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 [O2] in solution. The [O2] 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 (5μM at 37° for 1-3hr) had no effect on the respiration in cells or in SMP. Higher cisplatin concentrations (10-99μM at 37° for 1-3hr) produced <25% inhibition. Incubations with 4-hydroperoxycyclophosphamide (50-100μM at 37° for 1hr) inhibited oxygen consumption in SMP (∼70% inhibition at 50μM) and in cells (∼30% inhibition at 50μM). Incubations (37° for 1hr) of SMP with doxorubicin (25-100μM) and daunorubicin (25-100μM) had no inhibitory effect on the respiration. By contrast, incubations (37° for 1hr) of cells with doxorubicin (5-20μM) and daunorubicin (2-20μM) 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.
- Cellular respiration
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