Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.
An ideal scaffold should be biocompatible, having appropriate microstructure, excellent mechanical strength yet degrades. Chitosan exhibits most of these exceptional properties, but it is always associated with sub-optimal cytocompatibility. This study aimed to incorporate graphene oxide at wt % of 0, 2, 4, and 6 into chitosan matrix via direct blending of chitosan solution and graphene oxide, freezing, and freeze drying. Cell fixation, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, alkaline phosphatase colorimetric assays were conducted to assess cell adhesion, proliferation, and early differentiation of MG63 on chitosan–graphene oxide scaffolds respectively. The presence of alkaline phosphatase, an early osteoblast differentiation marker, was further detected in chitosan–graphene oxide scaffolds using western blot. These results strongly supported that chitosan scaffolds loaded with graphene oxide at 2 wt % mediated cell adhesion, proliferation, and early differentiation due to the presence of oxygen-containing functional groups of graphene oxide. Therefore, chitosan scaffolds loaded with graphene oxide at 2 wt % showed the potential to be developed into functional bone scaffolds.
Aims: The aim of this study was to sensitize the resistant breast adenocarcinoma cells towards Tumour Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced apoptosis. Background: Breast cancer is a heterogeneous disease involving complex mechanisms. TRAIL is a potential anti-cancer candidate for targeted treatment due to its selective killing effects on neoplastic cells. Nonetheless, resistance occurs in many cancers either intrinsically or after multiple treatments. objective: Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb) (TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis. Objective: Therefore, this research investigated whether the combination of Trichostatin A (TSA) and Zebularine (Zeb) (TZ) followed by TRAIL (TZT) could sensitize the human breast adenocarcinoma cells towards apoptosis. Methods: The breast adenocarcinoma cells, MDA-MB-231, MCF-7 and E-MDA-MB-231 (E-cadherin re-expressed MDA-MB-231) were treated with TSA, Zeb, TZ, TRAIL and TZT. The cells were subjected to hematoxylin and eosin (H & E) staining and FITC-Annexin V/Propidium Iodide apoptosis detection prior to proteome profiling. Results: Based on morphological observation, apoptosis was induced in all cells treated with all treatment regimens though it was more evident for the TZT-treated cells. In the apoptosis detection analysis, TZ increased early apoptosis significantly in MDA-MB-231 and MCF-7 while TRAIL induced late apoptosis significantly in E-MDA-MB-231. Based on the proteome profiling on MDA-MB-231, TRAIL R2 and Fas expression was increased. For E-MDA-MB-231, down-regulation of catalase, paraoxonase-2 (PON2), clusterin, an inhibitor of apoptosis proteins (IAPs) and cell stress proteins validated the notion that E-cadherin re-expression enhances TZT anti-cancer efficacy. Similar trend was observed in MCF-7 whereby TZT treatment down-regulated the anti-apoptotic catalase and PON2, increased the pro-apoptotic, B cell lymphoma 2 (Bcl-2)-associated agonist of cell death (Bad) and Bcl-2-associated X (Bax), second mitochondria-derived activator of caspase (SMAC) and HtrA serine peptidase 2 (HTRA2) as well as TRAIL receptors (TRAIL R1 and TRAIL R2). Conclusion: TZ treatment serves as an efficient treatment regimen for MDA-MB-231 and MCF-7, while TRAIL serves as a better treatment option for E-MDA-MB-231. other: Therefore, future studies on E-cadherin’s positive regulatory role in TRAIL-induced apoptosis are definitely warranted. Other: Therefore, future studies on E-cadherin’s positive regulatory role in TRAIL-induced apoptosis are warranted.
Breast cancer is the leading cause of death among women in which its definite cure remains uncovered. Tumour necrosis factor-related apoptosis inducing ligand (TRAIL) is a potential anti-cancer agent due to its selective killing towards cancer cells while sparing the healthy cells. However, it is limited by the development of TRAIL resistance. With the attempt to overcome TRAIL resistance, this research embarked to study the effect of epigenetic drugs, Trichostatin A (TSA) and Zebularine (Zeb) along with E-cadherin re-expression on anti-cancer effect in human breast adenocarcinoma cells. The MDA-MB-231 re-expressed with E-cadherin (231-EGFP) was treated with TSA and Zeb before being treated with TRAIL (TZT) to compare the effect on MDA-MB-231 and MCF-7. The cell viability, cell cycle and migration assays were conducted on these cells, prior to reverse-transcription-polymerase chain reaction (RT-PCR) targeted on proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 2 (CDK2), matrix metalloproteinase 9 (MMP9). TZT induced a significant increase in G0/G1-arrested cell population and reduction in cell viability in 231-EGFP. These were verified by the suppression of PCNA and CDK2 mRNA expression. However, there was a negligible effect to reduce the cell migration of the invasive MDA-MB-231 and 231-EGFP cells in accordance with the lack of down-regulation of MMP9. In conclusion, this research shows that TSA and Zeb have sensitized breast cancer towards TRAIL treatment in 231-EGFP cells, validating the potentiality of E-cadherin as a biomarker of TRAIL treatment efficacy in the invasive breast cancer.
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