Ronghua Liu

University of Guelph

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Frances J. Sharom

University of Guelph

Peihua Lu

University of Guelph

Tiannan Ji

Chinese PLA General Hospital

János Seprődi

Semmelweis University

Jack‐Michel Renoir

Institut Gustave Roussy

Curtis Hose

Frederick National Laboratory for Cancer Research

Marianna Müller

Innate Pharma (France)

Attilio Di Pietro

Université Claude Bernard Lyon 1

Z Wang

H. Grunicke

Universität Innsbruck

Cooperative Institutions

Centre National de la Recherche Scientifique

Hungarian Academy of Sciences

University of Guelph

Semmelweis University

National Cancer Institute

Eötvös Loránd University

Inserm

Science Applications International Corporation (United States)

National Institutes of Health

Université Claude Bernard Lyon 1

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MDR1 causes resistance to the antitumour drug miltefosine

British Journal of Cancer (2001)

Maria Rybczyńska Ronghua Liu Pei Hsuan Lu Frances J. Sharom Emmanuelle Steinfels

Miltefosine (hexadecylphosphocholine) is used for topical treatment of breast cancers. It has been shown previously that a high percentage of breast carcinomas express MDR1 or MRP. We investigated the sensitivity of MDR1-expressing cells to treatment with miltefosine. We show that cells overexpressing MDR1 (NCI/ADR-RES, KB-8-5, KB-C1, CCRF/VCR1000, CCRF/ADR5000) were less sensitive to miltefosine treatment when compared to the sensitive parental cell lines. HeLa cells transfected with MDR1 exhibited resistance to the compound, indicating that expression of this gene is sufficient to reduce the sensitivity to miltefosine. The resistance of MDR1-expressing cells to miltefosine was less pronounced than that to adriamycin or vinblastine. Expression of MDR2 did not correlate with the resistance to miltefosine. As shown by a fluorescence quenching assay using MIANS-labelled P-glycoprotein (PGP), miltefosine bound to PGP with a Kd of approximately 7 μM and inhibited PGP-ATPase activity with an IC50 of approximately 35 μM. Verapamil was not able to reverse the resistance to miltefosine. Concentrations of miltefosine up to approximately 60 μM stimulated, whereas higher concentrations inhibited the transport of [3H]-colchicine with an IC50 of approximately 297 μM. Binding studies indicated that miltefosine seems to interact with the transmembrane domain and not the cytosolic nucleotide-binding domain of PGP. These data indicate that expression of MDR1 may reduce the response to miltefosine in patients and that this compound interacts with PGP in a manner different from a number of other substrates. © 2001 Cancer Research Campaign

Miltefosine

P-glycoprotein

IC50

10.1054/bjoc.2001.1776

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Citations (37)

β‐Amyloid efflux mediated by p‐glycoprotein

Journal of Neurochemistry (2001)

Fred C. Lam Ronghua Liu Peihua Lu Adam B. Shapiro Jack‐Michel Renoir

A large body of evidence suggests that an increase in the brain β‐amyloid (Aβ) burden contributes to the etiology of Alzheimer's disease (AD). Much is now known about the intracellular processes regulating the production of Aβ, however, less is known regarding its secretion from cells. We now report that p‐glycoprotein (p‐gp), an ATP‐binding cassette (ABC) transporter, is an Aβ efflux pump. Pharmacological blockade of p‐gp rapidly decrease extracellular levels of Aβ secretion. In vitro binding studies showed that addition of synthetic human Aβ1–40 and Aβ1–42 peptides to hamster mdr1‐enriched vesicles labeled with the fluorophore MIANS resulted in saturable quenching, suggesting that both peptides interact directly with the transporter. Finally, we were able to directly measure transport of Aβ peptides across the plasma membranes of p‐gp enriched vesicles, and showed that this phenomenon was both ATP‐ and p‐gp‐dependent. Taken together, our study suggests a novel mechanism of Aβ detachment from cellular membranes, and represents an obvious route towards identification of such a mechanism in the brain.

P-glycoprotein

Efflux

Amyloid (mycology)

10.1046/j.1471-4159.2001.00113.x

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Citations (368)

Cytoplasmic p21 is responsible for paclitaxel resistance in ovarian cancer A2780 cells.

PubMed (2015)

Xuemei Xia Tiannan Ji Ronghua Liu Yuanchi Weng Fang Yu

P21 which bound to cyclin-dependent kinase complexes was originally described as a suppressor of cancer cell prolifera- tion, while many recent studies have shown p21, when accumulated in the cell cytoplasm, could promote tumor progression. This study was conducted to investigate the role of p21 in the paclitaxel (PTX) resistance of ovarian cancer.Regulation of cytoplasmic p21 was performed through transfection of Akt2 constitutively active vector, Akt2 shRNA and p21 siRNA in the ovar- ian cancer cell line A2780. Akt2, p-Akt, and p21 expression were examined by Western blot and cell apoptosis rates were assessed by flow cytometry after treatment with PTX.Induction of p21 translocation into the cytoplasm via constitutively active Akt2 transfection in A2780 enhanced the resistance to PTX, while inhibition of p21 translocation into the cytoplasm via Akt2 shRNA trans- fection in A2780 cells significantly increased PTX treatment sensitivity. Furthermore, knockdown of cytoplasmic p21 by direct p21 siRNA transfection in Akt2 overexpressed A2780 cells notably increased PTX-induced apoptosis.Cytoplasmic p21 may represent a potential therapeutic target for ovarian tumors that are resistant to PTX treatment.

AKT2

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Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells

Biochemical Pharmacology (1999)

Frances J. Sharom Xiaohong Yu Peihua Lu Ronghua Liu Joseph W.K. Chu

P-glycoprotein

Rhodamine 123

Calcein

Daunorubicin

10.1016/s0006-2952(99)00139-2