P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype.
P-glycoprotein (Pgp) expression is an independent prognostic factor for response to remission-induction chemotherapy in acute myeloblastic leukaemia, particularly in the elderly. There are several potential agents for modulating Pgp-mediated multi-drug resistance, such as cyclosporin A and PSC833, which are currently being evaluated in clinical trials. An alternative therapeutic strategy is to increase the use of drugs which are unaffected by Pgp. However, in this review, we explain why this may be more difficult than it appears. Evidence from in vitro studies of primary AML blasts supports the commonly held supposition that chemoresistance may be linked to apoptosis-resistance. We have found that Pgp has a drug-independent role in the inhibition of in vitro apoptosis in AML blasts. Modulation of cytokine efflux, signalling lipids and intracellular pH have all been suggested as ways by which Pgp may affect cellular resistance to apoptosis; these are discussed in this review. For a chemosensitising agent to be successful, it may be more important for it to enhance apoptosis than to increase drug uptake.
Pallis
Monica
M
Academic Haematology, Nottingham City Hospital, Nottingham, UK. monica.pallis@nottingham.ac.uk
Turzanski
Julie
J
Higashi
Yutaro
Y
Russell
Nigel
N
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000208:Acute Disease; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000502:physiology; D002648:Child; D016572:Cyclosporine / Q000494:pharmacology; D003524:Cyclosporins / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007951:Leukemia, Myeloid / Q000378:metabolism / Q000473:pathology*; D008148:Lovastatin / Q000494:pharmacology; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010087:Oxides / Q000494:pharmacology; D010641:Phenotype; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D016032:Randomized Controlled Trials as Topic; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001152:Arsenicals; D002518:Ceramides; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D010087:Oxides; D016572:Cyclosporine; D008148:Lovastatin; D011493:Protein Kinase C; C070272:valspodar; D000077237:Arsenic Trioxide