Multiaction Pt(IV) Prodrugs Releasing Cisplatin and Dasatinib Are Potent Anticancer and Anti-Invasive Agents Displaying Synergism between the Two Drugs

Herein, we describe the general design, synthesis, characterization,
and biological activity of new multitargeting Pt(IV) prodrugs that
combine antitumor cisplatin and dasatinib, a potent inhibitor of Src
kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive
activities in tumor cell lines in both two-dimensional (2D) monolayers
of cell cultures and three-dimensional (3D) spheroids. We show that
the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes
are both involved in the mechanism of action in MCF7 breast cancer
cells and act synergistically. Thus, combining dasatinib and cisplatin
into one molecule, compared to using individual components in a mix,
may bring several advantages, such as significantly higher activity
in cancer cell lines and higher selectivity for tumor cells. Most
importantly, Pt(IV)-dasatinib complexes hold significant promise for
potential anticancer therapies by targeting epithelial–mesenchymal
transition, thus preventing the spread and metastasis of tumors, a
value unachievable by a simple combination of both individual components.