Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate

Cytotoxic chemotherapies often give rise to multidrug resistance, which remains a major problem in cancer management. In pursuit of alternative treatments for chemoresistant tumor cells, we tested the response of multidrug-resistant (MDR) tumor cell lines to the aromatic fatty acids phenylacetate (P...

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Bibliographic Details
Published in:Clinical cancer research 1996-05, Vol.2 (5), p.865-872
Main Authors: SHACK, S, MILLER, A, LIU, L, PRASANNA, P, THIBAULT, A, SAMID, D
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents - pharmacology
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
Biological and medical sciences
Catalase - metabolism
Cell Differentiation - drug effects
Cell Division - drug effects
Doxorubicin - pharmacology
Drug Resistance, Multiple
Drug Resistance, Neoplasm
General aspects
Glutathione - metabolism
Humans
Medical sciences
Pharmacology. Drug treatments
Phenylacetates - pharmacology
Phenylbutyrates - pharmacology
Tumor Cells, Cultured
Verapamil - pharmacology
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Summary:Cytotoxic chemotherapies often give rise to multidrug resistance, which remains a major problem in cancer management. In pursuit of alternative treatments for chemoresistant tumor cells, we tested the response of multidrug-resistant (MDR) tumor cell lines to the aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB), two differentiation inducers currently in clinical trials. Both compounds induced cytostasis and maturation of multidrug-resistant breast, ovarian, and colon carcinoma cells with no significant effect on cell viability. In contrast to their poor response to doxorubicin, the MDR cells were generally more sensitive to growth arrest by PA and PB than their parental counterparts. The aromatic fatty acids, like the differentiation-inducing aliphatic fatty acid butyrate, up-regulated mdr-1 gene expression. However, while butyrate increased multidrug resistance, PA and PB potentiated the cytotoxic activity of doxorubicin against MDR cells. The latter was associated with time-dependent declines in glutathione levels and in the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, the antioxidant enzymes implicated in cell resistance to free radical-based therapies. Taken together, our in vitro data indicate that PA and PB, differentiation inducers of the aromatic fatty acid class, may provide an alternative approach to the treatment of MDR tumors.
ISSN:1078-0432
1557-3265