Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- κB) transcription factor plays a pivotal role in the regulation of genes that control various responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-κB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-κB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-κB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-κB signaling pathway inhibitors as promising anticancer drug candidates are described.
Diabetes mellitus is a chronic, complex and multifactorial disease associated characteristically with hyperglycemia. One of the most recently approved antidiabetic drug classes for clinical use are sodium-glucose cotransporter type 2 (SGLT-2) inhibitors. SGLT-2 is a protein expressed in the kidneys, responsible for glucose reabsorption from the glomerular filtrate to the plasma. It is known, nowadays, that diabetic patients show an increased glucose renal reabsorption capacity, caused by the overexpression of the SGLT-2 transporter, thus contributing to hyperglycemia. From establishing this correlation, the SGLT-2 transporter started to be considered as a therapeutic target of interest, culminating in the approval of the first antidiabetic SGLT-2 inhibitor, dapagliflozin (Forxiga® or Farxiga®, Bristol-Myers Squibb & AstraZeneca), in 2012 in Europe. On the other hand, canagliflozin (Invokana®, Janssen Pharmaceutical) was the first drug in this class to be approved by the FDA, the U.S. Food and Drug Administration, in 2013. This review concerns the discovery and development of the first representatives of this class of antidiabetic drugs, and the description of new optimized analogues that are currently in the clinical and preclinical stages of development.
The search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrP) conversion into protease-resistant forms (protease-resistant PrP [PrP] or the scrapie form of PrP [PrP]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identified to be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrP mRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP) as the substrate and PrP seeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrP globular domain. J8 also reduced the fibrillation of mouse rPrP seeded with -produced fibrils. Furthermore, most of the compounds decreased the amount of PrP on the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrP content on the cell surface.
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