Metallomics

Pt-ttpy, a G-quadruplex binding platinum complex, induces telomere dysfunction and G-rich regions DNA damage

Abstract Pt-ttpy (tolyl terpyridin-Pt complex) covalently binds to G-quadruplex (G4) structures in vitro and to telomeres in cellulo via its Pt moiety. Here, we identified its targets in the human genome, in comparison to Pt-tpy, its derivative without G4 affinity, and cisplatin. Pt-ttpy, but not Pt-tpy, induces the release of the shelterin protein TRF2 from telomeres concomitantly to the formation of DNA damage foci at telomeres but also at other chromosomal locations. γ-H2AX chromatin immunoprecipitation (ChIP-seq) after treatment with Pt-ttpy or cisplatin revealed accumulation in G- and A-rich tandemly repeated sequences, but not particularly in potential G4 forming sequences. Collectively, Pt-ttpy presents dual targeting efficiency on DNA, by inducing telomere dysfunction and genomic DNA damage at specific loci.

Dinuclear orthometallated gold(I)-gold(III) anticancer complexes with potent in vivo activity through an ROS-dependent mechanism

Abstract Increasingly explored over the last decade, gold complexes have shown great promise in the field of cancer therapeutics. A major obstacle to their clinical progression has been their lack of in vivo stability, particularly for gold(III) complexes, which often undergo a facile reduction in the presence of biomolecules such as glutathione. Herein, we report a new class of promising anticancer gold(I)–gold(III) complexes with the general formula [XAuI(μ-2-C6F4PPh2)(κ2-2-C6F4PPh2)AuIIIX] [X = Cl (1), Br (2), NO3 (3)] which feature two gold atoms in different oxidation states (I and III) in a single molecule. Interestingly, gold(I)–gold(III) complexes (1–3) are stable against glutathione reduction under physiological-like conditions. In addition, complexes 1–3 exhibit significant cytotoxicity (276-fold greater than cisplatin) toward the tested cancer cells compared to the noncancerous cells. Moreover, the gold(I)–gold(III) complexes do not interact with DNA-like cisplatin but target cellular thioredoxin reductase, an enzyme linked to the development of cisplatin drug resistance. Complexes 1–3 also showed potential to inhibit cancer and endothelial cell migration, as well as tube formation during angiogenesis. In vivo studies in a murine HeLa xenograft model further showed the gold compounds may inhibit tumor growth on par clinically used cisplatin, supporting the significant potential this new compound class has for further development as cancer therapeutic.

Single-cell and bulk ICP–MS investigation of accumulation patterns of Pt-based metallodrugs in cisplatin-sensitive and -resistant cell models

Abstract In research enabling preclinical development and attaining a deeper understanding of the behavior of metallodrugs in cancer cells with acquired resistance, intracellular Pt accumulation could be considered an important biomarker and analytical focus. In this work, Pt accumulation patterns in terms of the number of cells and Pt mass in single cells were precisely defined by using inductively coupled plasma-mass spectrometry (ICP–MS) operating in a fast time-resolved analysis mode. This technique is otherwise known as single-cell (SC)–ICP–MS. By applying the nascent and validated SC–ICP–MS technique, comparisons across three Pt drugs (cisplatin, carboplatin, and oxaliplatin) in the A2780 and A2780cis ovarian cancer cell models could be made. Additional roles of transporters on top of passive diffusion and the drugs’ bioactivity could be postulated. The SC–ICP–MS-based observations also served as a cross-validation point to augment preexisting research findings on Pt-resistance mechanisms. Conjectures regarding S and Fe metabolism were also derived based on an additional and direct ICP–MS analysis of endogenous elements. Overall, our work not only confirms the utility of SC–ICP–MS in chemotherapeutic research, but also provided insights into further ICP–MS-based analytical capacities to be developed.

Gold(iii) bis(dithiolene) complexes: from molecular conductors to prospective anticancer, antimicrobial and antiplasmodial agents

Abstract The anticancer, antimicrobial and antiplasmodial activities of six gold(iii) bis(dithiolene) complexes were studied. Complexes 1–6 showed relevant anticancer properties against A2780/A2780cisR ovarian cancer cells (IC50 values of 0.08–2 μM), also being able to overcome cisplatin resistance in A2780cisR cells. Complex 1 also exhibited significant antimicrobial activity against Staphylococcus aureus (minimum inhibitory concentration (MIC) values of 12.1 ± 3.9 μg mL−1) and both Candida glabrata and Candida albicans (MICs of 9.7 ± 2.7 and 19.9 ± 2.4 μg mL−1, respectively). In addition, all complexes displayed antiplasmodial activity against the Plasmodium berghei parasite liver stages, even exhibiting better results than the ones obtained using primaquine, an anti-malarial drug. Mechanistic studies support the idea that thioredoxin reductase, but not DNA, is a possible target of these complexes. Complex 1 is stable under biological conditions, which would be important if this compound is ever to be considered as a drug. Overall, the results obtained evidenced the promising biological activity of complex 1, which might have potential as a novel anticancer, antimicrobial and antiplasmodial agent to be used as an alternative to current therapeutics.