Tyrosine and phenylalanine restriction sensitizes adriamycin-resistant P388 leukemia cells to adriamycin.

Abstract

Cancer chemotherapy frequently fails, because tumors develop multiple drug resistance (MDR). Pharmacological efforts to reverse this MDR phenotype and sensitize resistant tumor cells have utilized verapamil (VER) to inhibit p-glycoprotein function and buthionine sulfoximine (BSO) to inhibit glutathione synthesis. Our previous results indicate that restriction of two amino acids, tyrosine (Tyr) and phenylalanine (Phe), may potentially suppress the MDR phenotype. These results show that in vivo Tyr and Phe restriction improves the therapeutic response of a metastatic variant of B16-BL6 (BL6) murine melanoma to adriamycin (ADR) and B16 melanoma to levodopa methyl ester. We examine whether in vitro limitation of Tyr and Phe suppresses ADR resistance of BL6 cells and whether Tyr-Phe modulation of the MDR phenotype is applicable to other tumor types, particularly P388 murine leukemia. Mechanisms underlying Tyr-Phe modulation of ADR resistance are examined in the presence of VER and BSO, singly and in combination. Our results indicate that in vitro Tyr and Phe restriction has no effect on BL6 resistance to ADR. However, Tyr and Phe restriction does increase the sensitivity of ADR-resistant P388 cells to ADR without affecting drug efflux, ADR uptake, or glutathione levels. In addition, this enhanced ADR sensitivity of P388 cells is even more pronounced in the presence of BSO. Suppression of ADR resistance in P388-resistant cells by Tyr and Phe restriction indicates that Tyr- and Phe-mediated modulation of the MDR phenotype is possible and that Tyr and Phe restriction may be useful as a potential adjuvant to effective cancer chemotherapy.