Targeting the Mitochondrial Metabolic Network: A Promising Strategy in Cancer Treatment

Abstract

Metabolic reprogramming is a hallmark of cancer, which implements a profound metabolic rewiring in order to support a high proliferation rate and to ensure cell survival in its complex microenvironment. Although initial studies considered glycolysis as a crucial metabolic pathway in tumor metabolism reprogramming (i.e., the Warburg effect), recently, the critical role of mitochondria in oncogenesis, tumor progression, and neoplastic dissemination has emerged. In this report, we examined the main mitochondrial metabolic pathways that are altered in cancer, which play key roles in the different stages of tumor progression. Furthermore, we reviewed the function of important molecules inhibiting the main mitochondrial metabolic processes, which have been proven to be promising anticancer candidates in recent years. In particular, inhibitors of oxidative phosphorylation (OXPHOS), heme flux, the tricarboxylic acid cycle (TCA), glutaminolysis, mitochondrial dynamics, and biogenesis are discussed. The examined mitochondrial metabolic network inhibitors have produced interesting results in both preclinical and clinical studies, advancing cancer research and emphasizing that mitochondrial targeting may represent an effective anticancer strategy.

Anti-Warburg Effect of Melatonin: A Proposed Mechanism to Explain its Inhibition of Multiple Diseases

“…Activation of HIF-1α is an adaptative response coupled to intracellular hypoxia resulting from the depressed oxygen supply that develops when rapidly dividing neoplastic cells exceed the ability of neovasculogenesis to keep pace with the growing solid tumor. Within a given solid tumor there may be a gradient from near the center of the tumor where the oxygen tension is lowest to the periphery where the cells may be normoxic; this is also reflected in the intensity of HIF-1α expression [ 104 , 105 , 106 , 107 ]. Unequivocally, HIF-1α has a central role in orchestrating the processes that allow cancer cells (and other diseased cells) to accommodate aerobic glycolysis [ 108 , 109 ].…”

“…The loss of intracellular melatonin production may be an important aspect of the ability of cells to reprogram pyruvate processing and to progress to Warburg-type metabolism since melatonin is an endogenous inhibitor of HIF-1α [85,111,124]. Within a given solid tumor there may be a gradient from near the center of the tumor where the oxygen tension is lowest to the periphery where the cells may be normoxic; this is also reflected in the intensity of HIF-1α expression [104][105][106][107] (Figure 5). Unequivocally, HIF-1α has a central role in orchestrating the processes that allow cancer cells (and other diseased cells) to accommodate aerobic glycolysis [108,109].…”

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

“…Inhibition of mitochondrial bioenergetics has raised increasing interest in the field of cancer therapeutics [ 31 , 32 , 33 , 34 , 35 , 36 ]. A number of different inhibitors are being evaluated, including inhibitors of the respiratory chain, the tricarboxylic acid cycle, and mtDNA [ 36 ].…”

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

“…The field of mitochondrial bioenergetics as a target for antineoplastic agents is expanding rapidly (Frattaruolo et al, 2020; Oliveira et al, 2021; Sica et al, 2020). The identification of metabolic vulnerabilities will be important in expanding this field and is expected to broaden the arsenal of clinically available therapeutics for treatment of advanced disease.…”

“…Inhibition of mitochondrial bioenergetics has raised increasing interest in the field of cancer therapeutics (Emmings et al, 2019; Molina et al, 2018; Sica et al, 2020; Zhang et al, 2016) (Frattaruolo et al, 2020; Oliveira et al, 2021). A number of different inhibitors are being evaluated, including inhibitors of the respiratory chain, the tricarboxylic acid cycle and mtDNA (Oliveira et al, 2021).…”