Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A

Yanmin Zhang, Arnaud Chevalier, Omar Khdour, Larisa Morales Soto, Sidney Hecht

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

In a recent study, several new derivatives of antimycin A (AMA) were produced by means of a novel transacylation reaction, and these were shown to mediate selective toxicity toward cultured A549 human lung epithelial adenocarcinoma cells, as compared with WI-38 normal human lung fibroblasts. The purpose of our study was to investigate whether the analogues all expressed their cytotoxicity by the same mechanism. This was done by studying the effects of the compounds in several types of cell lines. In comparison with 2- O -methylantimycin, which acts at the locus of Bcl-2, none of the new derivatives exhibited a difference in cytotoxicity toward cells expressing different levels of Bcl-2. In cell lines that over- or underexpress estrogen or Her2 receptors, AMA analogue 2 exhibited Her2 receptor dependency at low concentration. Three compounds ( 1, 4 , and 6 ) exhibited concentration-dependent increases in reactive oxygen species, with 6 being especially potent. Compounds 5 and 6 diminished mitochondrial membrane potential more potently than AMA, and 1 also displayed enhanced activity relative to 2 – 4 . Interestingly, only 1 and AMA displayed strong inhibition of the respiratory chain, as measured by monitoring NADH (reduced nicotinamide adenine dinucleotide) oxidase. Because four of the analogues have positively charged substituents, two of these ( 4 and 6 ) were studied to see whether the observed effects were due to much higher level of accumulation within the mitochondria. Their presence in the mitochondria was not dramatically enhanced. Neither of the two presently characterized mechanisms of cell killing by AMA can fully account for the observed results.

Original languageEnglish (US)
JournalPlanta Medica
DOIs
StateAccepted/In press - May 20 2017

Fingerprint

Antimycin A
Cell growth
Cells
Growth
Mitochondria
Neoplasms
Cytotoxicity
NAD
Derivatives
Cell Line
Mitochondrial Membrane Potential
Fibroblasts
Electron Transport
Toxicity
Reactive Oxygen Species
Oxidoreductases
Estrogens
Epithelial Cells
Membranes
Lung

Keywords

  • antimycin A
  • Bcl-2 expression
  • cytotoxicity
  • mitochondrial membrane potential
  • NADH oxidase inhibition
  • reactive oxygen species

ASJC Scopus subject areas

  • Analytical Chemistry
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Drug Discovery
  • Complementary and alternative medicine
  • Organic Chemistry

Cite this

Inhibition of Human Cancer Cell Growth by Analogues of Antimycin A. / Zhang, Yanmin; Chevalier, Arnaud; Khdour, Omar; Soto, Larisa Morales; Hecht, Sidney.

In: Planta Medica, 20.05.2017.

Research output: Contribution to journalArticle

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