Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

Lung cancer, especially lung adenocarcinoma, is one of the main causes of death worldwide. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a primary anticancer agent and a member of the tumor necrosis factor family that selectively induces apoptosis in various tumor cells, but not in normal cells. Combination chemotherapy can be used for treating specific cancer types even at progressive stages. In the present study, we observed that 5-fluorouracil, which exerts anticancer effects by inhibiting tumor cell proliferation, enhanced TRAIL-induced apoptosis of TRAIL-resistant human adenocarcinoma A549 cells. Interestingly, 5-fluorouracil treatment markedly increased Bax and p53 levels and 5-fluorouracil and TRAIL cotreatment increased Ac-cas3 and Ac-cas8 levels compared with those in control cells. Taken together, the present study demonstrated that 5-fluorouracil enhances TRAIL-induced apoptosis in TRAIL-resistant lung adenocarcinoma cells by activating Bax and p53, and also suggest that TRAIL and 5-fluorouracil cotreatment can be used as an adequate therapeutic strategy for TRAIL-resistant human cancers.

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Alzheimer’s disease (AD) is characterized by the formation of intracellular aggregate composed of heavily phosphorylated tau protein and extracellular deposit of amyloid-β (Aβ) plaques derived from proteolysis cleavage of amyloid precursor protein (APP). Autophagy refers to the lysosomal-mediated degradation of cytoplasmic constituents, which plays a critical role in maintaining cellular homeostasis. Importantly, recent studies reported that dysregulation of autophagy is associated in the pathogenesis of AD, and therefore, autophagy modulation has gained attention as a promising approach to treat AD pathogenesis. In AD, both the maturation of autolysosomes and its retrograde transports have been obstructed, which causes the accumulation of autophagic vacuoles and eventually leads to degenerating and dystrophic neurites function. However, the mechanism of autophagy modulation in APP processing and its pathogenesis have not yet been fully elucidated in AD. In the early stage of AD, APP processing and Aβ accumulation-mediated autophagy facilitate the removal of toxic protein aggregates via mTOR-dependent and -independent pathways. In addition, a number of autophagy-related genes (Atg) and APP are thought to influence the development of AD, providing a bidirectional link between autophagy and AD pathology. In this review, we summarized the current observations related to autophagy regulation and APP processing in AD, focusing on their modulation associated with the AD progression. Moreover, we emphasizes the application of small molecules and natural compounds to modulate autophagy for the removal and clearance of APP and Aβ deposits in the pathological condition of AD.

A major concern in the clinical application of tumor necrosis factor related apoptosis‐inducing ligand (TRAIL) in tumors is the development of resistance. Therefore, agents that can potentially restore TRAIL sensitivity are important therapeutic targets for cancer treatment. Herein, we evaluated lanatoside c and digoxin, both of which are widely used cardiac glycosides (CGs), for their ability to sensitize human hepatocellular carcinoma cells (Huh‐7 and HepG2) through TRAIL‐induced apoptosis. CGs functionalize TRAIL as shown by its effect on intracellular reactive oxygen species (ROS) generation, which damages mitochondrial integrity and thereby confers intrinsic apoptotic caspase cascade during combined treatment. Caspase activation is dependent on ROS as shown by the ability of CGs to generate ROS and the ROS‐N‐acetylcysteine (NAC) relationship, which inhibits apoptosis during cotreatment by preventing the formation of caspase‐8 and ‐3. Furthermore, CGs triggered p38MAPK phosphorylation and NAC pre‐exposure blocked p38MAPK phosphorylation, which demonstrated that p38MAPK was dependent upon ROS generation. Additionally, CGs were found to be potent inducers of AMPK‐mediated protective autophagy as pharmacological and genetic autophagy inhibition reached the higher threshold of TRAIL‐mediated apoptosis. Finally, CGs downregulated the expression of the antiapoptotic protein Bcl‐2 and increased the translocation of proapoptotic protein cytochrome c, thereby inducing apoptosis. Collectively, these results indicate that CGs potentiate the enhanced cytotoxic capacity to TRAIL through ROS generation, p38MAPK phosphorylation, cell survival protein downregulation, and protective autophagy inhibition.

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Glycosylation is the most common post-translational modification (PTM) of proteins. Cells of a malignant tumour frequently display altered glycosylation of cell surface proteins. These are common in cancers of the head and neck, most of which are squamous cell carcinomas (HNSCC). Many cell properties and functions are affected, including proliferation and movement, thus increasing the propensity to metastasise. HNSCC represents the sixth most frequent malignancy worldwide. These neoplasms, which arise from the mucous membranes of the various anatomical subsites of the upper aero-digestive tract, are heterogeneous in terms of aetiology and clinico-pathologic features. With current treatments, only about 50% of HNSCC patients survive beyond 5-years. Therefore, there is the pressing need to dissect NHSCC heterogeneity to inform treatment choices. In particular, reliable biomarkers of predictive and prognostic value are eagerly needed. This review describes the current state of the art and bio-pathological meaning of glycosylation signatures associated with HNSCC and explores the possible role of tumour specific glycoproteins as potential biomarkers and attractive therapeutic targets. We have also compiled data relating to altered glycosylation and the nature of glycoproteins as tools for the identification of circulating tumour cells (CTCs) in the new era of liquid biopsy. AbbreviationsAFP-α-fetoprotein; CEACAM6-Carcinoembryonic antigen-related cell adhesion molecule 6; OSCC-Oral squamous cell carcinoma; C1GALT1-Core 1 β1,3-galactosyltransferase; CTHRC1-Collagen triple helix repeat containing protein1; DPAGT1-Dolichyl-Phosphate N-Acetylglucosaminephosphotransferase 1; ESOSCC-Early stage oral squamous cell carcinoma; TA-

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