title: New insight into p-glycoprotein as a drug target.
abstract: Multidrug resistance (MDR) of cancer tissue is a phenomenon in which cancer cells exhibit reduced sensitivity to a large group of unrelated drugs with different mechanisms of pharmacological activity. Mechanisms that reduce cell sensitivity to damage induced by a variety of chemicals were found to be caused by diverse, albeit well-defined, phenotypic alterations. The molecular basis of MDR commonly involves overexpression of the plasma membrane drug efflux pump - P-glycoprotein (P-gp). This glycoprotein is an ABCB1 member of the ABC transporter family. Cells that develop MDR of this type express massive amounts of P-gp that can induce a drug resistance of more than 100 times higher than normal cells to several drugs, which are substrates of P-gp. Expression of P-gp could be inherent to cancer cells with regard to the specialized tissues from which the cells originated. This is often designated as intrinsic Pgp- mediated MDR. However, overexpression of P-gp may be induced by selection and/or adaptation of cells during exposure to anticancer drugs; this particular example is known as acquired P-gp-mediated MDR. Drugs that are potential inducers of P-gp are often substrates of this transporter. However, several substances that have been proven to not be transportable by P-gp (such as cisplatin or alltrans retinoic acid) could induce minor improvements in P-gp overexpression. It is generally accepted that the drug efflux activity of Pgp is a major cause of reduced cell sensitivity to several compounds. However, P-gp may have side effects that are independent of its drug efflux activity. Several authors have described a direct influence of P-gp on the function of proteins involved in regulatory pathways, including apoptotic progression (such as p53, caspase-3 and Pokemon). Moreover, alterations of cell regulatory pathways, including protein expression, glycosylation and phosphorylation, have been demonstrated in cells overexpressing P-gp, which may consequently induce changes in cell sensitivity to substances that are not P-gp substrates or modulators. We recently reported that P-gppositive L1210 cells exhibit reduced sensitivity to cisplatin, concanavalin A, thapsigargin and tunicamycin. Thus, P-gp-mediated MDR represents a more complex process than was expected, and the unintended effects of P-gp overexpression should be considered when describing this phenotype. The present review aims to provide the most current informations about P-gp-mediated MDR while paying particular attention to the possible dual function of this protein as a drug efflux pump and a regulatory protein that influences diverse cell processes. From a clinical standpoint, overexpression of P-gp in cancer cells represents a real obstacle to effective chemotherapy for malignant diseases. Therefore, this protein should be considered as a viable target for pharmaceutical design.
authors.affiliation: Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Vlárska 5, 83334 Bratislava, Slovak Republic. breier@up.upsav.sk
authors.forename: Albert
authors.initials: A
authors.lastname: Breier
authors.forename: Lenka
authors.initials: L
authors.lastname: Gibalova
authors.forename: Mario
authors.initials: M
authors.lastname: Seres
authors.forename: Miroslav
authors.initials: M
authors.lastname: Barancik
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Sulova
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000378:metabolism; D017209:Apoptosis; D019008:Drug Resistance, Neoplasm; D006031:Glycosylation; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011494:Protein Kinases / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D011494:Protein Kinases