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Brostallicin, a novel anticancer agent whose activity is enhanced upon binding to glutathione
Cristina Geroni1, Sergio Marchini, Paolo Cozzi
1Laboratory of Molecular Pharmacology, Department of Oncology, Mario Negri Institute of Pharmacological Research, via Eritrea 62, 20157 Milan, Italy.
Cancer Research
|April 17, 2002
Summary
Brostallicin, a DNA minor groove binder, shows enhanced antitumor activity in cancer cells with higher glutathione S-transferase pi (GST-pi) levels. This suggests GST-pi influences brostallicin
Area of Science:
- Pharmacology
- Molecular Biology
- Oncology
Background:
- Brostallicin (PNU-166196) is a second-generation DNA minor groove binder with broad preclinical antitumor activity.
- It exhibits reduced myelotoxicity compared to other minor groove binders.
- Its efficacy against melphalan-resistant leukemia cells suggests a unique mechanism of action.
Purpose of the Study:
- To investigate the role of glutathione (GSH) and glutathione S-transferase pi (GST-pi) in brostallicin's cytotoxicity and antitumor activity.
- To elucidate the mechanism by which brostallicin exerts its effects, particularly in drug-resistant cancer models.
Main Methods:
- Assessed brostallicin's cytotoxicity in melphalan-resistant L1210 murine leukemia cells and GSH-depleted A2780 human ovarian carcinoma cells.
- Generated and utilized A2780 and MCF-7 cancer cell lines with varying GST-pi expression levels via cDNA transfection.
- Evaluated brostallicin's antitumor activity in vivo using xenografts of GST-pi-transfected A2780 cells in nude mice.
- Investigated brostallicin's interaction with DNA in the presence and absence of GSH, and its metabolism by human recombinant GST isoenzymes.
Main Results:
- Brostallicin demonstrated significantly higher cytotoxicity in melphalan-resistant cells with elevated GSH levels.
- GSH depletion reduced brostallicin's cytotoxic and proapoptotic effects.
- Increased GST-pi expression in cancer cells led to a dose-dependent increase in brostallicin's cytotoxicity (2-5.8 fold).
- In vivo studies showed enhanced antitumor activity of brostallicin in tumors overexpressing GST-pi without increased toxicity.
- Brostallicin interacts with DNA minor grooves and undergoes GSH-dependent DNA nicking; metabolism is faster with GST mu-1-1 and pi-1 isoenzymes.
Conclusions:
- Glutathione S-transferase pi (GST-pi) plays a crucial role in mediating brostallicin's cytotoxic and antitumor effects.
- The alpha-bromoacrylamide moiety of brostallicin likely undergoes intracellular reaction with nucleophiles like GSH, potentially involving GST enzymes.
- Brostallicin's efficacy is enhanced in tumors with higher GST-pi expression, indicating its potential as a targeted therapy for specific cancer types.