Abstract
The high incidence of the resistance phenomenon represents one of the most important limitations to the clinical usefulness of cisplatin as an anticancer drug. Notwithstanding the considerable efforts to solve this problem, the circumvention of cisplatin resistance remains a challenge in the treatment of cancer. In this work, the synthesis and characterization of two trans-dichloro(triphenylarsino)(N,N-dialkylamino)platinum(II) complexes (1 and 2) were described. The trypan blue exclusion assay demonstrated an interesting antiproliferative effect for complex 1 in ovarian carcinoma-resistant cells, A2780cis. Quantitative analysis performed by ICP-AES demonstrated a scarce ability to platinate DNA, and a significant intracellular accumulation. The investigation of the mechanism of action highlighted the ability of 1 to inhibit the relaxation of supercoiled plasmid DNA mediated by topoisomerase II and to stabilize the cleavable complex. Cytofluorimetric analyses indicated the activation of the apoptotic pathway and the mitochondrial membrane depolarization. Therefore, topoisomerase II and mitochondria could represent possible intracellular targets. The biological properties of 1 and 2 were compared to those of the related trans-dichloro(triphenylphosphino)(N,N-dialkylamino)platinum(II) complexes in order to draw structure–activity relationships useful to face the resistance phenotype.
Highlights
The clinical use of cisplatin, the first platinum-based anticancer drug, was approved by the FDA in 1978 for the treatment of ovarian, testicular and bladder cancer
Platinum drug resistance is a complex multifactorial phenomenon, resulting from different mechanisms, such as the reduction of intracellular drug accumulation due to the downregulation of transporters and/or to the upregulation of proteins involved in its detoxification or efflux, the failure of the apoptotic pathways and the increase in repair of DNA damage [6,8,9,10]
The cytotoxic effect exerted by 1 in ovarian carcinoma cells is higher with respect to that exerted by cisplatin, with GI50 values two- (A2780) and three-fold (A2780cis) lower than that of the reference drug
Summary
The clinical use of cisplatin, the first platinum-based anticancer drug, was approved by the FDA in 1978 for the treatment of ovarian, testicular and bladder cancer. Triphenylphosphine and triphenylarsine share several characteristics, such as for the coordination mode to metals, it is known that the heavier analogue shows a less strong trans effect in platinum(II) complexes [23,24] This feature could be the basis for a different reactivity towards biological substrates and, for a different cytotoxicity profile. Molecules 2022, 27, 644 results are described for some dichloroplatinum(II) complexes bearing two aromatic arsino ligands and hydroxy and/or methoxy substituents on one of the three aromatic moieties These complexes proved a cytotoxicity profile against ovarian cancer cells comparable to that of carboplatin [30]. The results are discussed in comparison with the biological properties of the triphenylphosphine analogues
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
