Interactions of Antitumor Metallodrugs with Serum Proteins: Advances in Characterization Using Modern Analytical Methodology

Abstract

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Inhibition of cisplatin-resistance by RNA interference targeting metallothionein using reducible oligo-peptoplex

“…Aqua complexes of cisplatin are able to bind to N7 of two neighbouring guanine in the same or in opposite DNA strands, which induced cancer cell apoptosis. However, effective intracellular level of cisplatin following repeated injections can be decreased by the active efflux via ATP pump and by interaction with glutathione and metallothionein [9,10]. The cisplatin resistance resulting from increased inactivation by intracellular proteins has been considered to be major hurdles to overcome.…”

Direct determination of the primary binding site of cisplatin on cytochrome c by mass spectrometry

“…Because blood plasma proteins are good nucleophiles for cisplatin, they play an important role in transporting cisplatin to the tumor cells [5]. Unfortunately, some blood plasma protein-cisplatin binding is irreversible, which not only renders cisplatin inactive but also allows it to accumulate in tissues and induce side effects [6,7]. Exploration of protein-platinum metallodrug interactions provides insight into both the transportation role of the blood plasma proteins that enables therapeutic use and the irreversible binding that induces side effects.…”

Platinum speciation used for elucidating activation or inhibition of Pt-containing anti-cancer drugs

“…Other proteins explored with respect to the rate of binding to cisplatin were myoglobin, ubiquitin, metallothionein and again transferrin [6]. The kinetics of cisplatin binding to cellular metallothionein showed pseudo-first order, with a rate constant of 6.3 Â 10 À 4 s À 1 (t 1/2 =18 min), whilst Cox et al [34] discovered an essentially two-phase kinetic process for the cisplatinapotransferrin reaction by NMR measurements.…”

“…A typical approach to examine protein-drug interactions and their respective kinetics is realized by speciating unbound and bound fractions of the Pt-drug, mostly using SEC [28][29][30]. Predominantly such investigations were performed using albumin as interaction partner for cisplatin, however, experiments are also described with g-globulin and even cytochrome c [6]. A common result of several SEC-related studies was the two-stage nature of the binding process with the initial step being faster.…”

“…At present three intravenously administrable Pt(II) complexes, namely cisplatin, carboplatin and oxaliplatin, are applied worldwide in clinical practice [6]. Apart from these drugs, nedaplatin…”