Apoptotic and cell cycle response to homoharringtonine and harringtonine in wild and mutant p53 hepatocarcinoma cells

This study aimed to evaluate the modes of action of harringtonine (HT) and homoharringtonine (HHT) alkaloids in cell with wild (HepG2/C3A) and mutant p53 (HuH-7.5). We performed assays for cytotoxicity, genotoxicity, induction of apoptosis, cell cycle phase, and membrane integrity. Obtained data wer...

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Bibliographic Details
Published in:Human & experimental toxicology 2020-10, Vol.39 (10), p.1405-1416
Main Authors: Franco, DP, de Biazi, BI, Zanetti, TA, Marques, LA, de Lima, LVA, Lepri, SR, Mantovani, MS
Format: Article
Language:English
Subjects:
Alkaloids
Antineoplastic Agents, Phytogenic - pharmacology
Apoptosis
Apoptosis - drug effects
Carcinoma, Hepatocellular - drug therapy
Carcinoma, Hepatocellular - genetics
Cell cycle
Cell Cycle - drug effects
Cell death
Cell Line, Tumor
Cell Survival - drug effects
Cytotoxicity
Endoplasmic reticulum
Endoplasmic Reticulum Stress - drug effects
Gene expression
Genes
Genotoxicity
Harringtonines - pharmacology
Hepatocellular carcinoma
Humans
Liver cancer
Liver Neoplasms - drug therapy
Liver Neoplasms - genetics
Metabolism
Mutants
p53 Protein
Stress
Toxicity
TRAF2 protein
Tumor Suppressor Protein p53 - genetics
Xenobiotics
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Summary:This study aimed to evaluate the modes of action of harringtonine (HT) and homoharringtonine (HHT) alkaloids in cell with wild (HepG2/C3A) and mutant p53 (HuH-7.5). We performed assays for cytotoxicity, genotoxicity, induction of apoptosis, cell cycle phase, and membrane integrity. Obtained data were compared with the relative expression of mRNA of genes related to proliferation, apoptosis, cell cycle control, metabolism of xenobiotics, and reticulum endoplasmic stress. The relative expression of the genes showed an increase in apoptosis-inducing mRNAs, such as TNF and BBC3, as well as a reduction in BCL2 and BAK. The mRNAs of CYP2E1 and CYP2C19 xenobiotic metabolism genes increased in both lineages, while CYP3A4 increased only in the HuH-7.5 lineage. The mRNA expression of endoplasmic reticulum (ER) stress genes (ERN1 and EIF2AK3) was shown to increase in HHT and HT treatments. A similar increase was recorded in the mRNA expression of the TRAF2 gene. The changes observed in this study support the hypothesis that ER stress was more strongly associated with TNF induction, causing cell death by apoptosis in p53 mutant cells. This result with wild and mutant p53 cells may have clinical implications in the use of these compounds.
ISSN:0960-3271
1477-0903
DOI:10.1177/0960327120926257