Do P-glycoprotein and major vault protein (MVP/LRP) expression correlate with in vitro daunorubicin resistance in acute myeloid leukemia?

Two proteins that have been correlated with the occurrence of multidrug resistance in acute myeloid leukemia (AML) are P-glycoprotein (Pgp) and the major vault protein (Mvp/LRP). With the purpose of further quantifying the potential contributions of Pgp-mediated drug efflux and Mvp/LRP to drug resistance in AML we have investigated whether the transport function of Pgp and the expression of Mvp/LRP correlated with the accumulation of daunorubicin (DNR) and the in vitro resistance to DNR cytotoxicity (LC₅₀ by MTT assay) in AML cells. In de novo adult AML, the steady-state DNR accumulation (in pmol/10⁶ cells) correlated with Pgp activity or expression, whereas the LC₅₀ for DNR did not correlate with Pgp activity (measured as the modulation of rhodamine 123 or DNR accumulation by the Pgp inhibitor PSC833) or Pgp expression (measured by flow cytometry with the MRK-16 antibody). The contribution of MRP1 expression to a reduced DNR accumulation seems minor compared to Pgp. In addition, the modulation of the DNR LC₅₀ by PSC833 did not correlate with Pgp protein or activity. The steady-state DNR accumulation showed no correlation with the DNR LC₅₀. The Mvp/LRP expression (immunocytochemical staining) did neither correlate with DNR accumulation nor with the DNR LC₅₀. A significant negative correlation was seen between the Mvp/LRP immunocytochemical staining and Pgp activity, indicating that both markers define (partially) different populations. In conclusion, it is shown that Pgp function, but not Mvp/LRP or MRP1 expression correlate with a low steady-state DNR accumulation in de novo AML. The Pgp activity does, however, not predict the DNR sensitivity in AML measured as in vitro DNR LC₅₀ with an MTT-based assay. The reason for that seems to be that a low DNR accumulation may not be the most important factor in determining the LC₅₀. While the clinical usefulness of these drug resistance tests remains to be proven they do not seem to provide as yet a straightforward explanation for the major cause(s) of clinical chemotherapy failure.