VULNERABILITY OF MULTIDRUG-RESISTANT TUMOR-CELLS TO THE AROMATIC FATTY-ACIDS PHENYLACETATE AND PHENYLBUTYRATE

Cytotoxic chemotherapies often give rise to multidrug resistance, whic h remains a major problem in cancer management, In pursuit of alternat ive treatments for chemoresistant tumor cells, we tested the response of multi-drug-resistant (MDR) tumor cell lines to the aromatic fatty a cids phenylacetate (PA) and phenylbutyrate (PB), two differentiation i nducers currently in clinical trials, Both compounds induced cytostasi s and maturation of multidrug-resistant breast, ovarian, and colon car cinoma cells with no significant effect on cell viability, In contrast to their poor response to doxorubicin, the MDR cells were generally m ore sensitive to growth arrest by PA and PB than their parental counte rparts. The aromatic fatty acids, like the differentiation-inducing al iphatic fatty acid butyrate, up-regulated mdr-1 gene expression. Howev er, while butyrate increased multidrug resistance, PA and PB potentiat ed 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 peroxi dase, glutathione reductase, and glutathione S-transferase, the antiox idant enzymes implicated in cell resistance to free radical-based ther apies, Taken together, our in vitro data indicate that PA and PB, diff erentiation inducers of the aromatic fatty acid class, may provide an alternative approach to the treatment of MDR tumors.