Nitric oxide-releasing platinum(IV) prodrug efficiently inhibits proliferation and metastasis of cancer cells.

Nitric oxide (NO) is a gaseous signaling molecule involved in many physiological and pathological processes. Here a NO-donor (furoxan derivative) has been conjugated to cisplatin, generating a dual-functional Pt(IV) prodrug Pt-furoxan. Upon cellular internalization, Pt-furoxan releases cytotoxic cisplatin and a signaling molecule NO that can modulate the cellular response to the platinum agent, leading to synergistic anti-proliferation effects. Interestingly, Pt-furoxan also demonstrates promising anti-metastasis effect both in vitro and in vivo. Mechanism investigations indicates that Pt-furoxan suppresses the activity of MMP9 and MMP2, two key enzymes involved in tumor metastasis, and effectively inhibits the adhesion of tumor cells to vascular endothelial cells. This result offers a novel strategy to construct dual-functional agents by conjugation of NO-donors for the prevention of both proliferation and metastasis of tumor cells.