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      The Innovative Potential of Statins in Cancer: New Targets for New Therapies

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          Abstract

          Numerous and different types of cancers possess the dysregulation of the mevalonate pathway as a common feature. Statins, traditionally applied in cardiovascular diseases to reduce lipid levels, subsequently have been discovered to exhibit anti-cancer activities also. Indeed, statins influence proliferation, migration, and survival of cancer cells by regulating crucial signaling proteins, such as Rho, Ras, and Rac. Recently, several studies have demonstrated that simvastatin, fluvastatin, and lovastatin are implicated in different pathways that enhance the survival time of patients with cancer under treatment in combination with antineoplastic agents. In this minireview, we present an overview of the most important studies conducted regarding the use of statins in cancer therapy up to date.

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          Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer.

          CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.
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            Statins and cancer prevention.

            Randomized controlled trials for preventing cardiovascular disease indicated that statins had provocative and unexpected benefits for reducing colorectal cancer and melanoma. These findings have led to the intensive study of statins in cancer prevention, including recent, large population-based studies showing statin-associated reductions in overall, colorectal and prostate cancer. Understanding the complex cellular effects (for example, on angiogenesis and inflammation) and the underlying molecular mechanisms of statins (for example, 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase-dependent processes that involve geranylgeranylation of Rho proteins, and HMG-CoA-independent processes that involve lymphocyte-function-associated antigen 1) will advance the development of molecularly targeted agents for preventing cancer. This understanding might also help the development of drugs for other ageing-related diseases with interrelated molecular pathways.
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              Mevalonate pathway: a review of clinical and therapeutical implications.

              Mevalonate pathway is an important metabolic pathway which plays a key role in multiple cellular processes by synthesizing sterol isoprenoids, such as cholesterol, and non-sterol isoprenoids, such as dolichol, heme-A, isopentenyl tRNA and ubiquinone. While extensively studied in regard with cholesterol synthesis and its implications in cardiovascular diseases, in recent years the mevalonate pathway has become a challenging and, in the meantime, fascinating topic, when a large number of experimental and clinical studies suggested that inhibition of non-sterol isoprenoids might have valuable interest in human pathology. These molecules that are essential for cell growth and differentiation appear to be potential interesting therapeutic targets for many areas of ongoing research: oncology, autoimmune disorders, atherosclerosis, and Alzheimer disease. Also, considerable progress has been made in the past decade in understanding the pathophysiology of two auto-inflammatory disorders resulting from an inherited deficiency of mevalonate kinase, the first committed enzyme of the mevalonate pathway. Here we present a brief description of the biochemistry of the mevalonate pathway, together with a review of the current knowledge of the clinical and therapeutical implications of this fascinating and complex metabolic pathway.
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                Author and article information

                Contributors
                Journal
                Front Chem
                Front Chem
                Front. Chem.
                Frontiers in Chemistry
                Frontiers Media S.A.
                2296-2646
                18 June 2020
                2020
                : 8
                : 516
                Affiliations
                [1] 1Department of Drug Chemistry and Technologies, Sapienza University of Rome , Rome, Italy
                [2] 2Department of Precision Medicine, Luigi Vanvitelli, University of Campania , Naples, Italy
                Author notes

                Edited by: Alfonso Carotenuto, University of Naples Federico II, Italy

                Reviewed by: Adriano Mollica, University “G. d'Annunzio” of Chieti-Pescara, Italy; Sabrina Taliani, University of Pisa, Italy

                *Correspondence: Antonello Mai antonello.mai@ 123456uniroma1.it

                This article was submitted to Medicinal and Pharmaceutical Chemistry, a section of the journal Frontiers in Chemistry

                †These authors share first authorship

                Article
                10.3389/fchem.2020.00516
                7312214
                32626692
                c3040695-876d-4ed0-a5d8-f741dcefcdb9
                Copyright © 2020 Di Bello, Zwergel, Mai and Valente.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 19 April 2020
                : 19 May 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 58, Pages: 9, Words: 6743
                Funding
                Funded by: Associazione Italiana per la Ricerca sul Cancro 10.13039/501100005010
                Award ID: 19162
                Categories
                Chemistry
                Mini Review

                cancer,statins,drug combination,target therapy,mevalonate pathway,hmg-coa reductase

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