Toxic effects of copper-based antineoplastic drugs (Casiopeinas®) on mitochondrial functions

Marín‐Hernández, Álvaro; Gracia-Mora, Isabel; Ruiz-Ramı̀rez, Lena; Moreno‐Sánchez, Rafael

doi:10.1016/s0006-2952(03)00212-0

Cited by 116 publications

(70 citation statements)

References 40 publications

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“…Therefore, targeting both energy pathways seems mandatory. This can be attained by using multi-site drugs such as the copper-based anti-cancer drugs termed casiopeinas, which inhibit glycolysis at the hexokinase level [33] and OXPHOS at the PDH 2 -OGDH and SDH levels [34,35]. However, the use of less-specific drugs may bring about undesirable side effects such as cardio-, nephro- and neurotoxicity, and anti-angiogenic activity affecting endothelial cells.…”

Section: Challenges Of the Warburg Effectmentioning

confidence: 99%

Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism

et al. 2015

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Cancer is a major threat to human health. A considerable amount of research has focused on elucidating the nature of cancer from its pathogenesis to treatment and prevention. Tumor cell metabolism has been considered a hallmark of cancer. Cancer cells differ from normal cells through unlimited cell division, and show a greater need for energy for their rapid growth and duplication. Research on glycometabolism, as the key point of energy metabolism, has played a unique role. In the 1920s, Warburg found that cancer cells prefer to produce adenosine triphosphate (ATP) by glycolysis, which is a less efficient pathway compared to oxidative phosphorylation. This striking discovery, called ‘the Warburg effect', has influenced and guided the study of the mechanism and treatment of tumors for generations, but its causal relationship with cancer progression is still unclear. Some studies have now shown contradicting evidence and a new hypothesis, the reverse Warburg effect, has been put forward, in which cancer cells produce most of their ATP via glycolysis, even under aerobic conditions. In this review we discuss the new points concerning the energy metabolism of a tumor, as well as the current facts and perspectives.

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Section: Challenges Of the Warburg Effectmentioning

confidence: 99%

Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism

et al. 2015

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“…Casiopeina II-gly and rhodamine 123 diminish the mitochondrial activity due to their respiratory chain inhibitory and uncoupling effect, respectively (Lampidis et al, 1983;Marín-Hernández et al, 2003). Laherradurin, an acetogenin derived from Annonaceae plants, is a very potent respiratory chain site I inhibitor (González-Coloma et al, 2002).…”

Section: Effect Of Glycolytic or Oxidative Inhibitors On Hela Mcts Grmentioning

confidence: 99%

Energy metabolism transition in multi‐cellular human tumor spheroids

Rodrı́guez-Enrı́quez

Gallardo‐Pérez

Avilés‐Salas

et al. 2008

Journal Cellular Physiology

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124

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It is thought that glycolysis is the predominant energy pathway in cancer, particularly in solid and poorly vascularized tumors where hypoxic regions develop. To evaluate whether glycolysis does effectively predominate for ATP supply and to identify the underlying biochemical mechanisms, the glycolytic and oxidative phosphorylation (OxPhos) fluxes, ATP/ADP ratio, phosphorylation potential, and expression and activity of relevant energy metabolism enzymes were determined in multi-cellular tumor spheroids, as a model of human solid tumors. In HeLa and Hek293 young-spheroids, the OxPhos flux and cytochrome c oxidase protein content and activity were similar to those observed in monolayer cultured cells, whereas the glycolytic flux increased two- to fourfold; the contribution of OxPhos to ATP supply was 60%. In contrast, in old-spheroids, OxPhos, ATP content, ATP/ADP ratio, and phosphorylation potential diminished 50-70%, as well as the activity (88%) and content (3 times) of cytochrome c oxidase. Glycolysis and hexokinase increased significantly (both, 4 times); consequently glycolysis was the predominant pathway for ATP supply (80%). These changes were associated with an increase (3.3 times) in the HIF-1alpha content. After chronic exposure, both oxidative and glycolytic inhibitors blocked spheroid growth, although the glycolytic inhibitors, 2-deoxyglucose and gossypol (IC(50) of 15-17 nM), were more potent than the mitochondrial inhibitors, casiopeina II-gly, laherradurin, and rhodamine 123 (IC(50) > 100 nM). These results suggest that glycolysis and OxPhos might be considered as metabolic targets to diminish cellular proliferation in poorly vascularized, hypoxic solid tumors.

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“…In particular, in the search for new drugs the proposal that complexes based on essential metals may be less toxic than those with non essential ones led to the study of copper based drugs, some of them having an important cytotoxic effect [6][7][8]. Consequently, active copper compounds and their interaction with DNA have attracted great interest [5,[9][10][11].…”

Section: Introductionmentioning

confidence: 99%