Title

Inhibition of Cellular Respiration by Doxorubicin

Author(s)/Creator(s)

Zhimin Tao, Syracuse University
Henry G. Withers, State University of New York
Harvey S. Penefsky, Public Health Research Institute
Jerry Goodisman, Syracuse UniversityFollow
Abdul Kader Souid, State University of New York

Document Type

Article

Date

11-12-2005

Keywords

Chemistry

Disciplines

Chemistry

Description/Abstract

Doxorubicin executes apoptosis, a process known to produce leakage of cytochrome c and opening of the mitochondrial permeability transition pores. To define the loss of mitochondrial function by apoptosis, we monitored cellular respiration during continuous exposure to doxorubicin. A phosphorescence analyzer capable of stable measurements over at least 5 h was used to measure [O(2)]. In solutions containing glucose and cells, [O(2)] declined linearly with time, showing that the kinetics of oxygen consumption was zero order. Complete inhibition of oxygen consumption by cyanide indicated that oxidations occurred in the respiratory chain. A decline in the rate of respiration was evident in Jurkat and HL-60 cells exposed to doxorubicin. The decline was abrupt, occurring after about 2 h of incubation. The inhibition was concentration-dependent and was completely blocked by the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone. Respiration in resistant HL-60/MX2 cells, characterized by an altered topoisomerase II activity, was not inhibited by doxorubicin. A decline in cellular ATP was measured in Jurkat cells after 2-4 h of incubation with 20 microM doxorubicin, paralleling the decline in respiration rate. Thus, cells incubated with doxorubicin exhibit caspase-mediated inhibition of oxidative phosphorylation.

Additional Information

Reprinted with permission from Tao, Z., Withers, H. G., Penefsky, H. S., Goodisman, J., & Souid, A. -. (2006). Inhibition of cellular respiration by doxorubicin. Chemical Research in Toxicology, 19(8), 1051-1058. Copyright 2005 American Chemical Society.

http://pubs.acs.org/doi/pdf/10.1021/tx050315y

Recommended Citation

Tao, Z., Withers, H. G., Penefsky, H. S., Goodisman, J., & Souid, A. -. (2006). Inhibition of cellular respiration by doxorubicin. Chemical Research in Toxicology, 19(8), 1051-1058.

Source

Local input

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.