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

Layla El-Sawy; John R Rubin; Luke Broses; Christopher Patsalis; Marian L Henderson; Steven J Wilson; Shelly A Glase; Katherine A Munson; Guadalupe Lorenzatti Hiles; Angelica Cates; Amir Emamdjomeh; Andrew Chou; Joseph Farber; Jeff W Kampf; Brian Magnuson; Monica Liebert; Michelle T Paulsen; Kenneth Van Golen; Mats Ljungman; Armand Bankhead 3rd; Phillip L Palmbos; Kathleen C Day; Mark L Day

doi:10.1016/j.jbc.2025.110531

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

J Biol Chem. 2025 Sep;301(9):110531. doi: 10.1016/j.jbc.2025.110531. Epub 2025 Aug 5.

Authors

Layla El-Sawy¹, John R Rubin², Luke Broses², Christopher Patsalis³, Marian L Henderson⁴, Steven J Wilson², Shelly A Glase⁵, Katherine A Munson², Guadalupe Lorenzatti Hiles², Angelica Cates², Amir Emamdjomeh², Andrew Chou², Joseph Farber⁵, Jeff W Kampf⁶, Brian Magnuson⁷, Monica Liebert², Michelle T Paulsen⁸, Kenneth Van Golen⁹, Mats Ljungman⁸, Armand Bankhead 3rd¹⁰, Phillip L Palmbos⁴, Kathleen C Day¹¹, Mark L Day¹²

Affiliations

¹ Department of Urology, University of Michigan, Ann Arbor, Michigan, USA; European Egyptian Pharmaceutical Industries, Alexandria, Egypt.
² Department of Urology, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
³ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
⁵ Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
⁶ Department of Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
⁷ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
⁹ Department of Biological Sciences, University of Delaware, Newark, Delaware, USA.
¹⁰ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA.
¹¹ Department of Urology, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: kcday@umich.edu.
¹² Department of Urology, University of Michigan, Ann Arbor, Michigan, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan, USA. Electronic address: mday@umich.edu.

Abstract

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.

Keywords: STLs; ambrosin; bladder cancer; breast cancer; cancer stem cells; cancer therapy; glutamine; mitochondrial apoptosis; natural product.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Antineoplastic Agents, Phytogenic* / pharmacology
Apoptosis / drug effects
Breast Neoplasms* / drug therapy
Breast Neoplasms* / metabolism
Breast Neoplasms* / pathology
Cell Line, Tumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Female
Humans
Lactones* / chemistry
Lactones* / pharmacology
Phosphorylation / drug effects
Reactive Oxygen Species / metabolism
Sesquiterpenes* / chemistry
Sesquiterpenes* / pharmacology
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / metabolism
Urinary Bladder Neoplasms* / pathology

Substances

Sesquiterpenes
Reactive Oxygen Species
ErbB Receptors
Lactones
Antineoplastic Agents, Phytogenic
EGFR protein, human

Associated data

GEO/GSE293803

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding