechanisms underlying the anticancer activity of KP46 are nonetheless not effectively understood. Some studies - including several from our group - suggestedapoptotic cell death induction as one important mode of action for KP46 especially immediately after longer drug exposure instances [13, 30, 31].
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