The molecular mechanism of ambrosin-induced cytotoxicity of human breast cancer and bladder cancer cells

Sesquiterpene lactones (STL) are lipophilic compounds synthesized as secondary metabolites in species across the plant kingdom, most notably in the family Asteraceae. One STL, found in North African Ambrosia maritima (A. maritima), and Caribbean Ambrosia hispida (A. hispida), is the compound ambrosi...

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Published inThe Journal of biological chemistry Vol. 301; no. 9; p. 110531
Main Authors El-Sawy, Layla, Rubin, John R., Broses, Luke, Patsalis, Christopher, Henderson, Marian L., Wilson, Steven J., Glase, Shelly A., Munson, Katherine A., Hiles, Guadalupe Lorenzatti, Cates, Angelica, Emamdjomeh, Amir, Chou, Andrew, Farber, Joseph, Kampf, Jeff W., Magnuson, Brian, Liebert, Monica, Paulsen, Michelle T., Van Golen, Kenneth, Ljungman, Mats, Bankhead, Armand, Palmbos, Phillip L., Day, Kathleen C., Day, Mark L.
Format Journal Article
LanguageEnglish
Published United States Elsevier Inc 01.09.2025
Subjects
ambrosin
bladder cancer
breast cancer
cancer stem cells
cancer therapy
glutamine
mitochondrial apoptosis
natural product
STLs
BC
natural product
mitochondrial apoptosis
breast cancer
ambrosin
glutamine
STLs
EGFR
cancer therapy
BrC
bladder cancer
cancer stem cells
TNBC
GSH
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Summary:Sesquiterpene lactones (STL) are lipophilic compounds synthesized as secondary metabolites in species across the plant kingdom, most notably in the family Asteraceae. One STL, found in North African Ambrosia maritima (A. maritima), and Caribbean Ambrosia hispida (A. hispida), is the compound ambrosin. We have extracted ambrosin from A. maritima and A. hispida and demonstrated its toxicity in bladder cancer and breast cancer cell lines at low micromolar concentrations. Ambrosin also inhibited bladder cancer and breast cancer stem cell growth as non-adherent tumor spheroids. Sequencing of ambrosin-induced synthesis of nascent RNA revealed mitochondrial apoptotic gene signatures as well as activation of glutathione metabolism, indicating the generation of reactive oxygen species (ROS). Ambrosin exhibited antagonistic activity against EGFR tyrosine kinase and RhoC GTPase. Further studies showed that ambrosin inhibited EGFR auto-phosphorylation at tyrosine 1068 (Y1068) as well as the inhibition of RhoC GTPase activity. These findings indicate novel mechanisms of action and justify further considerations for the development of ambrosin as a potential agent for advanced bladder cancer and advanced breast cancer.
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ISSN:0021-9258
1083-351X
1083-351X
DOI:10.1016/j.jbc.2025.110531