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Epigenetic and Metabolic Alterations in Cancer Cells: Mechanisms and Therapeutic Approaches
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
HDACi are being actively pursued for the treatment of cancers. HDACi Vorinostat and Romidepsin are approved for treatment of cutaneous T cell lymphoma. HDACi has been shown to modulate tumor metabolism by virtue of its effect on gene expression. HDACi treatment was associated with a significant reduction in glucose uptake and glycolysis in breast, colon, lung and multiple myeloma cancer cell lines (Alcarraz-Vizan et al., 2010; Wardell et al., 2009; Amoedo et al., 2011; Rodrigues et al., 2015). Such alterations are driven by decreased expression glucose uptake transporters and key glycolytic enzymes (Wardell et al., 2009), and increase reliance on mitochondrial metabolism (Amoedo et al., 2011). These studies imply that HDACi might selectively target cancer cells with Warburg’s phenotype.
Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
A histone deacetylase inhibitor approved in 2015 by the FDA is panobinostat; the drug inhibits HDACs I, II, and IV and is used—in combination with the anti-cancer drug bortezomib (see above) and the corticoid dexamethasone—to treat adult patients suffering from multiple myeloma. The inhibition of HDACs leads to a reactivation of the expression of tumor suppressor genes. As HDACs are also involved in the expression of proteins important for cell proliferation and differentiation, apoptosis, etc., panobinostat affects in addition the cell-cycle control system. Another HDCAi is romidepsin (opposite scheme), a bicyclic depsipeptide antibiotic produced by the bacterium Chromobacterium violaceum. It is a prodrug the disulfide bond of which is reduced to a thiol moiety within the cells where it interacts reversibly with the Zn2+ ion in the binding pocket of the enzyme and blocks its activity. DNA methyltransferase inhibitors are 5-azacytidine and its deoxy derivative decitabine (also known as 5-aza-2′-deoxycytidine) causing hypomethylation of DNA. They are employed for the treatment of the myelodysplastic syndrome as well as for acute myeloid leukemia. Azacitidine as a ribonucleoside is incorporated into RNA (and to a lesser extent in DNA) whereas decitabine, a deoxyribonucleoside, is only incorporate into DNA. A review of additional novel drugs targeting epigenetic proteins together with key examples of epigenetic dysregulation in tumors has been provided by Campbell and Tummino (2014), and Pachaiyappan and Woster (2014).
New approaches towards the discovery and evaluation of bioactive peptides from natural resources
Published in Critical Reviews in Environmental Science and Technology, 2020
Nam Joo Kang, Hyeon-Su Jin, Sung-Eun Lee, Hyun Jung Kim, Hong Koh, Dong-Woo Lee
In recent years, due to advances in bioinformatics-based intelligent design and assembly of peptide modules as molecular medicines, emerging peptide technologies and novel strategies have expanded our ability to generate a wide range of new BPs as therapeutics. Their chemical basis can be categorized into three segments; native, analogous, and heterologous peptides (Lau & Dunn, 2018; Uhlig et al., 2014). Multiple BPs such as Leuprorelin, Octreotide, Ecallantide, Liraglutide, and Romidepsin have been developed that mimic the biological roles of BPs in living systems; these compounds have been applied to therapeutic purposes such as prevention of cancer, diabetes, obesity, or vaccine development (Albericio & Kruger, 2012; Fosgerau & Hoffmann, 2015; Usmani et al., 2017). The activities of BPs include promotion of wound-healing and amelioration or prevention of hypertension, skin aging, inflammation, and microbial activity (Sánchez & Vázquez, 2017). Consequently, synthetic peptide therapeutics (including nutraceuticals) is a very promising field to treat human diseases because they have several advantages in terms of de novo design, diversity, high biological activity, high specificity, and low toxicity (Lau & Dunn, 2018). Despite these advantages over small molecules, there are certain limitations of BPs, including short plasma half-life and negligible oral bioavailability due to physicochemical instability and proteolysis (Antosova, Mackova, Kral, & Macek, 2009; Otvos & Wade, 2014; Renukuntla, Vadlapudi, Patel, Boddu, & Mitra, 2013).