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A Multi‐action Pt IV Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells
Author(s) -
Kostrhunova Hana,
Zajac Juraj,
Markova Lenka,
Brabec Viktor,
Kasparkova Jana
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202009491
Subject(s) - prodrug , conjugate , chemistry , cancer cell , cancer research , breast cancer , cancer , stereochemistry , biochemistry , biology , medicine , mathematical analysis , mathematics
Abstract HER2‐positive breast cancer is an aggressive subtype that typically responds poorly to standard chemotherapy. To design an anticancer drug selective for HER2‐expressing breast cancer, a 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 a DNA‐damage‐mediated mechanism. Simultaneously, the released oleic and cinnamic acid can effectively inhibit HER2 expression. To our knowledge, this is the first platinum‐based complex inhibiting HER2 expression that does not contain protein or peptide. Moreover, this 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.