Malignant peripheral nerve sheath tumors (
MPNST) develop in approximately 10% of
neurofibromatosis type-1 patients and are a major contributing factor to neurofibromatosis-1 patient mortality and morbidity. MPNSTs are multidrug resistant, and thus long-term patient survival rates are poor after standard
doxorubicin or multiagent
chemotherapies. We show that the
hyaluronan receptor CD44 forms complexes with multidrug transporters, BCRP (ABCG2) and
P-glycoprotein (ABCB1), in the plasma membrane of human
MPNST cells. Small
hyaluronan oligosaccharides antagonize hyaluronan-CD44-mediated processes and inhibit
hyaluronan production. Treatment of
MPNST cells with the
hyaluronan oligomers causes disassembly of CD44-transporter complexes and induces internalization of CD44, BCRP, and
P-glycoprotein. Consequently, the oligomers suppress
drug transporter activity and increase sensitivity to
doxorubicin treatment in culture. In vivo, systemic administration of
hyaluronan oligomers inhibits growth of
MPNST xenografts. Moreover, the oligomers and
doxorubicin act synergistically in vivo, in that combined suboptimal doses induce
tumor regression to a greater extent than the additive effects of each agent alone. These findings indicate that constitutive hyaluronan-CD44 interactions contribute to
drug transporter localization and function at the plasma membrane, and that attenuating hyaluronan-CD44 interactions sensitizes MPNSTs to
doxorubicin in vitro and in vivo. These results also show the potential efficacy of
hyaluronan oligomers, which are nontoxic and nonimmunogenic, as an adjuvant for
chemotherapy in
MPNST patients.