Effects of Ion Gradients on H<sup>+</sup> Transport Mediated by Human MDR 1 Protein

Santai, Catherine T.; Fritz, Friederike; Roepe, Paul D.

doi:10.1021/bi981930m

Cited by 9 publications

(7 citation statements)

References 21 publications

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“…of cell proliferation is commonly reported (15). A similar moderate decrease in the growth rate has been also observed in cells transfected with the mdr-1 gene (16). We hypothesize that intercellular transfer of P-gp may slow the growth of AqMDR cells and stabilize the relative proportions of intrinsically resistant, AqMDR cells and sensitive cells in coculture.…”

Section: P-gp Transfer Is Unstable and Does Not Occur Through Small Msupporting

confidence: 77%

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Levchenko

Mehta

Niu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

172

156

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The overexpression of P-glycoprotein (P-gp) causes resistance to chemotherapy in many tumor types. Here, we report intercellular transfer of functional P-gp from P-gp-positive to P-gp-negative cells in vitro and in vivo. The expression of acquired P-gp is transient in isolated cells but persists in the presence of P-gppositive cells or under the selective pressure of colchicine. The intercellular transfer of functional P-gp occurs between different tumor cell types and results in increased drug resistance both in vitro and in vivo. Most importantly, the acquired resistance permits tumor cells to survive potentially toxic drug concentrations long enough to develop intrinsic P-gp-mediated resistance. P-gp transfer also occurs to putative components of tumor stroma, such as fibroblasts, raising the possibility that multidrug resistance could be conferred by resistant tumor cells to critical stromal elements within the tumor mass. This is the first report, to our knowledge, that a protein transferred between cells retains its function and confers a complex biologic property upon the recipient cell. These findings have important implications for proteomic analyses in tumor samples and resistance to cancer therapy.cell-cell communication ͉ multidrug resistance phenotype C ell-cell communication is an inherent feature of all life forms from bacteria to humans. A frequent result of cell-cell communication is collective population behavior that can potentially lead to complex phenotypes not observed in separate individual cells, e.g., in development or tumor formation (see, for example, ref.

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Section: P-gp Transfer Is Unstable and Does Not Occur Through Small Msupporting

confidence: 77%

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Levchenko

Mehta

Niu

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

172

156

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“…Interestingly, LmrA, a Lactococcus lactis homolog of human MDR1, has been shown to be a symporter of proton and ethidium [85]. Although human MDR1 has also been suggested to function as a proton pump [86], measurable proton transport activity could not be detected [87].…”

Section: B Protonation States Of Abc Transportersmentioning

confidence: 99%

Potential Application of Network Descriptions for Understanding Conformational Changes and Protonation States of ABC Transporters

Hegedüs¹,

Gyimesi²,

Gáspár³

et al. 2013

CPD

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Abstract:The ABC (ATP Binding Cassette) transporter protein superfamily comprises a large number of ubiquitous and functionally versatile proteins conserved from archaea to humans. ABC transporters have a key role in many human diseases and also in the development of multidrug resistance in cancer and in parasites. Although a dramatic progress has been achieved in ABC protein studies in the last decades, we are still far from a detailed understanding of their molecular functions. Several aspects of pharmacological ABC transporter targeting also remain unclear. Here we summarize the conformational and protonation changes of ABC transporters and the potential use of this information in pharmacological design. Network related methods, which recently became useful tools to describe protein structure and dynamics, have not been applied to study allosteric coupling in ABC proteins as yet. A detailed description of the strengths and limitations of these methods is given, and their potential use in describing ABC transporter dynamics is outlined. Finally, we highlight possible future aspects of pharmacological utilization of network methods and outline the future trends of this exciting field.

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“…This process is presumably responsible for altered pH cyt and ∆Ψ in MDR cells, however, much remains to be elucidated with regard to the thermodynamics and regulation of this process (see [31,44,45]). …”

Section: A Different Hypothesis: Altered Partitioningmentioning

confidence: 99%

“…The overall point is that physiological effects of hu MDR 1 overexpression (such as changes in steady state pH and membrane potential, and other consequences of alterations in normal ion transport) have several effects on different pharmacologically relevant pathways. Changing biophysical parameters that perturb distribution of drugs by altering the electrochemical driving forces for their passive diffusion is but one facet of the overall emerging Additional studies involving expression of hu MDR 1 in a yeast strain partially defective in K + uptake were recently published by Roepe and colleagues [44,45]. Key conclusions from this work included that the well -known resistance of yeast strains expressing MDR protein to the K + ionophore valinomycin was highly dependent on the external concentration of K + , which would be consistent with a function for hu MDR 1 that included modulating membrane potential.…”

Section: New Data With Yeast or Bacteria Expressing Hu Mdrmentioning

confidence: 99%

What is the Precise Role of Human MDR 1 Protein in Chemotherapeutic Drug Resistance

Roepe¹

2000

CPD

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Elucidating the molecular function of hu MDR 1 protein (also called P-glycoprotein or P-gp 1) and the precise role this protein plays in clinically relevant tumor drug resistance remains a perplexing problem. Hundreds of reports over the past decades summarize a dizzying array of observations relevant to hu MDR 1 protein function. A dominant model in the MDR literature that is used to explain many observations is the well known "drug pump" model first suggested by Keld Dano in 1973 [1]. Although this model has proved useful in conceptualizing additional experiments, it violates fundamental laws of biology and chemistry and in well over a decade of intense effort, active outward drug pumping via hu MDR 1 protein has still never been unequivocally measured. Also, in recent years it has become clear that the drug pump model cannot explain several important phenomena that are highly relevant to the cancer clinic. Thus, other models have also proved increasingly popular. One is the altered partitioning model, which does not violate fundamental laws, is consistent with the vast majority of available data, and has important predictive ability. This newer model has several novel facets that are relevant for cancer pharmacology, and that help explain phenomena not explained by the drug pump model. The basic principle of this model is that MDR proteins do not directly transport drugs, but that their altered expression leads to altered regulation of ion transport or signal transduction that is critical for setting key biophysical parameters of the cell (e.g. compartmental pH and membrane potentials) that dictate relative passive diffusion of drugs as well as important signal transduction linked to the cytotoxic actions of these drugs. Along with debate over the molecular details of hu MDR 1 function, additional controversy surrounds the precise role of hu MDR 1 in the clinic. Many investigators now debate the significance of its function (regardless of precise mechanism) with regard to "real" drug resistance phenotypes exhibited in the clinic. I believe that thorough debate on the pros and cons of various molecular models for hu MDR 1 function will help to address confusion over the clinical relevance of hu MDR1. In the current atmosphere of disappointment over the relative success of clinical trials based in large part on the logic of the drug pump model, it is important that we not lose sight of critical points. Namely, hu MDR 1 protein remains an extremely important window in on the complex pathways that lead to induced chemotherapeutic drug resistance. Exploring the rationale behind newer models for hu MDR 1 function leads to key predictions that can be tested.

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Effects of Ion Gradients on H⁺ Transport Mediated by Human MDR 1 Protein

Cited by 9 publications

References 21 publications

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Potential Application of Network Descriptions for Understanding Conformational Changes and Protonation States of ABC Transporters

What is the Precise Role of Human MDR 1 Protein in Chemotherapeutic Drug Resistance

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Effects of Ion Gradients on H+ Transport Mediated by Human MDR 1 Protein

Cited by 9 publications

References 21 publications

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Intercellular transfer of P-glycoprotein mediates acquired multidrug resistance in tumor cells

Potential Application of Network Descriptions for Understanding Conformational Changes and Protonation States of ABC Transporters

What is the Precise Role of Human MDR 1 Protein in Chemotherapeutic Drug Resistance

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Effects of Ion Gradients on H⁺ Transport Mediated by Human MDR 1 Protein