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Immediate effects of anticancer drugs on mitochondrial oxygen consumption
Abdul-Kader Souid1, Kirk A Tacka, Karen A Galvan
1Department of Pediatrics, State University of New York, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA. souida@upstate.edu
Abstract:
The evolving role of mitochondria as a target for many anticancer drugs (e.g. platinum-based compounds, alkylating agents and anthracyclines) prompted us to investigate their immediate effects on the mitochondrial respiratory chain. For this purpose, we used a phosphorescence analyzer that measures [O(2)] in solution. The [O(2)] of solutions containing an appropriate substrate and various cell lines, tumors from patients or beef heart submitochondrial particles (SMPs) declined almost linearly (r>0.99) as a function of time, indicating that the kinetics of cellular oxygen consumption were zero order. Rotenone inhibited respiration, confirming that oxygen was consumed by the respiratory chain. Exposure to a clinically relevant concentration of cisplatin (5 microM at 37 degrees for 1-3 hr) had no effect on the respiration in cells or in SMP. Higher cisplatin concentrations (10-99 microM at 37 degrees for 1-3 hr) produced <25% inhibition. Incubations with 4-hydroperoxycyclophosphamide (50-100 microM at 37 degrees for 1 hr) inhibited oxygen consumption in SMP ( approximately 70% inhibition at 50 microM) and in cells ( approximately 30% inhibition at 50 microM). Incubations (37 degrees for 1 hr) of SMP with doxorubicin (25-100 microM) and daunorubicin (25-100 microM) had no inhibitory effect on the respiration. By contrast, incubations (37 degrees for 1 hr) of cells with doxorubicin (5-20 microM) and daunorubicin (2-20 microM) produced significant inhibition. We conclude that cisplatin does not directly damage the energy converting mechanism of mitochondria. On the other hand, comparable exposures to alkylating agents and anthracyclines produce immediate and dose-dependent impairment of cellular respiration.
Insights
Anticancer drugs like cisplatin do not directly harm mitochondrial respiration. However, alkylating agents and anthracyclines impair cellular respiration, impacting energy production in cancer cells.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Mitochondria are key targets for anticancer drugs, including platinum-based compounds, alkylating agents, and anthracyclines.
- Understanding the immediate effects of these drugs on mitochondrial function is crucial for cancer therapy.
- The mitochondrial respiratory chain is vital for cellular energy production.
Purpose of the Study:
- To investigate the direct effects of anticancer drugs on the mitochondrial respiratory chain.
- To determine if cisplatin, alkylating agents, and anthracyclines impact cellular oxygen consumption.
- To differentiate the mechanisms of action of various chemotherapy agents on mitochondrial respiration.
Main Methods:
- Utilized a phosphorescence analyzer to measure oxygen consumption in solutions.
- Assessed oxygen consumption kinetics in various cell lines, patient tumors, and beef heart submitochondrial particles (SMPs).
- Tested the effects of cisplatin, 4-hydroperoxycyclophosphamide, doxorubicin, and daunorubicin at clinically relevant concentrations.
Main Results:
- Cisplatin, even at high concentrations, showed no significant inhibition of mitochondrial respiration in cells or SMPs.
- 4-hydroperoxycyclophosphamide (an alkylating agent) caused significant inhibition of oxygen consumption in both SMPs and cells.
- Doxorubicin and daunorubicin (anthracyclines) inhibited respiration in cells but not in isolated SMPs.
Conclusions:
- Cisplatin does not directly damage the mitochondrial energy-converting mechanism.
- Alkylating agents and anthracyclines cause immediate, dose-dependent impairment of cellular respiration.
- The differential effects suggest distinct mechanisms of action for these drug classes on mitochondrial function.