Naturally occurring anti-cancer agents targeting EZH2.
Natural products are considered as promising tools for the prevention and treatment of cancer. The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase unit of polycomb repressor complexes such as PRC2 complex that has oncogenic roles through interference with growth and metastatic potential. Several agents targeting EZH2 has been discovered but they often induce side effects in clinical trials. Recently, EZH2 has emerged as a potential target of natural products with documented anti-cancer effects and this discloses a new scenario for the development of EZH2 inhibitory strategies with agents with low cytotoxic detrimental effects. In fact, several natural products such as curcumin, triptolide, ursolic acid, sulforaphane, davidiin, tanshindiols, gambogic acid, berberine and Alcea rosea have been shown to serve as EZH2 modulators. Mechanisms like inhibition of histone H3K4, H3K27 and H3K36 trimethylation, down-regulation of matrix metalloproteinase expression, competitive binding to the S-adenosylmethionine binding site of EZH2 and modulation of tumor-suppressive microRNAs have been demonstrated to mediate the EZH2-inhibitory activity of the mentioned natural products. This review summarizes the pathways that are regulated by various natural products resulting in the suppression of EZH2, and provides a plausible molecular mechanism for the putative anti-cancer effects of these compounds.
National Cell Bank of Iran, Pasteur Institute of Iran, Tehran, Iran.
Fahimeh
F
Shahabipour
Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Via L. De Crecchio 7, Naples, Italy. Electronic address: michele.caraglia@unicampania.it.
Michele
M
Caraglia
Sabinsa Inc, East Windsor, NJ, United States.
Muhammed
M
Majeed
Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, Italy; Molecular Medicine Laboratory, University of Pavia, Pavia, Italy.
Giuseppe
G
Derosa
Department of Internal Medicine and Therapeutics, University of Pavia and Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; PhD School in Experimental Medicine, University of Pavia, Pavia, Italy.
Pamela
P
Maffioli
Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad 9177948564, Iran. Electronic address: sahebkara@mums.ac.ir.
Amirhossein
A
Sahebkar
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
Cancer; Chemosensitization; EZH2; Natural compounds; PRC2; Polycomb proteins