Ferruginol Diterpenoid Selectively Inhibits Human Thyroid Cancer Growth by Inducing Mitochondrial Dependent Apoptosis, Endogenous Reactive Oxygen Species (ROS) Production, Mitochondrial Membrane Potential Loss and Suppression of Mitogen-Activated Protein Kinase (MAPK) and PI3K/AKT Signaling Pathways.

Abstract

BACKGROUND Thyroid cancer causes considerable mortality and morbidity across the globe. Owing to the unavailability of biomarkers and the adverse effects of existing drugs, there is an urgent need to develop efficient chemotherapy for the treatment of thyroid cancers. Plants have served as exceptional source of drugs for the treatment of lethal diseases. The purpose of this study was to evaluate the anticancer effects of ferruginol against thyroid cancer cells. MATERIAL AND METHODS We monitored the cell proliferation rate using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using 4',6-diamidino-2-phenylindole (DAPI), acridine orange/ethidium bromide (AO/EB), and annexin V/propidium iodide (PI) staining. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) levels were examined by fluorescence microscopy. Protein expressed was examined by western blotting. RESULTS We found that ferruginol exerted potent antiproliferative action against thyroid cancer cells, and an IC₅₀ of 12 µM was observed for ferruginol against the MDA-T32 cell line. The toxic effects of ferruginol were less pronounced against normal cells. The anticancer effects of ferruginol were likely due to the induction of apoptosis which was also associated with upregulation of Bax and downregulation of Bcl-2. Ferruginol also caused ROS mediated alterations in the MMP of MDA-T32 cells. In MDA-T32 cells, ferruginol might also block the MAPK and PI3K/AKT signaling pathway, which is believed to be an important therapeutic target of anticancer drugs. CONCLUSIONS In conclusion, in view of the results of this study, it might be suggested that ferruginol might serve as an essential lead molecule for the treatment of thyroid cancer provided further in-depth studies especially studying ferruginol toxicological as well as in vivo studies are needed.

• Authors: Guoqing Luo, Jingjing Zhou, Guanjie Li, Ningdong Hu, Xu Xia, Haibo Zhou
• Journal: Medical science monitor : international medical journal of experimental and clinical research (Med Sci Monit) Vol. 25 Pg. 2935-2942 (04 21 2019) ISSN: 1643-3750 [Electronic] United States
• PMID: 31005958 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Abietanes
• Antineoplastic Agents, Phytogenic
• Diterpenes
• Plant Extracts
• Reactive Oxygen Species
• ferruginol
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases

Topics

• Abietanes (metabolism, pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• China
• Diterpenes (metabolism, pharmacology)
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (metabolism)
• Mitochondrial Membranes (drug effects)
• Mitogen-Activated Protein Kinases (drug effects, metabolism)
• Phosphatidylinositol 3-Kinases (drug effects, metabolism)
• Plant Extracts (pharmacology)
• Proto-Oncogene Proteins c-akt (drug effects, metabolism)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Thyroid Neoplasms (drug therapy)
• Up-Regulation (drug effects)