A Multi-action PtIV Conjugate with Oleate and Cinnamate Ligands Targets Human Epithelial Growth Factor Receptor HER2 in Aggressive Breast Cancer Cells
Language English Country Germany Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- breast cancer, medicinal chemistry, metals in medicine, platinum, prodrugs,
- MeSH
- Cell Differentiation drug effects MeSH
- Cinnamates chemistry pharmacology MeSH
- Coordination Complexes chemical synthesis chemistry pharmacology MeSH
- Oleic Acid chemistry pharmacology MeSH
- Humans MeSH
- MCF-7 Cells MeSH
- Molecular Structure MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms drug therapy metabolism pathology MeSH
- Platinum chemistry pharmacology MeSH
- Cell Proliferation drug effects MeSH
- Antineoplastic Agents chemical synthesis chemistry pharmacology MeSH
- Receptor, ErbB-2 antagonists & inhibitors genetics metabolism MeSH
- Drug Screening Assays, Antitumor MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cinnamates MeSH
- ERBB2 protein, human MeSH Browser
- Coordination Complexes MeSH
- Oleic Acid MeSH
- Platinum MeSH
- Antineoplastic Agents MeSH
- Receptor, ErbB-2 MeSH
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 PtIV 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 PtII 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 PtIV 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.
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