Targeting Mitochondrial Singlet Oxygen Dynamics Offers New Perspectives for Effective Metabolic Therapies of Cancer

Abstract

The occurrence of mitochondrial respiration has allowed evolution toward more complex and advanced life forms. However, its dysfunction is now also seen as the most probable cause of one of the biggest scourges in human health, cancer. Conventional cancer treatments such as chemotherapy, which mainly focus on disrupting the cell division process, have shown being effective in the attenuation of various cancers but also showing significant limits as well as serious sides effects. Indeed, the idea that cancer is a metabolic disease with mitochondria as the central site of the pathology is now emerging, and we provide here a review supporting this "novel" hypothesis re-actualizing past century Otto Warburg's thoughts. Our conclusion, while integrating literature, is that mitochondrial activity and, in particular, the activity of cytochrome c oxidase, complex IV of the ETC, plays a fundamental role in the effectiveness or non-effectiveness of chemotherapy, immunotherapy and probably radiotherapy treatments. We therefore propose that cancer cells mitochondrial singlet oxygen (1 O 2) dynamics may be an efficient target for metabolic therapy development.

Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal

“…At this point, the metal center seems to be the key, since although HL4 and L4-M complexes are able to interact with DNA only the iridium derivative cleaves DNA by an O2 dependent mechanism. The ability of L4-Ir to generate singlet oxygen constitutes an important advantage for its potential as antitumor agent over its analogues, since singlet oxygen is identified as one of the major ROS produced in mitochondria and altering its levels is reported as an efficient strategy for cancer therapy [131]. Since only the iridium complex display DNA chemical nuclease activity, the underlying mechanism was further investigated by means of a cleavage electrophoresis assay in which several well-known radical scavengers such as DMSO for OH • , L-histidine for 1 O 2 , sodium pyruvate for H 2 O 2 and superoxide dismutase (SOD) for O 2 were included (Figure 9) [129].…”

“…At this point, the metal center seems to be the key, since although HL4 and L4-M complexes are able to interact with DNA only the iridium derivative cleaves DNA by an O 2 dependent mechanism. The ability of L4-Ir to generate singlet oxygen constitutes an important advantage for its potential as antitumor agent over its analogues, since singlet oxygen is identified as one of the major ROS produced in mitochondria and altering its levels is reported as an efficient strategy for cancer therapy [131].…”

MCUR1 Promotes Osteosarcoma Cell Growth Through AKT/p53 Pathway

“…Thus, mitochondria are reported to be imperative regulators of tumorigenesis, of which process generally requires adaption to cellular and environmental changes [15,16]. These evidence suggests that it is necessary to understand the biology of mitochondria in cancer in order to develop novel cancer treatment strategies [17]. It has been well documented that calcium ion, one of the most important second messenger molecules, harbors vital roles in a broad spectrum of physical processes including cell proliferation, apoptosis, autophagy and metabolism [18].…”

Biological Action of Singlet Molecular Oxygen from the Standpoint of Cell Signaling, Injury and Death

“…Concerning oxidatively generated damage in cells, some organelles are also sensitive targets of 1 O 2 , and mitochondria and lysosomes are the primary target organelles of 1 O 2 generated by PDT [ 104 ]. A sublethal dose of UVA irradiation causes the common deletion in mitochondrial DNA in human fibroblasts, which can be attributable to the generation of 1 O 2 within mitochondria [ 105 ].…”