Abstract
Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of PtIV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.
Original language | English (US) |
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Pages (from-to) | 3029-3036 |
Number of pages | 8 |
Journal | Chemistry - A European Journal |
Volume | 22 |
Issue number | 9 |
DOIs | |
State | Published - Feb 24 2016 |
Externally published | Yes |
Keywords
- alkylating agent
- cancer
- cisplatin
- DNA repair
- glutathione
ASJC Scopus subject areas
- Chemistry(all)