A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth

Valeria R Fantin; Marcelo J Berardi; Luca Scorrano; Stanley J Korsmeyer; Philip Leder

doi:10.1016/s1535-6108(02)00082-x

A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth

Cancer Cell. 2002 Jul;2(1):29-42. doi: 10.1016/s1535-6108(02)00082-x.

Authors

Valeria R Fantin¹, Marcelo J Berardi, Luca Scorrano, Stanley J Korsmeyer, Philip Leder

Affiliation

¹ Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

PMID: 12150823
DOI: 10.1016/s1535-6108(02)00082-x

Abstract

Tumorigenesis results from events that impinge on a variety of collaborating metabolic pathways. To assess their role in this process, we utilized a cell-based assay to perform a high-throughput, chemical library screen. In so doing, we identified F16, a small molecule that selectively inhibits proliferation of mammary epithelial, neu-overexpressing cells, as well as a variety of mouse mammary tumor and human breast cancer cell lines. F16 belongs to a group of structurally similar molecules with a delocalized positive charge. The compound is accumulated in mitochondria of responsive cells, driven by the membrane potential, and it compromises their functional integrity. Mitochondrial hyperpolarization is a shared feature of many tumor cell lines, explaining the broad action spectrum of this novel delocalized lipophilic cation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Breast Neoplasms / pathology
Cations / pharmacology
Cations / toxicity
Cell Cycle / drug effects
Cell Division / drug effects
Cell Line, Transformed
Epithelial Cells / drug effects
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Genes, erbB-2 / genetics*
Growth Inhibitors / chemistry
Growth Inhibitors / pharmacology*
Growth Inhibitors / toxicity
Humans
Indoles / metabolism*
Indoles / pharmacology
Mammary Neoplasms, Animal / genetics
Mammary Neoplasms, Animal / metabolism*
Mammary Neoplasms, Animal / pathology
Mammary Neoplasms, Experimental / metabolism*
Membrane Potentials
Mice
Mice, Inbred BALB C
Mice, Transgenic
Mitochondria / metabolism*
Mitochondria / ultrastructure
Pyridinium Compounds / metabolism*
Pyridinium Compounds / pharmacology
Receptor, ErbB-2 / metabolism
Signal Transduction / drug effects
Tumor Cells, Cultured

Substances

Cations
Growth Inhibitors
Indoles
Pyridinium Compounds
4-(2-(indol-3-yl)vinyl)-1-methylpyridinium
Receptor, ErbB-2