Cytotoxicity of the Sesquiterpene Lactone Spiciformin and Its Acetyl Derivative against the Human Leukemia Cell Lines U-937 and HL-60.

Abstract

Spiciformin (1) is a sesquiterpene lactone with a germacrane skeleton that is found in two Tanacetum species endemic to the Canary Islands. In this study, the cytotoxicities of 1 and its acetyl derivative (2) were evaluated against human tumor cells. These sesquiterpene lactones were cytotoxic against human acute myeloid leukemia (U-937 and HL-60) cells, even in cells over-expressing the pro-survival protein Bcl-2, but melanoma (SK-MEL-1) and human mononuclear cells isolated from blood of healthy donors were more resistant. Both compounds are apoptotic inducers in human leukemia U-937 cells. Cell death was mediated by the processing and activation of initiator and effector caspases and the cleavage of poly(ADP-ribose) polymerase, and it was blocked by a broad-spectrum caspase inhibitor and (in the case of sesquiterpene lactone 2) by the selective caspase-3/7, -8, and -9 inhibitors. In addition, certainly in the case of compound 2, this was found to be associated with a decrease in mitochondrial membrane potential, downregulation of the anti-apoptotic protein Bcl-2, activation of the mitogen-activated protein kinases signaling pathway, and generation of reactive oxygen species. It will, therefore, be relevant to continue characterization of this class of compounds.

• Authors: Ester Saavedra, Francisco Estévez-Sarmiento, Mercedes Said, José Luis Eiroa, Sara Rubio, José Quintana, Francisco Estévez
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 8 (Apr 16 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32316340 (Publication Type: Journal Article)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antineoplastic Agents
• Lactones
• Proto-Oncogene Proteins c-bcl-2
• Reactive Oxygen Species
• Sesquiterpenes
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Poly(ADP-ribose) Polymerases
• Mitogen-Activated Protein Kinases
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Antineoplastic Agents (chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspases (chemistry, metabolism)
• Cell Line, Tumor
• HL-60 Cells
• Humans
• Lactones (chemistry)
• Leukemia, Promyelocytic, Acute (metabolism, pathology)
• Membrane Potential, Mitochondrial (drug effects)
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphorylation (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Reactive Oxygen Species (metabolism)
• Sesquiterpenes (chemistry, pharmacology)
• Signal Transduction (drug effects)