Cellular accumulation and DNA platination of two new platinum(II) anticancer compounds based on anthracene derivatives as carrier ligands

Cytotoxic activity and cellular processing in human ovarian carcinoma cell lines of a new platinum(II) compound containing a fluorescent substituted propylene diamine ligand

“…The cytotoxicity assays in A2780 and A2780R cells have been performed as previously described [17]. For GSH-depleted A2780R cytotoxicity assays the cells were seeded in 96-wells flat A c c e p t e d M a n u s c r i p t 6 bottom microtiter plates using medium containing 50 μM L-BSO, as previously described [18].…”

Determination of Pt–DNA adducts and the sub-cellular distribution of Pt in human cancer cell lines and the leukocytes of cancer patients, following mono- or combination treatments, by inductively-coupled plasma mass spectrometry

“…At the molecular level both Pt-drugs are believed to kill cancer cells by binding to DNA, their ultimate pharmacological target [17][18][19]. Not surprisingly therefore, many experimental and theoretical studies have focused on Pt attachment to DNA [20][21][22][23]. Oxaliplatin undergoes ligand exchange in physiological conditions where the oxalate ligand is replaced by two chloride ligands to form [Pt(dach)(Cl) 2 ] [24].…”

“…Intracellular Pt content is considered to play a significant role in cytotoxicity and resistance. Several studies have investigated the accumulation of cisplatin in various cancer cell types and have examined the cellular uptake of the drug as a function of exposure time [23,[33][34][35][36][37]. Decreased intracellular Pt concentration due to increased efflux or decreased drug uptake was also shown to cause cisplatin resistance [7,[38][39][40][41][42].…”

“…These reactions partially inactivate the drugs and reduce their subcellular uptake. In order to reduce such interactions and to improve the cellular uptake, recent studies have focused on modifying the structure of the drugs or combining them with other molecules such as bafilomycin and methyl-β-cyclodextrin to improve their permeability through cell membranes [23,[34][35][36][37]. Inside the cell, a plethora of ligands other than DNA are available to compete for the platinum, it is thus not surprising that only a very small fraction of either intracellular cisplatin or oxaliplatin binds to their pharmacological target [49].…”

“…Inside the cell, a plethora of ligands other than DNA are available to compete for the platinum, it is thus not surprising that only a very small fraction of either intracellular cisplatin or oxaliplatin binds to their pharmacological target [49]. The isolation and quantification of these scarce Pt-DNA complexes has been the subject of many recent reports [19,22,23,36]. Non-DNA interactions not only account for the majority of the intra-cellular adducts formed by the Pt-drugs, thus reducing their efficacy, but there is also strong evidence suggesting that such adducts are responsible for induced resistance in cancer cells [50][51][52].…”