Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline

Kupsáková, Ivana; Rybar, A.; Dočolomanský, Peter; Drobná, Zuzana; Stein, Ulf; Walther, Wolfgang; Barančı́k, Miroslav; Breier, Albert

doi:10.1016/j.ejps.2003.10.019

Cited by 26 publications

(20 citation statements)

References 24 publications

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“…Pgp inhibitory agents (in literature often termed overcoming agents or chemosensitizers) are a group of diverse, yet well characterized substances including calcium and sodium channel blockers, calmodulin antagonists, local anaesthetics, steroidal and structurally related compounds, immunosupressive agents, protein kinase inhibitors, flavonoids, detergents, indole alkaloids, macrolide compounds, methylxanthines derived from pentoxifylline, etc. [12,19,20,46,63,119,121,[146][147][148][149][150][151][152][153]. As reversers of P-gp-mediated MDR, these substances may act by different mechanisms: (i) direct interaction with the P-gp molecule at its ATP-binding site, drug binding sites or other loci that are critical for its transport function; (ii) modulation of expression of mdr genes encoding P-gp; (iii) modulation of P-gp activity by inhibition of its post-translational modifications (phosphorylation or glycosylation); (iv) indirect modulation of P-gp transport activities by other systems.…”

Section: Reversal Of P-glycoprotein-mediated Multidrug Resistancementioning

confidence: 99%

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

Breier¹,

Barančı́k²,

Sulová³

et al. 2005

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108

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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.

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Section: Reversal Of P-glycoprotein-mediated Multidrug Resistancementioning

confidence: 99%

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

Breier¹,

Barančı́k²,

Sulová³

et al. 2005

CCDT

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108

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“…The IC 50 values were obtained by fitting dose-response curves according to the following exponential decay equation (Eq. 1) using non-linear regression (Kupsakova et al 2004):…”

Section: Effect Of Vcr Mitoxantrone (Mtx) Doxorubicin (Dox) and Cismentioning

confidence: 99%

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

Pavlíková

Šereš²,

Imrichova³

et al. 2016

gpb

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Abstract. In P-gp-positive cell variants obtained from L1210 cells either by selection with vincristine (L1210/R) or by transfection with the human gene encoding P-gp (L1210/T), we have previously described cross-resistance to tunicamycin (TNM), a protein N-glycosylation inhibitor. Here we studied whether this cross-resistance also underlies P-gp-positive variants of human acute myeloid leukemia cells (AML) derived from SKM-1 and MOLM-13 cells (SKM-1/VCR, SKM-1/LEN, MOLM-13/ VCR) by selection with vincristine (VCR) and lenalidomide (LEN). While SKM-1/LEN cells were P-gp positive, no P-gp was detected in MOLM-13/LEN cells. P-gp-positive cells could be repeatedly passaged in medium containing TNM. In contrast, more than 90% of P-gp-negative cells were entering and progressing through cell death mechanisms after the third passage in medium containing TNM. Combined apoptosis/necrosis cell death was detected in L1210 cells after exposure to TNM. Passaging of P-gp-negative AML cells in medium containing TNM induced preferentially apoptosis. Damage to P-gp-negative cells induced with TNM was associated with arrest in the G1 phase of the cell cycle. P-gp-positive leukemia cells differed from P-gp-negative cells in the composition of plasma membrane glycoproteins, which we monitored with the aid of different lectins. The application of TNM to cells induced additional changes in membrane-linked glycosides.

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“…Dose-response curves were fitted according to an exponential decay equation (Eq. 1) by non-linear regression as previously described (Kupsakova et al 2004;Sulova et al 2005):…”

Section: Cells (5 × 10mentioning

confidence: 99%

Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript

Imrichova¹,

Coculova²,

Messingerová³

et al. 2014

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Abstract.Nestin is a class 6 filament protein typically expressed in neural stem/progenitor cells. However, nestin expression has been observed in other tissues during mammalian embryogenesis. In human neural stem/progenitor cells, coexpression of nestin and P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family) was detected. P-gp-mediated drug efflux is the most common molecular cause of multidrug resistance in neoplastic cells. Nestin expression has also been detected in various human solid tumours as well as in the corresponding established cell lines. Interestingly, expression of nestin in different leukemia cells has been recently reported. Here, we show that expression of P-gp is associated with the simultaneous expression of nestin in acute myeloid leukemia cell lines (MOLM-13 and SKM-1) under the selective pressure of vincristine, a substance that may induce P-gp expression in neoplastic cells.

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Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline

Cited by 26 publications

References 24 publications

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

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

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

Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript

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Reversal of P-glycoprotein mediated vincristine resistance of L1210/VCR cells by analogues of pentoxifylline

Cited by 26 publications

References 24 publications

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

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

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

Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript

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Vincristine-induced expression of P-glycoprotein in MOLM-13 and SKM-1 acute myeloid leukemia cell lines is associated with coexpression of nestin transcript