Abstract
Drug resistance is the main obstacle for a successful cancer therapy. There are many mechanisms by which cancers avoid drug-mediated death, including alterations in cellular metabolism and apoptotic programs. Mitochondria represent the cell’s powerhouse and the connection between carbohydrate, lipid and proteins metabolism, as well as crucial controllers of apoptosis, playing an important role not only in tumor growth and progression, but also in drug response. Alterations in tricarboxylic acid cycle (TCA) caused by mutations in three TCA enzymes—isocitrate dehydrogenase, succinate dehydrogenase and fumarate hydratase—lead to the accumulation of 2-hydroxyglutarate, succinate and fumarate respectively, collectively known as oncometabolites. Oncometabolites have pleiotropic effects on cancer biology. For instance, they generate a pseudohypoxic phenotype and induce epigenetic changes, two factors that may promote cancer drug resistance leading to disease progression and poor therapy outcome. This review sums up the most recent findings about the role of TCA-derived oncometabolites in cancer aggressiveness and drug resistance, highlighting possible pharmacological strategies targeting oncometabolites production in order to improve the efficacy of cancer treatment.
Highlights
Mitochondria in CancerTreating advanced tumors is still an important challenge because of the concomitant presence of intrinsic and acquired resistance to the commonly used anti-cancer drugs
Since succinate and fumarate accumulation mainly derive from loss-of-function mutations in succinate dehydrogenase (SDH)
The involvement of mitochondria metabolism in cancer growth, progression and drug resistance has been established since a long time
Summary
Treating advanced tumors is still an important challenge because of the concomitant presence of intrinsic and acquired resistance to the commonly used anti-cancer drugs. Since mtDNA mainly encodes for mitochondrial translation machinery and ETC complexes, mutations in these key players of OXPHOS may produce the synthesis of complexes characterized by a defective reduction of electron shuttles (ubiquinone, cytochrome c), structural components (Fe-S cluster-, cytochrome-containing proteins) or O2 , determining the generation of radical species or ROS. This mitochondrial dysfunction promotes metabolic alterations, changes the ROS buffering and the balance between pro-apoptotic and anti-apoptotic signaling, contributing to drug resistance [11]. We will focus on potential pharmacological strategies targeting the production of oncometabolites as potential tools improving the efficacy of anti-cancer treatments
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