Mechanistic insight into the cellular uptake and processing of cisplatin 30 years after its approval by FDA

When cisplatin was first synthesized, over 150 years ago, inorganic chemistry was in its infancy and no one would have foreseen a role in medicine. Some 120 years later, Rosenberg discovered by serendipity the antitumor activity of this compound but, again, no one would have thought of the existence of specific proteins able to transport platinum across cell membranes or to specifically recognize DNA modified by this drug. However such proteins do exist and, furthermore, are specific for the platinum substrate considered. In this review article the issue of how copper transporter 1 protein (CTR1) can assist the platinum species in entering the cell will be addressed. Platinum binding to double-stranded DNA generates a kinked chelated structure that is recognized by certain proteins in the nucleus, with a direct or indirect consequence on cell viability and induction of apoptosis. Different processing of DNA cross-links formed by species containing enantiomeric diamine carrier ligands (including the carrier ligand of oxaliplatin) will be highlighted.