Back to Search
Start Over
A Cancer-Selective Zinc Ionophore Inspired by the Natural Product Naamidine A
- Source :
- ACS Chem Biol
- Publication Year :
- 2018
- Publisher :
- American Chemical Society (ACS), 2018.
-
Abstract
- We present data demonstrating the natural product mimic, zinaamidole A (ZNA), is a modulator of metal ion homeostasis causing cancer-selective cell death by specifically inducing cellular Zn(2+)-uptake in transformed cells. ZNA’s cancer selectivity was evaluated using metastatic, patient-derived breast cancer cells, established human breast cancer cell lines, and three-dimensional organoid models derived from normal and transformed mouse mammary glands. Structural analysis of ZNA demonstrated that the compound interacts with zinc through the N(2)-acyl-2-aminoimidazole core. Combination treatment with ZnSO(4) strongly potentiated ZNA’s cancer-specific cell death mechanism, an effect that was not observed with other transition metals. We show that Zn(2+)-dyshomeostasis induced by ZNA is unique and markedly more selective than other known Zn(2+)interacting compounds such as clioquinol. The in vivo bioactivity of ZNA was also assessed and revealed that tumor-bearing mice treated with ZNA had improved survival outcomes. Collectively, these data demonstrate that the N(2)-acyl-2aminoimidazole core of ZNA represents a powerful chemotype to induce cell death in cancer cells concurrently with a disruption in zinc homeostasis.
- Subjects :
- 0301 basic medicine
Programmed cell death
Ionophore
01 natural sciences
Biochemistry
Article
Mice
03 medical and health sciences
In vivo
medicine
Organoid
Animals
Humans
Cell Proliferation
Metal ion homeostasis
Ionophores
010405 organic chemistry
Chemistry
Clioquinol
Imidazoles
Cancer
General Medicine
medicine.disease
0104 chemical sciences
Cell biology
Zinc
030104 developmental biology
Cancer cell
Molecular Medicine
Female
medicine.drug
Subjects
Details
- ISSN :
- 15548937 and 15548929
- Volume :
- 14
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Biology
- Accession number :
- edsair.doi.dedup.....415e9a60b837012fa377775caac7e9e1