DNA or not DNA —that is the question determining the design of platinum anticancer drugs

Platinum drugs are the most widely used chemotherapeutics to treat various tumors. Their primary mode of action is supposed to be inducing apoptosis of cancer cells via covalent binding to DNA. This mechanism has shackled the design of new platinum drugs for many years. Mounting evidence shows that many platinum complexes form non-covalent adducts with DNA or interact with proteins to exhibit significant antitumor activity, thus implying some distinct mechanisms from that of traditional platinum drugs. These unconventional examples indicate that covalent DNA binding is not the precondition for the antitumor activity of platinum complexes, and diversified reactions or interactions with biomolecules, organelles, signal pathways, or immune system could lead to the antitumor activity of platinum complexes. The atypical mechanisms break the classical DNA-only paradigm and structure−activity relationships, thus opening a wide avenue for the design of innovative platinum anticancer drugs.