Metal Complexes for Therapy and Diagnosis of Drug Resistance

Sharma, Vijay; Piwnica‐Worms, David

doi:10.1021/cr980429x

Cited by 116 publications

(96 citation statements)

References 143 publications

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“…In effect, Pgp indirectly modulates intracellular Rluc enzyme kinetics by regulating the transmembrane translocation and availability of substrate. This fundamentally differs from readouts obtained with fluorescent probes such as rhodamine 123 and Hoechst 33342 (34,35), BCECF-AM and SPQ (36), or activated fluorescent compounds such as calcein-AM (37) or radiotracer substrates (23,38,39) that interact with Pgp. These probes and their output signals are retained for significant times after exposure of the cells to the probes, or alternatively, the Pgp-mediated readout depends on washout kinetics over time.…”

Section: Discussionmentioning

confidence: 85%

Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine

Pichler

Prior

Piwnica‐Worms³

2004

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

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129

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Coelenterazine is widely distributed among marine organisms, producing bioluminescence by calcium-insensitive oxidation mediated by Renilla luciferase (Rluc) and calcium-dependent oxidation mediated by the photoprotein aequorin. Despite its abundance in nature and wide use of both proteins as reporters of gene expression and signal transduction, little is known about mechanisms of coelenterazine transport and cell permeation. Interestingly, coelenterazine analogues share structural and physiochemical properties of compounds transported by the multidrug resistance MDR1 P-glycoprotein (Pgp). Herein, we report that living cells stably transfected with a codon-humanized Rluc show coelenterazinemediated bioluminescence in a highly MDR1 Pgp-modulated manner. In Pgp-expressing Rluc cells, low baseline bioluminescence could be fully enhanced (reversed) to non-Pgp matched control levels with potent and selective Pgp inhibitors. Therefore, using coelenterazine and noninvasive bioluminescence imaging in vivo, we could directly monitor tumor-specific Pgp transport inhibition in living mice. While enabling molecular imaging and highthroughput screening of drug resistance pathways, these data also raise concern for the indiscriminate use of Rluc and aequorin as reporters in intact cells or transgenic animals, wherein Pgp-mediated alterations in coelenterazine permeability may impact results. B ioluminescence, a common phenomenon particularly in marine ecosystems, is the emission of light by living organisms, representing a major form of communication and camouflage and a potential adaptation to oxidative stress (1). A substrate (luciferin) is oxidized by an enzyme (luciferase) in the presence of oxygen, yielding an excited intermediate that emits light on returning to the ground state (2, 3). Coelenterazine, the imidazolopyrazine luciferin, is widely distributed among coelenterates, fishes, squids, and shrimps (4, 5). Renilla luciferase (Rluc), purified from a bioluminescent soft coral known as sea pansy (Renilla reniformis), catalyzes the calcium-insensitive oxidation of coelenterazine (6). The gene has been cloned and sequenced (7) and used extensively in reporter gene assays in bacteria, yeast, plant, and mammalian cells (8) for bioluminescence resonance energy transfer studies and for high throughput drug screening (9-11). Rluc provides a kinetically rapid, alternative bioluminescence signal to firefly (Photinus pyralis) luciferase and, when coexpressed, enables dual reporter readouts.A rapidly evolving area of biomedical research, use of bioluminescence as an optical marker for gene expression has been recently extended to noninvasive, real-time analysis of molecular events in intact cells and living animals (12)(13)(14). Although previous data suggested that Rluc could be used for reporter imaging in mice in vivo (15), limited utility and poor bioavailability of coelenterazine was reported in a mouse model of viral infection with an Rluc reporter strain of herpes simplex virus 1 (16). Interestingly, anabolic enzymes ena...

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Section: Discussionmentioning

confidence: 85%

Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine

Pichler

Prior

Piwnica‐Worms³

2004

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

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129

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“…It should be emphasized that, apart from covalent bonding to the DNA double helix, both electrostatic interactions and formation of hydrogen bonds 37 play a very important role in the mechanism of interaction of these kinds of cationic polyamine metal complexes with DNA, which determines their antiproliferative and cytotoxic action. According to Cleare and Hoeschele's structure-activity relationships (SARs) for platinum(II) complexes, 38,39 for such compounds to display significant antitumor activity they should have a cis geometry with the general formula cis-[PtX 2 (Am) 2 ], Am being an inert amine containing at least one NH moiety and X being an anionic leaving group with a weaker trans effect than the amine. All the complexes reported in the present work comply with these conditions except for the number of X groups (which is, in some of the chelates studied, only 1).…”

Section: Resultsmentioning

confidence: 99%

“…These compounds, containing two PtCl(NH 3 ) 2 or PtCl 2 (NH 3 ) moieties linked by polyamine groups in a cis orientation, can be compared to complex IV presently studied, which comprises two cisplatin-like PtCl 2 (NH)(NH 2 ) fragments in a trans conformation instead. The IC 50 values reported by Farrell for those dinuclear chelates against leukemia cell lines are lower than 1 µM, as opposed to the very high values now obtained for lines THP-1, MOLT-3, and CCRF-CEM cells ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

et al. 2004

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Several polynuclear Pt(II) chelates with biogenic polyamines were synthesized and screened for their potential antiproliferative and cytotoxic activity in different human cancer cell lines. To gather information regarding the structure-activity relationships underlying their biological activity, the complexes studied were designed to differ in geometrical parameters such as the nature of the ligand and the number and chemical environment of the metal centers. Distinct effects were found for different cell lines and different structural characteristics of the complexes; chelates II, III, and IV displayed specificity toward the HeLa and HSC-3 epithelial-type cells, while V, VI, and VII were clearly more effective against the THP-1, MOLT-3, and CCRF-CEM leukemia cell lines. The toxicity of these Pt(II) complexes on noncancer cells was, in all cases, found to be reversed upon drug removal.

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“…Effects of Pgp on E m were measured directly by whole-cell patch clamping, and transport activity of the protein was studied with Tc-Sestamibi, an organotechnetium cationic substrate for Pgp (7,8). In the absence of MDR1 Pgp, Tc-Sestamibi accumulates within the mitochondrial matrix of living cells in response to negative mitochondrial inner membrane potentials (⌬) and E m while showing negligible nonspecific binding to lipids and proteins (9 -11).…”

mentioning

confidence: 99%

“…In the absence of MDR1 Pgp, Tc-Sestamibi accumulates within the mitochondrial matrix of living cells in response to negative mitochondrial inner membrane potentials (⌬) and E m while showing negligible nonspecific binding to lipids and proteins (9 -11). Tc-Sestamibi has no titratable proton, making accumulation within cells independent of intracellular pH (8,12). Using this system, we determined the effects of MDR1 Pgp on substrate content under steady-state and unidirectional influx or efflux conditions.…”

mentioning

confidence: 99%

MDR1 P-glycoprotein Reduces Influx of Substrates without Affecting Membrane Potential

Luker

Flagg

Sha

et al. 2001

Journal of Biological Chemistry

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MDR1 (multidrug resistance) P-glycoprotein (Pgp; ABCB1) decreases intracellular concentrations of structurally diverse drugs. Although Pgp is generally thought to be an efflux transporter, the mechanism of action remains elusive. To determine whether Pgp confers drug resistance through changes in transmembrane potential (E m ) or ion conductance, we studied electrical currents and drug transport in Pgp-negative MCF-7 cells and MCF-7/MDR1 stable transfectants that were established and maintained without chemotherapeutic drugs. Although E m and total membrane conductance did not differ between MCF-7 and MCF-7/MDR1 cells, Pgp reduced unidirectional influx and steady-state cellular content of Tc-Sestamibi, a substrate for MDR1 Pgp, without affecting unidirectional efflux of substrate from cells. Depolarization of membrane potentials with various concentrations of extracellular K ؉ in the presence of valinomycin did not inhibit the ability of Pgp to reduce intracellular concentration of Tc-Sestamibi, strongly suggesting that the drug transport activity of MDR1 Pgp is independent of changes in E m or total ion conductance. Tetraphenyl borate, a lipophilic anion, enhanced unidirectional influx of Tc-Sestamibi to a greater extent in MCF-7/MDR1 cells than in control cells, suggesting that Pgp may, directly or indirectly, increase the positive dipole potential within the plasma membrane bilayer. Overall, these data demonstrate that changes in E m or macroscopic conductance are not coupled with function of Pgp in multidrug resistance. The dominant effect of MDR1 Pgp in this system is reduction of drug influx, possibly through an increase in intramembranous dipole potential.MDR1 P-glycoprotein (Pgp), 1 a member of the ATP-binding cassette family of membrane transporters, decreases intracellular concentrations of structurally diverse compounds, many of which are hydrophobic and cationic. Conventionally, Pgp is thought to function as an efflux transporter, although it is unclear whether any experiment has demonstrated unequivocally that Pgp mediates transport of a substrate across a membrane bilayer against its electrochemical gradient.Several models have been proposed to account for the apparent function and remarkable variety of compounds that are recognized by this protein. Pgp may be an efflux transporter that recognizes substrates within the lipid bilayer ("hydrophobic vacuum cleaner") (1). Pgp has been hypothesized to be a pump with multiple binding sites for different drugs (2), a translocase for lipids (3), or a modifier of vesicular trafficking (4). Another model suggests that MDR1 Pgp indirectly alters partitioning of substrates within cells through effects on transmembrane potential (E m ), intracellular pH, and/or surface potentials and does not directly transport drugs (5). These disparate hypotheses may result from comparisons of data from transfected cells that have not been exposed to chemotherapeutic agents with cell lines in which expression of MDR1 is induced or maintained through exposure to drugs in the M...

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Metal Complexes for Therapy and Diagnosis of Drug Resistance

Cited by 116 publications

References 143 publications

Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine

Imaging reversal of multidrug resistance in living mice with bioluminescence: MDR1 P-glycoprotein transports coelenterazine

Cytotoxic Activity of Metal Complexes of Biogenic Polyamines: Polynuclear Platinum(II) Chelates

MDR1 P-glycoprotein Reduces Influx of Substrates without Affecting Membrane Potential

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