Dactinomycin impairs cellular respiration and reduces accompanying ATP formation

Zhimin Tao, Syed S. Ahmad, Harvey S. Penefsky, Jerry Goodisman, Abdul Kader Souid

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)


The effect of dactinomycin on cellular respiration and accompanying ATP formation was investigated in Jurkat and HL-60 cells. Cellular mitochondrial oxygen consumption (measured by a homemade phosphorescence analyzer) and ATP content (measured by the luciferin-luciferase bioluminescence system) were determined as functions of time t during continuous exposure to the drug. The rate of respiration, k, was the negative of the slope of [O2] versus t. Oxygen consumption and ATP content were diminished by cyanide, confirming that both processes involved oxidations in the mitochondrial respiratory chain. In the presence of dactinomycin, k decreased gradually with t, the decrease being more pronounced at higher drug concentrations. Cellular ATP remained constant for 5 h in untreated cells, but in the presence of 20 μM dactinomycin it decreased gradually (to one-tenth the value at 5 h for untreated cells). The drug-induced inhibition of respiration and decrease in ATP were blocked by the pancaspase inhibitor benzyloxycarbonyl-Val-Ala-DL-Asp- fluoromethyl ketone (zVAD-fmk). A rapid but temporary decrease in cellular ATP observed on the addition of zVAD-fmk was shown to be due to DMSO (added with zVAD-fmk). The effect of dactinomycin on respiration differed from that of doxorubicin. Plots of [O2] versus t were curved for dactinomycin so that k decreased gradually with t. The corresponding plots for doxorubicin were well fit by two straight lines; so k was constant for ∼150 min, at which time k decreased, remaining constant at a lower level thereafter. The results for cells treated with mixtures of the two drugs indicated that the drugs acted synergistically. These results show the onset and severity of mitochondrial dysfunction in cells undergoing apoptosis induced by dactinomycin.

Original languageEnglish
Pages (from-to)762-772
Number of pages11
JournalMolecular Pharmaceutics
Issue number6
Publication statusPublished - Nov 2006
Externally publishedYes


  • Pd phosphor, palladium derivative of meso-tetra-(4-sulfonatophenyl)- tetrabenzoporphyrin
  • k, zero-order rate constant for cellular oxygen consumption
  • zVAD-fmk, benzyloxycarbonyl-val-ala-asp-fluoromethyl ketone

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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