Overexpression of Lung Resistance-Related Protein and P-Glycoprotein and Response to Induction Chemotherapy in Acute Myelogenous Leukemia

Abstract

Lung resistance-related protein (LRP) and P-glycoprotein (P-gp) are associated with multidrug resistance. P-gp overexpression reduces intracellular anticancer drug concentrations and is correlated with low remission rates. However, whether the presence of LRP influences the response to induction chemotherapy remains controversial. Therefore, we investigated the relationship of LRP and P-gp overexpression with the response to induction chemotherapy. Univariate analysis revealed that there was a significant difference between complete remission rates for acute myelogenous leukemia patients depending on their blast cell expressions, between LRP positive versus negative, P-gp positive versus negative, and LRP/P-gp double positive versus other groups. Crude odds ratios (ORs) for complete remission were 0.390, 0.360, and 0.307 for LRP positive, for P-gp positive, and LRP/P-gp double positive patients, respectively. After controlling the confounding variables by stepwise multivariate logistical regression analysis, the presence of LRP/P-gp double positivity and P-gp positivity were found to be independent prognostic factors; adjusted ORs were 0.233 and 0.393, respectively. Furthermore, the monoclonal antibody against LRP significantly increased daunorubicin acumulation (P=0.004) in the nuclei of leukemic blast cells with LRP positivity in more than 10% of the cells. An LRP reversing agent, PAK-104P, was found to increase the daunorubicin content with marginal significance (P=0.060). The present results suggest that not only the presence of P-gp, but also LRP in leukemic blast cells is a risk factor for resistance to induction chemotherapy. Inhibiting LRP function, similar to the inhibition of P-gp function, will be necessary to improve the effectiveness of induction chemotherapy.