MTR-04DOWN-REGULATION OF MDR1 BY DKK3 ATTENUATES CHEMORESISTANCE TO TEMOZOLOMIDE, AND POTENTIATES ITS ANTI-TUMOR EFFECTS

BACKGROUND AND PURPOSE: Some patients with glioblastoma multiforme (GBM) do not respond to temozolomide (TMZ), a target for the multidrug resistance transporter MDR1/ABCB1. The genotype of the MDR1 exon12 C1236T single nucleotide polymorphism is reported as a predictive factor of the efficacy of TMZ in GBM. The expression of MDR1 is inhibited via JNK activation. Elsewhere we reported that the overexpression of DKK3 exerted anti-tumor effects in association with JNK activation. However, the regulation of MDR1 by DKK3 remains to be elucidated. We tested our hypothesis that the DKK3-induced activation of JNK down-regulates MDR1, thereby attenuating the chemoresistance of GBM to TMZ. METHODS: We compared the results of treating GBM cells, i.e. U87MG- and primary TGB105 cells with TMZ alone and with TMZ plus Ad-DKK3. RESULTS: The viability of U87MG- and TGB105 cells was not significantly affected by TMZ or Ad-DKK3 alone. However, in combination, they augmented cell death. In a GBM xenograft mice model, treatment with TMZ or Ad-DKK3 exerted anti-tumor effects that were enhanced by their combined administration without affecting the animals' body weight. The increased expression of MDR1 in GBM cells was reduced by Ad-DKK3. The decrease in MDR1 expression elicited by Ad-DKK3 was inversely correlated with the expression of p-JNK, c-JUN, and p-c-JUN but not of JNK, which was eliminated by the JNK inhibitor SP600125. Our findings suggest that the Ad-DKK3-induced activation of JNK downregulates MDR1, thereby attenuating the chemoresistance of GBM cells to TMZ and enhancing its anti-tumor effects. CONCLUSION: Ad-DKK3 may not only exert anti-tumor effects but also serve as an adjuvant therapy for GBM. Chemotherapy targeting JNK may be a promising treatment option.