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Mitochondrial translocator protein (TSPO) ligands prevent doxorubicin-induced mechanical dysfunction and cell death
Alexandra d'Anglemont de Tassigny1, Rana Assaly, Sophie Schaller
1INSERM U955, équipe 3, Créteil F-94010, France; Université Paris-Est, Faculté de Médecine, Créteil F-94010, France; Institut Supérieur des BioSciences, Faculté de Médecine, Créteil F-94010, France.
Abstract:
Contractile dysfunction and subsequent development of cardiomyopathies are well known limiting factors in the treatment of cancer with doxorubicin and have been linked to mitochondrial dysfunction. Here, using adult isolated paced cardiomyocytes, we have demonstrated that ligands of translocator protein (TSPO) 4'-chlorodiazepam and TRO40303 prevented the doxorubicin-induced alterations in contractility and improved cardiomyocyte viability. This cardioprotective effect was closely associated with both a potent reduction in reactive oxygen species production and inhibition of mitochondrial permeability transition pore opening. Thus, preventive administration of TSPO ligands may represent a novel pharmacological strategy to protect the heart during doxorubicin treatment.
Insights
Ligands targeting the translocator protein (TSPO) protected heart cells from doxorubicin damage. This novel strategy reduced reactive oxygen species and improved heart cell survival during cancer treatment.
Area of Science:
- Cardiology
- Pharmacology
- Mitochondrial Biology
Background:
- Doxorubicin chemotherapy can cause heart problems (cardiomyopathy) by damaging mitochondria.
- Mitochondrial dysfunction is a key factor in doxorubicin-induced heart damage.
Purpose of the Study:
- To investigate if translocator protein (TSPO) ligands can protect heart cells from doxorubicin.
- To explore the mechanisms behind the potential cardioprotective effects of TSPO ligands.
Main Methods:
- Isolated adult rat cardiomyocytes were used.
- Cells were treated with doxorubicin with or without TSPO ligands (4'-chlorodiazepam and TRO40303).
- Contractility, viability, reactive oxygen species (ROS) production, and mitochondrial permeability transition pore (mPTP) opening were measured.
Main Results:
- TSPO ligands prevented doxorubicin-induced contractile dysfunction and improved cell survival.
- TSPO ligands significantly reduced ROS production.
- TSPO ligands inhibited mitochondrial permeability transition pore opening.
Conclusions:
- TSPO ligands demonstrate cardioprotective effects against doxorubicin.
- The protective mechanism involves reducing oxidative stress and preventing mPTP opening.
- Preventive TSPO ligand administration is a potential strategy to mitigate doxorubicin cardiotoxicity.
