A New Multi-action Pt(IV) Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells

HER2-positive breast cancer represents aggressive subtype typical of poor response to standard chemotherapy. To design an anticancer drug selective for HER2 expressing breast cancer, the new Pt(IV) prodrug with axial oleate and cinnamate ligands was synthesized. We demonstrate its superior antiproliferative activity in monolayer and 3D spheroid models; the antiproliferative efficiency increases gradually with increasing expression of HER2. The results also suggest that the released Pt(II) compound inhibits the proliferation of cancer cells by DNA-damage mediated mechanism. Simultaneously, the released oleic and cinnamic acid can effectively inhibit HER2 expression. To the best of our knowledge, this is the first platinum-based complex inhibiting HER2 expression containing no protein or peptide. Moreover, the new Pt(IV) prodrug is capable of overcoming the resistance of cancer stem cells (CSCs) inducing death in both CSCs and differentiated cancer cells. Thus, the results substantiate our design strategy and demonstrate the potential of this approach for the development of new, therapeutically relevant compounds.

Keywords: Breast cancer; antitumor agents; cancer stem cells; medicinal chemistry; platinates.