Cancer Research 2015-07-15

Vacuolar-ATPase Inhibition Blocks Iron Metabolism to Mediate Therapeutic Effects in Breast Cancer.

Lina S Schneider, Karin von Schwarzenberg, Thorsten Lehr, Melanie Ulrich, Rebekka Kubisch-Dohmen, Johanna Liebl, Dirk Trauner, Dirk Menche, Angelika M Vollmar

Index: Cancer Res. 75 , 2863-74, (2015)

Full Text: HTML

Abstract

Generalized strategies to improve breast cancer treatment remain of interest to develop. In this study, we offer preclinical evidence of an important metabolic mechanism underlying the antitumor activity of inhibitors of the vacuolar-type ATPase (V-ATPase), a heteromultimeric proton pump. Specifically, our investigations in the 4T1 model of metastatic breast cancer of the V-ATPase inhibitor archazolid suggested that its ability to trigger metabolic stress and apoptosis associated with tumor growth inhibition related to an interference with hypoxia-inducible factor-1α signaling pathways and iron metabolism. As a consequence of disturbed iron metabolism, archazolid caused S-phase arrest, double-stranded DNA breaks, and p53 stabilization, leading to apoptosis. Our findings link V-ATPase to cell-cycle progression and DNA synthesis in cancer cells, and highlight the basis for the clinical exploration of V-ATPase as a potentially generalizable therapy for breast cancer.©2015 American Association for Cancer Research.

Related Compounds

Structure Name/CAS No. Articles
HEPES Structure HEPES
CAS:7365-45-9
Ferric Citrate Structure Ferric Citrate
CAS:3522-50-7
Calcein-AM Structure Calcein-AM
CAS:148504-34-1
PMSF Structure PMSF
CAS:329-98-6
potassium chloride Structure potassium chloride
CAS:7447-40-7
Triapine Structure Triapine
CAS:143621-35-6
3-Aminopyrazole Structure 3-Aminopyrazole
CAS:1820-80-0
1,4-Dithiothreitol Structure 1,4-Dithiothreitol
CAS:16096-97-2
Propidium Iodide Structure Propidium Iodide
CAS:25535-16-4
Ethylenediaminetetraacetic acid Structure Ethylenediaminetetraacetic acid
CAS:60-00-4