P-Glycoprotein - Implications of Metabolism of Neoplastic Cells and Cancer Therapy

Abstract

Multidrug resistance (MDR) of neoplastic tissues is a major obstacle in cancer chemotherapy. The predominant cause of MDR is the overexpression and drug transport activity of P-glycoprotein (P-gp, a product of the MDR gene). P-gp is a member of the ATP binding cassette (ABC) transporters family, with broad substrate specificity for several substances including anticancer drugs, linear and cyclic peptides, inhibitors of HIV protease, and several other substances. The development of P-gp-mediated MDR is often associated with several changes in cell structure and metabolism of resistant cells. In the present review are discussed the relations between glucosylceramide synthase activity, Pregnane X receptor and development of P-gp mediated MDR phenotype. Attention is also focused on the changes in protein kinase systems (mitogen-activated protein kinases, protein kinase C, Akt kinase) that are associated with the development of MDR phenotype and to the possible role of these kinase cascades in modulation of P-gp expression and function. The overexpression of P-gp may be associated with changes in metabolism of sugars as well as energy production. Structural and ultrastructural characteristics of multidrug resistant cells expressing P-gp are typical for cells engaged in a metabolically demanding process of protein synthesis and transport. P-gp mediated MDR phenotype is often also associated with alterations in cytoskeletal elements, microtubule and mitochondria distribution, Golgi apparatus, chromatin texture, vacuoles and caveolae formation. The current review also aims at bringing some state-of-the-art information on interactions of P-glycoprotein with various substances. To capture and transport the numerous unrelated substances, P-gp should contain site(s) able to bind compounds with a molecular weight of several hundreds and comprising hydrophobic and/or base regions that are protonated under physiological conditions. Drug binding sites that are able to recognize substances with different chemical structures may have a complex architecture in which different parts are responsible for binding of different drugs. For P-gp substrates and inhibitors, a pharmacophore-based model has been described. The pharmacophores have to contain parts with hydrophobic and aromatic characteristics and functional groups that can act as hydrogen-bond donors and/or acceptors. Several drugs are known to be P-glycoprotein antagonizing agents. They represent a large group of structurally unrelated substances that can act via direct interaction with P-gp and inhibition of its transport activity, or via possible modulation of processes (such as phosphorylation) regulating P-gp transport activity. Effects of MDR reversal agents on the P-gp expression have also been reported. Function and expression of P-gp can be affected indirectly as well, e.g. through cyclooxygenase-2 or carbonic anhydrase-IX expression and effects.

Multidrug resistance gene 1 C1236T polymorphism and susceptibility to leukemia: A meta-analysis

“…Multiple mutations in the MDR1 gene have been demonstrated in previous studies and ≥50 SNPs have been identified in all 28 exons of the MDR1 gene (11,12,18). The most frequent SNP non-synonymous triallelic G2677T/A in exon 21 results in amino acid substitution from the lipophilic residue Ala to the hydrophilic residue Ser or Thr, and this polymorphism was significantly associated with an increased or decreased plasma concentration of P-gp substrates (28).…”

The expression of P-gp in leukemia cells is associated with cross-resistance to protein N-glycosylation inhibitor tunicamycin

“…This indicated that induction of P-gp in neoplastic cells is associated with alterations in transglycosylation reactions, including glycosylation of proteins (reviewed in Breier et al 2005). Such alterations of protein glycosylation are responsible for changes in glycoprotein contents that can be detected by lectins in isolated fractions of intracellular proteins (Fiala et al 2003) or in surface proteins detected on whole cells Bubencikova et al 2012).…”

“…This leads to differences in protein glycosylation between P-gp-positive and -negative cells (reviewed in Breier et al 2005Breier et al , 2013. Consistent with this, overexpression of P-gp in leukemia cells leads to large-scale remodeling of the cell surface glycosides that can be detected by several lectins (Molnar et al 2009;Sulova et al 2009Sulova et al , 2010Bubencikova et al 2012).…”

Increased P-glycoprotein expression in mitochondria is related to acquired multidrug resistance in human hepatoma cells depleted of mitochondrial DNA

“…P-gp functions as a pump and extrudes anticancer drugs and other compounds from the cells (14,36,37). MDR can be intrinsic or acquired during chemotherapy, and is characterized by the fact that cells show cross-resistance to a variety of structurally and functionally unrelated drugs (38). The overexpression of P-gp and MRPs, such as MRP1 and MRP2, are the main causes of pump-related multidrug resistance in different cancer cells (14,15).…”