Background: Resistance, either at the onset of the treatment or developed after
an initial positive response, is a major limitation of antitumor therapy. In the case of platinum-
based drugs, copper transporters have been found to interfere with drug trafficking
by facilitating the import or favoring the platinum export and inactivation.
Methods: The use of powerful spectroscopic, spectrometric and computational methods
has allowed a deep structural insight into the mode of interaction of platinum drugs with
the metal-binding domains of the transporter proteins.
Results: This review article focuses on the mode in which platinum drugs can compete
with copper ion for binding to transport proteins and consequent structural and biological
effects. Three types of transporters are discussed in detail: copper transporter 1 (Ctr1), the
major responsible for Cu+ uptake; antioxidant-1 copper chaperone (Atox1), responsible
for copper transfer within the cytoplasm; and copper ATPases (ATP7A/B), responsible
for copper export into specific subcellular compartments and outside the cell.
Conclusion: The body of knowledge summarized in this review can help in shaping current
chemotherapy to optimize the efficacy of platinum drugs (particularly in relation to
resistance) and to mitigate adverse effects on copper metabolism.