Molecular Mechanisms of Antiproliferative Effects of Natural Chalcones

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.

Keywords: angiogenesis; apoptosis; autophagy; cell cycle arrest; cell death; chalcones; signaling pathway.

Figure 1

Basic chalcone structure. Original figure made for this review using the Zoner Callisto 5 software.

Figure 2

Molecular mechanism of extrinsic, intrinsic and endoplasmic reticulum pathways involved in apoptosis. Abbreviations: (pro)Casp—(pro)caspase, AIF—apoptosis inducing factor, APAF-1—apoptotic protease activating factor 1, ATF 4/6—activating transcription factors 4/6, BiP—binding immunoglobulin protein, Bcl-2/Bcl-Xl—antiapoptotic factors, Bad/Bax/Bid—proapoptotic factors, eIF-2α—eukaryotic translation initiation factor 2 A, ER—endoplasmic reticulum, FADD—Fas associated via death domain, CHOP—C/EBP homologous protein, IAPs—inhibitors of apoptosis, IRE1—inositol-requiring enzyme 1, MOMP—mitochondrial outer membrane permeabilization, Omi/HTRA2—Omi/high temperature requirement factor A2, PARP—poly (ADP-ribose) polymerase, PERK—PKR-like endoplasmic reticulum kinase, Smac/DIABLO—second mitochondria-derived activator of caspase/direct inhibitor of apoptosis-binding protein with low pI, UPR—unfolded protein response, XBP1—X-box binding protein 1. Original figure made for this review using the Zoner Callisto 5 software.

Figure 3

The main steps of autophagy in cells. Abbreviations: (pro)LC I/II—(pro)microtubule-associated proteins 1A/1B light chain 3B, Akt—protein kinase B, AMPK—AMP-activated protein kinase, Atg 3/4/5/7/12/13/14L/16L/101—autophagy-related proteins, ATP—adenosine triphosphate, ER—endoplasmic reticulum, FIP200—family-interacting protein of 200 kD, LAMP1—lysosomal-associated membrane protein 1, mTOR—mammalian target of rapamycin, p53—p53 protein, p62—sequestosome 1, PDK1—phosphoinositide-dependent kinase-1, PE—phosphatidylethanolamine, PI3K—phosphoinositide-3-kinase, PI3KC3 complex I—phosphatidylinositol 3-kinase catalytic subunit type 3 complex I, PIP2—phosphatidylinositol-2-phosphate, PIP3—phosphatidylinositol-3-phosphate, PTEN—phosphatase and tensin homolog, ULK1—Unc-51 like autophagy activating kinase, Vps 15/34—vacuolar protein sorting proteins. Original figure made for this review using the Zoner Callisto 5 software.

Figure 4

Basic steps in cell cycle regulation and p53 function. Abbreviations: Apaf-1—apoptotic protease activating factor 1, ATM—ataxia-telangiectasia mutated, ATR—ataxia telangiectasia and Rad3 related, Bad/Bak/Bax/Bid—proapoptotic factors, Cdc25 A/C—cell division cycle 25 homolog A/C phosphatase, CDK 1/2/4/6—cyclin-dependent kinases, Cip/Kip—CDK interacting protein/Kinase inhibitory protein, E2F—E2 factor, CHK 1/2—checkpoint kinases, INK4—inhibitors of CDK4, MDM2—Mouse double minute 2 homolog, Myt1—myelin transcription factor 1, Noxa—phorbol-12-myristate-13-acetate-induced protein 1, p53—protein 53, PARP—Poly (ADP-ribose) polymerase, PUMA—p53 upregulated modulator of apoptosis, Rb—retinoblastoma protein, Wee1—inhibitor of CDK1. Original figure made for this review using the Zoner Callisto 5 software.

Figure 5

Major oncogenic intracellular signaling pathways. Abbreviations: ADAM—a disintegrin and metalloprotease protein, Akt—protein kinase B, AMPK—AMP-activated protein kinase, ATP—adenosine triphosphate, ERK—extracellular signal-regulated kinase, Fz receptor—frizzled receptor, GDP—guanosine diphosphate, Grb2—growth factor receptor-bound protein 2, GSK-3 β—glycogen synthase kinase-3 β, GTP—guanosine triphosphate, IKK—IκB kinase, IκBα—inhibitor of nuclear factor kappa B, JAK—Janus kinase, Keap1—Kelch-like ECH-associated protein 1, MDM2—mouse double minute 2 homolog, MEK—MAPK/Erk kinase, mTOR—mammalian target of rapamycin, N1VAL—activated Notch1 receptor domain, N3ICD—intracellular domain of Notch3, Nf-Kb—nuclear factor kappa B, Nrf2—nuclear factor erythroid 2-related factor 2, p53—protein 53, PDK1—phosphoinositide-dependent kinase-1, PI3K—phosphoinositide-3-kinase, PIP2—phosphatidylinositol-2-phosphate, PIP3—phosphatidylinositol-3-phosphate, PTEN—phosphatase and tensin homolog, RAF—rapidly accelerated fibrosarcoma, RAS—rat sarcoma protein, SOS 1—SOS Ras/Rac guanine nucleotide exchange factor 1, Src—proto-oncogene tyrosine-protein kinase Src, STAT—signal transducer and activator of transcription protein, TNF α—tumor necrosis factor α, Wnt—wingless-related integration site protein. Original figure made for this review using the Zoner Callisto 5 software.