Yin Yang‐1 (YY1) is a zinc finger protein and member of the GLI‐Kruppel family that can activate or inactivate gene expression depending on interacting partners, promoter context and chromatin ...structure, and may be involved in the transcriptional control of ∼10% of the total mammalian gene set. A growing body of literature indicates that YY1 is overexpressed in multiple cancer types and that increased YY1 levels correlate with poor clinical outcomes in many cancers. However, the role of YY1 in the promotion or suppression of tumor growth remains controversial and its regulatory effects may be tumor cell type dependent at least in experimental systems. The molecular mechanisms responsible for the apparently conflicting roles of YY1 are not yet fully elucidated. This review highlights recent advances in our understanding of regulatory insights involving YY1 function in a range of cancer types. For example, YY1's roles in tumor growth involve stabilization of hypoxia‐inducible factor HIF‐1α in a p53 independent manner, negative regulation of miR‐9 transcription, control of MYCT1 transcription, a novel miR‐193a‐5p‐YY1‐APC axis, intracellular ROS and mitochondrial superoxide generation, p53 reduction and EGFR activation, control of genes associated with mitochondrial energy metabolism and miRNA regulatory networks involving miR‐7, miR‐9, miR‐34a, miR‐186, miR‐381, miR‐584‐3p and miR‐635. On the other hand, tumor suppressor roles of YY1 appear to involve YY1 stimulation of tumor suppressor BRCA1, increased Bax transcription and apoptosis involving cytochrome c release and caspase‐3/‐7 cleavage, induction of heme oxygenase‐1, inhibition of pRb phosphorylation and p21 binding to cyclin D1 and cdk4, reduced expression of long noncoding RNA of SOX2 overlapping transcript, and MUC4/ErbB2/p38/MEF2C‐dependent downregulation of MMP‐10. YY1 expression is associated with that of cancer stem cell markers SOX2, BMI1 and OCT4 across many cancers suggesting multidynamic regulatory control and groups of cancers with distinct molecular signatures. Greater understanding of the mechanistic roles of YY1 will in turn lead to the development of more specific approaches to modulate YY1 expression and activity with therapeutic potential.
Early growth response-1 (Egr-1) is a master regulator and transcriptional sensor in vascular dysfunction and disease. This article reviews recent developments in our understanding of the regulatory ...roles this zinc finger protein and product of an immediate-early gene plays in a range of cardiovascular and inflammatory disorders. Egr-1 can amplify pathologic signals from the extracellular environment by serving as a molecular conduit in the inducible expression of proliferative, migratory and proinflammatory genes driving disease progression. Strategies targeting Egr-1 may provide therapeutic benefit in cardiovascular and inflammatory disorders.
RNA-cleaving deoxyribozymes (DNAzymes) are synthetic single-stranded DNA-based catalytic molecules that can be engineered to bind to and cleave target mRNA at predetermined sites. These have been ...used as therapeutic agents in a range of preclinical cancer models and have entered clinical trials in Europe, China, and Australia. This review surveys regulatory insights into mechanisms of disease brought about by use of catalytic DNA
and
, including recent uses as nanosensors, nanoflowers, and nanosponges, and the emerging role of adaptive immunity underlying DNAzyme inhibition of cancer growth. DNAzymes represent a promising new class of nucleic acid-based therapeutics in cancer. This article discusses mechanistic and therapeutic insights brought about by DNAzyme use as nanotools and reagents in a range of basic science, experimental therapeutic and clinical applications. Current limitations and future perspectives are also discussed.
While flubendazole has been used as a macrofilaricide in humans and animals for some 40 years, work in vitro and in preclinical models over the last decade has suggested its potential use as an ...anticancer agent. This article reviews recent studies in a range of tumor types indicating novel functions for flubendazole in its control of processes associated with tumor growth, spread and renewal including ferroptosis, autophagy, cancer stem-like cell killing and suppression of intratumoral myeloid-derived suppressor cell accumulation and programmed cell death protein 1. Flubendazole’s potential use in clinical oncology will require further understanding of its mechanistic roles, range of inhibition of cancer types, capacity for adjunctive therapy and possible reformulation for enhanced solubility, bioavailability and potency.
•Flubendazole has been used as a macrofilaricide in humans and animals for 40 years but recent studies suggest its potential use as an anticancer agent.•Flubendazole regulates tumor growth, spread and renewal. It inhibits tumor angiogenesis and can synergize with chemotherapeutic agents.•Emerging evidence indicate that flubendazole has effects on ferroptosis, autophagy, cancer stem-like cells, intratumoral myeloid-derived suppressor cell accumulation and PD-1 levels.•These properties suggest the utility of flubendazole and other benzimidazole derivatives as repurposed or derivatized cancer agents.
Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the pathogenesis of CVD are regulated by the ...zinc finger transcription factor and product of an immediate-early gene, early growth response-1 (Egr-1). Egr-1 regulates multiple pro-inflammatory processes that underpin the manifestation of CVD. The activity of Egr-1 itself is influenced by a range of post-translational modifications including sumoylation, ubiquitination and acetylation. Egr-1 also undergoes phosphorylation by protein kinases, such as extracellular-signal regulated kinase (ERK) which is itself phosphorylated by MEK. This article reviews recent progress on the MEK-ERK-Egr-1 cascade, notably regulation in conjunction with factors and agents such as TET2, TRIB2, MIAT, SphK1, cAMP, teneligliptin, cholinergic drugs, red wine and flavonoids, wogonin, febuxostat, docosahexaenoic acid and AT1R blockade. Such insights should provide new opportunity for therapeutic intervention in CVD.
Neointima formation after percutaneous coronary intervention (PCI) is a manifestation of "phenotype switching" by vascular smooth muscle cells (SMC), a process that involves de-differentiation from a ...contractile quiescent phenotype to one that is richly synthetic. In response to injury, SMCs migrate, proliferate, down-regulate SMC-specific differentiation genes, and later, can revert to the contractile phenotype. The vascular response to injury is regulated by microRNAs (or miRNAs), small non-coding RNAs that control gene expression. Interactions between miRNAs and transcription factors impact gene regulatory networks. This article briefly reviews the roles of a range of miRNAs in molecular and cellular processes that control intimal thickening, focusing mainly on transcription factors, some of which are encoded by immediate-early genes. Examples include Egr-1, junB, KLF4, KLF5, Elk-1, Ets-1, HMGB1, Smad1, Smad3, FoxO4, SRF, Rb, Sp1 and c-Myb. Such mechanistic information could inform the development of strategies that block SMC growth, neointima formation, and potentially overcome limitations of lasting efficacy following PCI.
•Drug discovery is exciting and transformative but conflicts exist between the incentive to invent and the rights of others to access medicines•Tensions between fundamental rights to access essential ...medicines and rights of the inventor and investors are considered•Effective incentives to innovate in developed countries can lead to global improvements in access to medicine if the intellectual property system is calibrated to permit this•Compulsory licensing and alternative mechanisms facilitating global access to drugs in the context of rights to the highest attainable standard of health and intellectual property are also discussed
In developed countries that protect core aspects of the fundamental human right to the highest attainable standard of health, how does that right intersect with intellectual property rights? Here, the human rights implication of providing access to all cancer drugs recommended by experts in a developed country is considered in the context of conflict between the incentive to invent and the rights of others to access medicines. Effective incentives to innovate in developed countries can lead to global improvements in access to medicine if the intellectual property system is calibrated to permit this. This depends partly on the usefulness of compulsory licensing and alternative mechanisms facilitating global access to drugs. This review considers tensions between fundamental rights to access essential medicines and rights of the inventor and investors, including the pharmaceutical industry.
This article reviews the regulatory roles of the immediate-early gene product and prototypic zinc finger transcription factor, early growth response-1 in models of cardiovascular pathobiology, ...focusing on insights using microRNA, DNAzymes, small hairpin RNA, small interfering RNA, oligonucleotide decoy strategies and mice deficient in early growth response-1.
Repurposing Drugs for Skin Cancer Khachigian, Levon M
Current medicinal chemistry,
01/2020, Letnik:
27, Številka:
42
Journal Article
Recenzirano
Drug repurposing is the process of developing existing or abandoned drugs for a different disease. Repurposing can circumvent higher costs and times associated with conventional drug discovery ...strategies because toxicity and pharmacokinetics profiles are typically already established. This brief review focuses on efforts to repurpose drugs for skin cancer and includes reuse of antihypertensives, anthelmintics and antifungals among a range of other medicines. Repurposing not only ushers promising known drugs for new indications, the process of repurposing can uncover new mechanistic insights in the pathogenesis of disease and uncover new opportunities for pharmaceutical intervention.
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