A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia

Abstract

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) funcoxidative phosphorylation, such as cyanide and azide, thereby tion we showed previously that there was a discordance depleting cellular ATP and inhibiting all energy-dependent between the ability of acute myeloid leukemic (AML) blast cells processes. This strategy was used originally to demonstrate the to accumulate daunorubicin and P-gp antigen expression (Xie ATP dependence of P-gp, 7 and more recently has been shown et al, Leukemia 1995; 9: 1882-1887). This discordance suggests to inhibit drug efflux via MRP. 8,9 We now report that it also that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study appears to show the presence of high levels of non-P-gp The following human cell lines were used to study energy- AML lines OCI/AML 1-5, established in this Institute. In

Exosomal evasion of humoral immunotherapy in aggressive B-cell lymphoma modulated by ATP-binding cassette transporter A3

“…The classical concept of ABC transporter-mediated drug resistance describes direct transport of a cytotoxic substrate (41,42). Our observations document clearly that ABC transporter function may impact on cell structure and metabolism and that such changes may entail a significant mechanism of drug resistance.…”

Double-Edged Sword of Chemosensitizer: Increase of Multidrug Resistance Protein (MRP) in Leukemic Cells by an MRP Inhibitor Probenecid

“…In addition to their clinical use, chemosensitizers have been used in a strategy to determine novel resistant mechanisms as the multidrug resistance phenotypes resulting from the decreased accumulation of drugs cannot be completely explained with P-glycoprotein and MRP. This strategy was motivated by a recent report showing that AML cells contain a novel form of an energy-dependent drug efflux mechanism, which has not yet been identified (32). Therefore, selection for resistance to doxorubicin in the presence of an MRP inhibitor may be attempted with the anticipation of expressing any novel resistance gene(s) except an MRP and P-glycoprotein.…”

Overexpression of lung‐resistance protein and increased P‐glycoprotein function in acute myeloid leukaemia cells predict a poor response to chemotherapy and reduced patient survival

“…This unhinging of Pgp function from expression arose primarily because of Pgp-positive samples with poor or no efflux and, to a lesser extent, from samples with elevated efflux which were Pgp negative. The former could possibly be due to Pgp mutations (Stein et al, 1994) or post-translational modification of Pgp (Bailly et al, 1995), whereas the latter may represent a recently described novel drug transport pump which is sensitive to cyclosporin A (Hedley et al, 1997). Increasing Pgp function was significantly associated with higher levels of CD34 expression and secondary AML.…”