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      Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

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          Abstract

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          Despite the important progress in cancer treatment in the past decades, the mortality rates in some types of cancer have not significantly decreased. Therefore, the search for novel anticancer drugs has become a topic of great interest. Chalcones, precursors of flavonoid synthesis in plants, have been documented as natural compounds with pleiotropic biological effects including antiproliferative/anticancer activity. This article focuses on the knowledge on molecular mechanisms of antiproliferative action of chalcones and draws attention to this group of natural compounds that may be of importance in the treatment of cancer disease.

          Abstract

          Although great progress has been made in the treatment of cancer, the search for new promising molecules with antitumor activity is still one of the greatest challenges in the fight against cancer due to the increasing number of new cases each year. Chalcones (1,3-diphenyl-2-propen-1-one), the precursors of flavonoid synthesis in higher plants, possess a wide spectrum of biological activities including antimicrobial, anti-inflammatory, antioxidant, and anticancer. A plethora of molecular mechanisms of action have been documented, including induction of apoptosis, autophagy, or other types of cell death, cell cycle changes, and modulation of several signaling pathways associated with cell survival or death. In addition, blockade of several steps of angiogenesis and proteasome inhibition has also been documented. This review summarizes the basic molecular mechanisms related to the antiproliferative effects of chalcones, focusing on research articles from the years January 2015–February 2021.

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          The Hallmarks of Cancer

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            Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

            Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.
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              Oncogenic Signaling Pathways in The Cancer Genome Atlas

              Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, P53 and β-catenin/WNT. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                31 May 2021
                June 2021
                : 13
                : 11
                : 2730
                Affiliations
                Department of Pharmacology, Faculty of Medicine, Pavol Jozef Šafárik University, 040 01 Košice, Slovakia; radka.michalkova@ 123456student.upjs.sk (R.M.); ladislav.mirossay@ 123456upjs.sk (L.M.); maria.gazdova@ 123456student.upjs.sk (M.G.); martin.kello@ 123456upjs.sk (M.K.)
                Author notes
                [* ]Correspondence: jan.mojzis@ 123456upjs.sk
                Author information
                https://orcid.org/0000-0002-2454-5799
                https://orcid.org/0000-0002-7974-4525
                Article
                cancers-13-02730
                10.3390/cancers13112730
                8198114
                34073042
                1417b5e3-0792-4382-8067-43904e32286e
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 28 April 2021
                : 27 May 2021
                Categories
                Review

                chalcones,cell death,apoptosis,autophagy,cell cycle arrest,angiogenesis,signaling pathway

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