Preferential Energy- and Potential-Dependent Accumulation of Cisplatin–Gutathione Complexes in Human Cancer Cell Lines (GLC4 and K562): A Likely Role of Mitochondria

Abstract

cis-Diamminedichloroplatinum(II) (CDDP) is an important chemotherapeutic agent used in the treatment of a wide variety of solid tumors. We have recently shown that aquated forms of cisplatin (aqua-Pt) rapidly accumulate in K562 and GLC4 cultured cells, in comparison to CDDP. Thus, when cells are incubated with aquated forms of cisplatin a gradient of concentration is observed after a short time, approximately 40 min, with an intracellular concentration of aqua-Pt of 20-30 times higher than that of extracellular aqua-Pt. The same gradient of concentration is observed when cells are incubated with CDDP but it takes a longer time, i.e., about 24 h. Therefore, the question arises as to the identity of the intracellular sites of accumulation of aqua-Pt. Using several agents to modulate membrane potential, acidic compartment pH and/or ATP level, we obtained evidence that aqua-Pt may accumulate rapidly inside mitochondria as this accumulation is energy- and membrane-potential-dependent. However, aqua-Pt complexes are not characterized by a delocalized charge and a lipophilic character that would permit their movement through the inner membrane. Therefore, it is suggested that intracellular aqua-Pt reacts rapidly with glutathione with the resultant complex being transported inside the mitochondria via one of the known glutathione transporters, i.e., dicarboxylate and/or 2-oxoglutarate transporters present in the inner membrane.

Effect of reactivity on cellular accumulation and cytotoxicity of oxaliplatin analogues

“…Until now a broad spectrum of nucleophiles have been used to quantify the reactivity of platinum complexes, e.g., G-actin [15], L-methionine [12,32], glutathione [32][33][34], calf thymus DNA [35,36] and guanosine 5 0 -monophosphate (5 0 -GMP) [10,12,32]. The selection of an appropriate model compound for investigation of the influence of reactivity on cellular accumulation is hampered by lack of knowledge of the transport mechanism(s) involved.…”

Defining cisplatin incorporation properties in thermosensitive injectable biodegradable hydrogel for sustained delivery and enhanced cytotoxicity

“…Despite its clinical success, intravenous Cis administration can lead to nephrotoxicity, bone marrow toxicity, intractable vomiting, peripheral neuropathy, deafness, seizures and blindness (Genc et al, 2014;Wang et al, 2014). Drug resistance during therapy is another important limitation to its use requiring the use of increasing doses (Dzamitika et al, 2006). Locoregional administration of Cis solution via intraperitoneal, transarterial or intratumoral administration is not practical as the drug rapidly passes into the blood, thus, limiting its retention time at the tumor site (Konishi et al, 2003).…”

Preparation and cytotoxicity of cisplatin-containing liposomes

“…Four main events accompany it in most cases: i) decreased accumulation of drug concentration (to below that necessary for cytotoxic activity), ii) increased levels of sulfur-containing molecules such as glutathione or metallothionein (which could play a role in metal detoxification), iii) enhanced repair of DNA damage caused by CDDP-DNA adducts by nucleotide excision repair proteins such as ERCC1, XPA, and XPB which can remove DNA adducts produced by CDDP, and iv) increased tolerance to CDDP-DNA adducts as a consequence of deficiencies in the mismatch repair system and enhanced replication bypass (15)(16)(17)(18). Among the various resistance mechanisms involved, decreased cellular accumulation of CDDP has been demonstrated in most cases (19)(20)(21)(22)(23)(24). Reduced intracellular CDDP concentration results in decreased DNA platination, which leads to CDDP resistance.…”