The sesquiterpenes alantolactone (ATL) and germacrone (GER) are potential anticancer agents of natural origin. Their toxicity and biological activity have been evaluated using the differentiated HepaRG (dHepaRG) cells, a hepatocyte-like model. The half-maximal inhibitory concentrations of cell viability after 24-h treatment of dHepaRG cells are approximately 60 µM for ATL and 250 µM for GER. However, both sesquiterpenes induce reactive oxygen species (ROS) formation in non-toxic concentrations and significantly dysregulate the mRNA expression of several functional markers of mature hepatocytes. They similarly decrease the protein level of signal transducer and activator of transcription 3 (STAT3), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and their transcription target, intercellular adhesion molecule 1 (ICAM-1). Based on the results of a BATMAN-TCM analysis, the effects of sesquiterpenes on cholesterol and lipid metabolism were studied. Sesquiterpene-mediated dysregulation of both cholesterol and lipid metabolism was observed, during which these compounds influenced the protein expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and sterol regulatory element-binding protein 2 (SREBP-2), as well as the mRNA expression of HMGCR, CYP19A1, PLIN2, FASN, SCD, ACACB, and GPAM genes. In conclusion, the two sesquiterpenes caused ROS induction at non-toxic concentrations and alterations in cholesterol and lipid metabolism at slightly toxic and toxic concentrations, suggesting a risk of liver damage if administered to humans.
- MeSH
- Hep G2 Cells MeSH
- Cholesterol metabolism MeSH
- Gene Expression drug effects MeSH
- Antineoplastic Agents, Phytogenic toxicity MeSH
- Hydroxymethylglutaryl CoA Reductases genetics metabolism MeSH
- Liver metabolism MeSH
- Lactones toxicity MeSH
- Humans MeSH
- RNA, Messenger genetics metabolism MeSH
- Lipid Metabolism drug effects MeSH
- Intercellular Adhesion Molecule-1 metabolism MeSH
- NF-kappa B metabolism MeSH
- Sterol Regulatory Element Binding Protein 2 genetics metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Sesquiterpenes, Eudesmane toxicity MeSH
- Sesquiterpenes, Germacrane toxicity MeSH
- STAT3 Transcription Factor metabolism MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Dermatophytes are the etiological agents of cutaneous mycoses, including the prevalent nail infections and athlete's foot. Candida spp. are opportunistic and emerging pathogens, causing superficial to deeper infections related to high mortality rates. As a consequence of prolonged application of antifungal drugs, the treatment failures combined with multidrug-resistance have become a serious problem in clinical practice. Therefore, novel alternative antifungals are required urgently. δ-Lactones have attracted great interest owing to their wide range of biological activity. This article describes the antifungal activity of synthetic δ-lactones against yeasts of the genus Candida spp. and dermatophytes (through the broth microdilution method), discusses the pathways by which the compounds exert this action (toward the fungal cell wall and/or membrane), and evaluates the toxicity to human leukocytes and chorioallantoic membrane (by the hen's egg test-chorioallantoic membrane). Two of the compounds in the series presented broader spectrum of antifungal activity, including against resistant fungal species. The mechanism of action was related to damage in the fungal cell wall and membrane, with specific target action dependent on the type of substituent present in the δ-lactone structure. The damage in the fungal cell was corroborated by electron microscopy images, which evidenced lysed and completely altered cells after in vitro treatment with δ-lactones. Toxicity was dose dependent for the viability of human leukocytes, but none of the compounds was mutagenic, genotoxic, or membrane irritant when evaluated at higher concentrations than MIC. In this way, δ-lactones constitute a class with excellent perspectives regarding their potential applications as antifungals.
- MeSH
- Antifungal Agents chemistry pharmacology toxicity MeSH
- Arthrodermataceae drug effects MeSH
- Cell Wall drug effects MeSH
- Candida drug effects MeSH
- Lactones chemistry pharmacology toxicity MeSH
- Leukocytes drug effects MeSH
- Humans MeSH
- Microbial Sensitivity Tests MeSH
- Drug Development MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- MeSH
- Angiotensin Receptor Antagonists adverse effects therapeutic use toxicity MeSH
- Diphosphonates adverse effects therapeutic use MeSH
- Femoral Fractures etiology complications MeSH
- Drug Information Services standards organization & administration utilization MeSH
- Liver drug effects MeSH
- Carcinogens MeSH
- Lactones adverse effects therapeutic use toxicity MeSH
- Humans MeSH
- Meta-Analysis as Topic MeSH
- Drug-Related Side Effects and Adverse Reactions complications MeSH
- Statistics as Topic MeSH
- Government Agencies utilization legislation & jurisprudence MeSH
- Check Tag
- Humans MeSH
- MeSH
- Cynara scolymus * chemistry toxicity MeSH
- Ecdysteroids pharmacokinetics pharmacology toxicity MeSH
- Animal Experimentation MeSH
- Flavonoids pharmacokinetics pharmacology toxicity MeSH
- Horses MeSH
- Rats MeSH
- Lactones pharmacokinetics pharmacology toxicity MeSH
- Leuzea * chemistry MeSH
- Humans MeSH
- Dietary Supplements MeSH
- Antineoplastic Agents therapeutic use MeSH
- Plant Extracts * MeSH
- Plant Stems MeSH
- Check Tag
- Rats MeSH
- Humans MeSH
- MeSH
- Alanine Transaminase blood MeSH
- Alkaline Phosphatase blood MeSH
- Aspartate Aminotransferases blood MeSH
- Cell Division drug effects MeSH
- Carcinoma, Ehrlich Tumor drug therapy MeSH
- Mammary Neoplasms, Experimental drug therapy MeSH
- Neoplasms, Experimental drug therapy MeSH
- Sarcoma, Experimental drug therapy MeSH
- Carcinoma, Hepatocellular drug therapy MeSH
- Keto Acids blood MeSH
- Rats MeSH
- Lactones pharmacology toxicity MeSH
- Mice MeSH
- Liver Neoplasms drug therapy MeSH
- Lymphoma, Non-Hodgkin drug therapy MeSH
- Prognosis MeSH
- Antineoplastic Agents pharmacology toxicity MeSH
- Sarcoma 180 drug therapy MeSH
- Sarcoma, Yoshida drug therapy MeSH
- Sodium pharmacology MeSH
- Neoplasm Transplantation MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
