Abstract
Mitochondrial ion channels are emerging oncological targets, as modulation of these ion-transporting proteins may impact on mitochondrial membrane potential, efficiency of oxidative phosphorylation and reactive oxygen production. In turn, these factors affect the release of cytochrome c, which is the point of no return during mitochondrial apoptosis. Many of the currently used chemotherapeutics induce programmed cell death causing damage to DNA and subsequent activation of p53-dependent pathways that finally leads to cytochrome c release from the mitochondrial inter-membrane space. The view is emerging, as summarized in the present review, that ion channels located in this organelle may account in several cases for the resistance that cancer cells can develop against classical chemotherapeutics, by preventing drug-induced apoptosis. Thus, pharmacological modulation of these channel activities might be beneficial to fight chemo-resistance of different types of cancer cells.
Highlights
Apoptosis-resistance is of the key hallmarks of cancer cells [1]
Mitochondria may contribute in two major ways to resistance towards chemotherapy: i) by producing ATP, that allows the function of ATP-binding cassette family members, such as multidrug resistance (MDR) proteins that actively extrude xenobiotics from malignant cells [3,4]; ii) by defective outer membrane permeabilization (MOMP) and/or impaired opening of the mitochondrial permeability transition pore (MPTP) that may prevent release of pro-apoptotic factors, thereby leading to resistance to apoptosis-inducing agents
In the present review we summarized the currently available information regarding the roles of mitochondrial ion channels and pore-forming proteins in the regulation of apoptosis and in the context of chemo-resistance
Summary
Apoptosis-resistance is of the key hallmarks of cancer cells [1]. Defective regulation of apoptosis importantly contributes to tumorigenesis and cancer progression leading to accumulation of pathologic cells. Mitochondria may contribute in two major ways to resistance towards chemotherapy: i) by producing ATP, that allows the function of ATP-binding cassette family members, such as multidrug resistance (MDR) proteins that actively extrude xenobiotics (chemotherapeutics) from malignant cells [3,4]; ii) by defective outer membrane permeabilization (MOMP) and/or impaired opening of the mitochondrial permeability transition pore (MPTP) that may prevent release of pro-apoptotic factors, thereby leading to resistance to apoptosis-inducing agents. O, pumps at the plasma membrane (depicted as ABC); 2) by modulating oxidative phosphorylation pumps at the plasma membrane (depicted as ABC); 2) by modulating oxidative phosphorylation efficiency 2, IMM channels may lead to increased ROS release that in turn triggers opening of MPTP. 3 and subsequent release of cytochrome c and other pro-apoptotic factors 4; 3) by modulating and subsequent release ofofcytochrome c and other pro-apoptotic factors
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