Capturing platinum in cisplatin: kinetic reactions with recombinant human apo-metallothionein 1a

Abstract

cis-Diamminedichloroplatinum(ii) (cisplatin), a powerful chemotherapeutic, can incur chemoresistance in cancers, reducing therapeutic success. Metallothioneins (MTs) are suspected of metallodrug interference via ligand removal and metal sequestration. The mechanistic details and reactions rates kobs for the systematic deconstruction of cisplatin by apo-human MT are reported and analysed from mass spectral data.

Interplay between Carbonic Anhydrases and Metallothioneins: Structural Control of Metalation

“…Currently, MTs are known to interfere with platinum-based anticancer drugs and doxorubicin treatment of breast cancer [ 105 ]. In vitro studies show MTs binding to xenobiotic metal drugs cisplatin [ 106 , 107 , 108 ] and therapeutically relevant ruthenium and rhodium complexes in unusually anarchistic ways [ 39 , 109 , 110 , 111 ]. Unlike CAs, xenobiotic metal replacement does not deactivate MT activity.…”

“…Notably, MTs are heavily implicated in drug-resistance [ 36 ], particularly with the cancer-therapeutic cis- diamminodichloro platinum(II), known as cisplatin [ 37 , 38 ]. The Pt-ligand complex is broken down, and the native Zn 2+ is released into the cytoplasm, triggering metal response elements (MREs) to signal for MT production [ 39 , 40 ]. Additionally, therapeutic alkylating agents can also induce MT-driven drug resistance, especially if antioxidant or glucocorticoid response elements are triggered [ 41 ].…”

Towards an Understanding of Specific Response of Metallothionein (Sub)Isoforms to Exposure to Platinum-Based Anticancer Drugs

“…MTs are suspected to interfere with the metal-based drugs through ligand removal and metal sequestration. Wong and Stillman (2018) studied the mechanistic details and deconstruction of cisplatin by human MTs. Skowron et al (2018) report on cisplatin resistance in long term treatment on cancer cell lines and observed the complexity of cisplatin resistance mechanisms even within one tumor entity.…”

Metallothionein: An Aggressive Scavenger—The Metabolism of Rhodium(II) Tetraacetate (Rh2(CH3CO2)4)

“…It is becoming clear through studies of metalation, where M ≠ Cd(II) or Zn(II), alternate mechanisms are in play, notably with the nonclustering As(III) binding, 36,37 or complex deconstruction of cisplatin. 33 While metalation of MTs with metal ions is well understood in vitro, the interaction of these proteins with nontraditional metals and metal complexes-carrying ligands are not fully understood.…”

“…15 Cisplatin resistance and its relationship with MT’s aggressive metal binding behavior is the focus of much research. 31,33,55−60 MTs are rich in highly reactive cysteine thiolates, which are suspected of being involved in the interference of platinum drugs. The many stress inducers of MT may easily cause upregulation of the protein following a dosage of platinum drugs.…”