Unique Use of Alkylation for Chemo-Redox Activity by a Pt(IV) Prodrug.

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.

• Authors: Rakesh K Pathak, Shanta Dhar
• Journal: Chemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 22 Issue 9 Pg. 3029-36 (Feb 24 2016) ISSN: 1521-3765 [Electronic] Germany
• PMID: 26807548 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Organoplatinum Compounds
• Prodrugs
• platin-B
• Glutathione
• Cisplatin

Topics

• Alkylation
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cisplatin (chemistry, pharmacology)
• DNA Repair
• Glutathione (chemistry)
• Humans
• Mitochondria (chemistry)
• Organoplatinum Compounds (chemistry, pharmacology, therapeutic use)
• Oxidation-Reduction
• Prodrugs (chemistry, therapeutic use)