Abstract
Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and 1H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEPn (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEPn to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC50 = 2.1 ± 0.4 μM versus 3.7 ± 0.9 μM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.
Original language | English |
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Pages (from-to) | 557-564 |
Number of pages | 8 |
Journal | Chemistry and Biology |
Volume | 11 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2004 |
Keywords
- Breast Neoplasms/drug therapy
- Cell Line, Tumor
- Cell Survival/drug effects
- Dose-Response Relationship, Drug
- Drug Design
- Drug Screening Assays, Antitumor
- Estradiol/pharmacology
- Estrogens/chemistry
- Gene Expression/drug effects
- HMGB1 Protein/drug effects
- Humans
- Organoplatinum Compounds/chemical synthesis
- Receptors, Estrogen/drug effects
- Structure-Activity Relationship