The triterpenoid natural products have played an important role in understanding mechanistic models of human diseases. These natural products are diverse, but many have been characterized as reactive oxygen species (ROS) modulators. ROS can regulate cell survival and function, which ultimately affects biological processes leading to disease. The triterpenoids offer an untapped source of creativity to generate tool compounds with high selectivity to regulate ROS. This brief Review highlights the diverse complexity by which these secondary metabolites induce many cell death modalities (apoptosis, autophagy, ferroptosis, etc.) that can affect various complex cell signaling pathways through ROS and ultimately lead to evading or accelerating cell death.

Triterpenoids as Reactive Oxygen Species Modulators of Cell Fate

Nowadays, one of the leading causes of death in humans is cancer, which is still on the rise globally and is in great need of intense study on the pathogenic mechanism and effective therapy. Epigenetics is a discipline that studies heritable changes in gene expression without alteration of DNA sequence. Epigenetic changes mainly involve DNA methylation, histone modifications and non-coding RNA (ncRNA) expression, which are interconnected to play a crucial role in the initiation and progression of various malignancies. Curcumin is a type of plant-derived polyphenolic compound with strong bioactivity against various disorders, particularly cancer. Retrieving commonly used databases such as PubMed, Google Scholar and CNKI, we summarized recent advances in the efficacy of curcumin on cancer and its epigenetic regulation in terms of DNA methylation, histone modifications and ncRNA expression. Furthermore, we also focused on improving the bioavailability of curcumin by development of novel curcumin analogs with high bioavailability, nanoparticles-loaded drug delivery system for curcumin, and combination therapy of curcumin with other agents. This review provides comprehensive insights into the molecular mechanisms, on the basis of epigenetic regulation, underlying the clinical application of curcumin in cancer. 

Curcumin: An epigenetic regulator and its application in cancer.

Inhibitors of epigenetic writers such as DNA methyltransferases (DNMTs) are attractive compounds for epigenetic drug and probe discovery. To advance epigenetic probes and drug discovery, chemical companies are developing focused libraries for epigenetic targets. Based on a knowledge-based approach, herein we report the identification of two quinazoline-based derivatives identified in focused libraries with sub-micromolar inhibition of DNMT1 (30 and 81 nM), more potent than S-adenosylhomocysteine. Also, both compounds had a low micromolar affinity of DNMT3A and did not inhibit DNMT3B. The enzymatic inhibitory activity of DNMT1 and DNMT3A was rationalized with molecular modeling. The quinazolines reported in this work are known to have low cell toxicity and be potent inhibitors of the epigenetic target G9a. Therefore, the quinazoline-based compounds presented are attractive not only as novel potent inhibitors of DNMTs but also as dual and selective epigenetic agents targeting two families of epigenetic writers.

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7-Aminoalkoxy-Quinazolines from Epigenetic Focused Libraries Are Potent and Selective Inhibitors of DNA Methyltransferase 1

ABSTRACT Introduction In this article, authors report an inclusive discussion about the combinatorial approach for the treatment of cardiovascular diseases (CVDs) and for counteracting the cardiovascular risk factors. The mentioned strategy was demonstrated to be useful for improving the efficacy of pharmacological treatments and in CVDs showed superior efficacy with respect to the classical monotherapeutic approach. Areas covered According to this topic, authors analyzed the combinatorial treatments that are available on the market, highlighting clinical studies that demonstrated the efficacy of combinatorial drug strategies to cure CVDs and related risk factors. Furthermore, the review gives an outlook on the future perspective of this therapeutic option, highlighting novel drug targets and disease models that could help the future cardiovascular drug discovery Expert opinion The use of specifically designed and increasingly rational and effective drug combination therapies can therefore be considered the evolution of polypharmacy in cardiometabolic and CVDs. This approach can allow to intervene on multiple etiopathogenetic mechanisms of the disease or to act simultaneously on different pathologies/risk factors, using the combinations most suitable from a pharmacodynamic, pharmacokinetic, and toxicological perspective, thus finding the most appropriate therapeutic option.

Combinatorial approaches for novel cardiovascular drug discovery: a review of the literature

Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial–mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as COL5A2, ITGAV, SERPINH1, CALD1, SPARC, and ACTA2 were associated with upregulation of TGF-β signaling, hedgehog signaling, and IL-2-STAT5 signaling and downregulation of the IFN-α and IFN-γ response. Immune checkpoints such as CTLA4, CD274 (PD-L1), PDCD1LG2 (PD-L2), PDCD1 (PD-1), and TIGIT were upregulated, while LAG3, LGALS9, and VTCN1 were downregulated with the expression of MESO EMT genes. CD160, KIR2DL1, and KIR2DL3 were also broadly downregulated with the expression of MESO EMT genes. In conclusion, we observed that the expression of a panel of MESO EMT genes was associated with hypermethylation of epigenetic genes and loss of expression of CDKN2A and CDKN2B. Expression of MESO EMT genes was associated with downregulation of the type I and type II IFN response, loss of cytotoxicity and NK cell activity, and upregulation of specific immune checkpoints, as well as upregulation of the TGF-β1/TGFBR1 pathway.

https://www.mdpi.com/1422-0067/24/5/4264/pdf?version=1676965603

Alice Lanne

Papers

Drug discovery for epigenetics targets.