Cisplatin handover between copper transporters: the effect of reducing agents.
Copper (Cu) transporters emerged as key factors at the basis of the biological response to antitumor platinum (Pt) drugs, which are among the most potent and broadly used chemotherapeutics. ATP7A and ATP7B (the Menkes and Wilson disease proteins, respectively) appear to be implicated in promoting tumor cell resistance to cisplatin. Cu-ATPases could bind the drug and, with the alleged involvement of the chaperone ATOX1, contribute to cell detoxification and survival. Here, we report the spectroscopic characterization of cisplatin binding to ATOX1 and MNK1, the first metal-binding domain of ATP7A, in the presence of the physiological reducing agent glutathione, a sulfur-containing molecule responsible for the majority of Pt detoxification in the cytosol. Under conditions mimicking the cellular environment, we show that cisplatin transfer from ATOX1 to MNK1 does not occur at a detectable rate. These results appear to contradict other literature data which, however, were obtained in the presence of exogenous reducing agents such as tris(2-carboxyethyl)phosphine (TCEP) having good coordinating ability for soft metal ions (such as Pt) and strong trans-labilizing effect. A better understanding of Pt drug processing by Cu trafficking proteins under physiological conditions may help to answer key issues, such as drug availability in tumor cells and resistance.
Department of Chemistry, University of Bari "Aldo Moro", via E. Orabona 4, 70125, Bari, Italy.
Angela
A
Galliani
Maurizio
M
Losacco
Alessia
A
Lasorsa
Giovanni
G
Natile
Fabio
F
Arnesano
D002945:Cisplatin / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D000079922:Copper Transport Proteins; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D056511:Metallochaperones / Q000737:chemistry / Q000378:metabolism; D018832:Molecular Chaperones; D010720:Phosphines / Q000737:chemistry; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism; D019163:Reducing Agents / Q000737:chemistry*
D002945:Cisplatin; D003300:Copper; D000079922:Copper Transport Proteins; D005978:Glutathione; D047908:Intracellular Signaling Peptides and Proteins; D056511:Metallochaperones; D018832:Molecular Chaperones; D010720:Phosphines; D017346:Protein Serine-Threonine Kinases; D019163:Reducing Agents; C474500:ATOX1 protein, human; C080938:tris(2-carboxyethyl)phosphine; C491395:MKNK1 protein, human