Abstract
This mini-review reports on the existing knowledge of the metabolic effects of palladium [Pd(II)] complexes with potential anticancer activity, on cell lines and murine models. Most studies have addressed mononuclear Pd(II) complexes, although increasing interest has been noted in bidentate complexes, as polynuclear structures. In addition, the majority of records have reported in vitro studies on cancer cell lines, some including the impact on healthy cells, as potentially informative in relation to side effects. Generally, these studies address metabolic effects related to the mechanisms of induced cell death and antioxidant defense, often involving the measurement of gene and protein expression patterns, and evaluation of the levels of reactive oxygen species or specific metabolites, such as ATP and glutathione, in relation to mitochondrial respiration and antioxidant mechanisms. An important tendency is noted toward the use of more untargeted approaches, such as the use of omic sciences e.g., proteomics and metabolomics. In the discussion section of this mini-review, the developments carried out so far are summarized and suggestions of possible future developments are advanced, aiming at recognizing that metabolites and metabolic pathways make up an important part of cell response and adaptation to therapeutic agents, their further study potentially contributing valuably for a more complete understanding of processes such as biotoxicity or development of drug resistance.
Highlights
The discovery of the important antitumor activity of cisplatin [cis-diamminedichloroplatinum(II), cis-Pt(NH3)2Cl2, cDDP] [1], a complex that targets DNA resulting in the formation of intra- and inter-strand DNA cross-links and triggering apoptotic cell death, led to it becoming the first successful metal-based anticancer drug [2]
When combined with doxorubicin and methotrexate, the Pd(II) complex impacted more strongly on cancer cells, in a similar way to the equivalent cisplatin-based combination: apoptosis was induced and strong variations were noted in lipids, choline compounds, several amino acids, nucleotides, and compounds related to antioxidative defense mechanisms (GSH and, possibly, inositol and hypoxanthine)
Knowledge, no further specific metabolic information has been reported on either toxicity or anticancer activity of Pd(II) complexes in an in vivo context, clearly unveiling a niche of research which would be interesting to pursue. This mini-review has shown that most of the existing knowledge on the effects of Pd(II) complexes with potential anticancer activity on cell lines has been based on the important understanding of the mechanisms of induced cell death and antioxidant defense
Summary
The discovery of the important antitumor activity of cisplatin [cis-diamminedichloroplatinum(II), cis-Pt(NH3)2Cl2, cDDP] [1], a complex that targets DNA resulting in the formation of intra- and inter-strand DNA cross-links and triggering apoptotic cell death, led to it becoming the first successful metal-based anticancer drug [2]. Neutral/cationic Pd-dppm complexes: apoptosis through (compared to Pt(II) analogues and cDDP); DU145, HCT116
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