Differential mRNA expression in the induction of DNA damage, G2/M arrest, and cell death by zerumbone in HepG2/C3A cells

• Published in: Toxicology in vitro 2022-12, Vol.85, p.105474-105474, Article 105474
• Main Authors: Rondina, Débora Berbel Lirio, de Lima, Luan Vitor Alves, da Silva, Matheus Felipe, Zanetti, Thalita Alves, Felicidade, Ingrid, Marques, Lilian Areal, Coatti, Giuliana Castello, Mantovani, Mario Sergio
• Format: Article
• Language: English
• Subjects: Cancer; Cell death; Endoplasmic reticulum stress; Genotoxicity; Phytochemical
• ISSN: 0887-2333; 1879-3177
• DOI: 10.1016/j.tiv.2022.105474

Zerumbone (ZER) is a phytochemical with antioxidant and antiproliferative properties. This study evaluated the cytoxicity of ZER combined with chemotherapeutic agents and the expression of mRNA genes related to cell cycle, cell death, xenobiotic metabolism, DNA damage, and endoplasmic reticulum (ER) stress in HepG2/C3A cells. ZER was cytotoxic (IC50, 44.31 μM). ZER-induced apoptosis was related to BBC3 and ERN1 upregulation (ER stress), and its antiproliferative effects were attributable to MYC, IGF1, and NF-kB mRNA inhibition. ZER-induced G2/M arrest and DNA damage was associated with mRNA expression of cell cycle (CDKN1A) and DNA damage (GADD45A) genes. Increased CYP1A2 and CYP2C19 mRNA expression suggested ZER metabolization, and reduced CYP1A1 and CYP2D6 expression indicated a longer time of action of ZER in the cell, enhancing its pharmacological effect. ZER downregulated TP53, PARP1, BIRC5 (apoptosis), and MAP1LC3A (autophagy). In apoptosis assay, the data of the association treatments with ZER suggested antagonism. In cytotoxicity assay, the data of the association treatments with ZER suggested synergism action to cisplatin and antagonism action to doxorubicin and 5-fluorouracil. Thus, ZER has potential for application in chemotherapy as it modulates mRNA targets; however, it may not have the desired efficiency when combined with other chemotherapeutic agents. Graphic summary of the biological effects of ZER in HepG2/C3A cells. (A) ZER has antiproliferative activity, induces apoptosis-like death, induces DNA damage, and alters mRNA expression. (B) ZER promotes alterations in cell morphology, induces genotoxic and ER stress and cell cycle arrest in G2/M, increases BBC3 (4.70×), CDKN1A (2.94×), GADD45A (3.993×), ERN1 (11.81×), CYP1A2 (3.06×), and CYP2C19 (5.04×) mRNA expression, and decreases TP53 (2.9×), PARP1 (3.73×), BIRC5 (2.75×), MYC (2.75×), CYP1A1 (7.87×), CYP2D6 (2.15×), MAP1LC3A (5.15×), NF-KB (2.38×), and IGF1 (2.66×) mRNA expression. [Display omitted] •ZER-induced apoptosis was related to BBC3 and ERN1 upregulation (ER stress).•ZER-induced G2/M arrest and DNA damage was associated with mRNA expression of CDKN1A and GADD45A genes.•ZER-Increased CYP1A2 and CYP2C19 mRNA expression, and reduced CYP1A1 and CYP2D6, enhancing its pharmacological effect.•ZER downregulated TP53, PARP1, BIRC5 (apoptosis), and MAP1LC3A (autophagy).•ZER suggested synergism action to cisplatin and antagonism action to doxorubicin and 5-fluorouracil.