Reversal of Multidrug-Resistance Phenotype by Surfactants: Relationship to Membrane Lipid Fluidity

Dudeja, Pradeep K.; Anderson, K.M.; Harris, Jules S.; Buckingham, Lela; Coon, John S.

doi:10.1006/abbi.1995.1298

Cited by 137 publications

(77 citation statements)

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“…It has been proposed that nonionic surfactants inhibit/modulate P-gp by various mechanisms, including changing membrane fluidity, inhibiting P-gp ATPase activity, and depleting ATP stores. [36][37][38][39][40] Interestingly, as we have previously demonstrated, if PCL5 is not maintained above an inhibitory concentration, PTX rapidly effluxes from the MDCKII-MDR1 cells, resulting in reduced inhibition of cell proliferation. 20 An additional experiment was conducted to determine the IC 50 of PTX-loaded nanospheres or micelles in the presence of PCL5 at its most effective concentration (0.05%).…”

Section: Cytotoxicity Of Ptx-loaded Nanoparticlesmentioning

confidence: 71%

The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

Wan¹,

Letchford²,

Jackson³

et al. 2013

IJN

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Two types of nanoparticles were prepared using the diblock copolymer methoxy poly(ethylene glycol)-block-poly(caprolactone) (MePEG-b-PCL), with either a short PCL block length, which forms micelles, or with a longer PCL block length, which forms kinetically "frozen core" structures termed nanospheres. Paclitaxel (PTX)-loaded micelles and nanospheres were evaluated for their cytotoxicity, cellular polymer uptake, and drug accumulation in drug-sensitive (Madin-Darby Canine Kidney [MDCK]II) and multidrug-resistant (MDR) P-glycoprotein (P-gp)-overexpressing (MDCKII-MDR1) cell lines. Both types of PTX-loaded nanoparticles were equally effective at inhibiting proliferation of MDCKII cells, but PTX-loaded micelles were more cytotoxic than nanospheres in MDCKII-MDR1 cells. The intracellular accumulation of both PTX and the diblock copolymers were similar for both nanoparticles, suggesting that the difference in cytotoxicity might be due to the different drug-release profiles. Furthermore, the cytotoxicity of these PTX-loaded nanoparticles was enhanced when these systems were subsequently or concurrently combined with a low-molecular-weight MePEG-b-PCL diblock copolymer, which we have previously demonstrated to be an effective P-gp inhibitor. These results suggest that the dual functionality of MePEG-b-PCL might be useful in delivering drug intracellularly and in modulating P-gp in order to optimize the cytotoxicity of PTX in multidrug-resistant cells.

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Section: Cytotoxicity Of Ptx-loaded Nanoparticlesmentioning

confidence: 71%

The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

Wan¹,

Letchford²,

Jackson³

et al. 2013

IJN

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“…Many absorption enhancers such as bile salts, fatty acids, and surfactants have been shown to inhibit P-gp (Dudeja et al, 1995;Lo & Huang, 2000). These enhancers exert the P-gp inhibition activity by changing the membrane control NaDC19 NaDC49 NaDC69 NaGC19 NaGC49 NaGC69…”

Section: Resultsmentioning

confidence: 99%

Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats

et al. 2010

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“…However, transport of drug out of the cell is an obvious candidate mechanism. A number of lipophilic agents, including verapamil the calcium ion channel blocker, are able to reverse the MDR phenotype in vitro [51,53,57,58] but many of these agents are highly toxic to the host; consequently a number of pharmacologically relatively inert surfactants have also been trialed. Cremophor EL and Solutol HS 15 are fatty acid ester surfactants and are proven modulators of MDR [57].…”

Section: Multiple Drug Resistancementioning

confidence: 99%

“…A number of lipophilic agents, including verapamil the calcium ion channel blocker, are able to reverse the MDR phenotype in vitro [51,53,57,58] but many of these agents are highly toxic to the host; consequently a number of pharmacologically relatively inert surfactants have also been trialed. Cremophor EL and Solutol HS 15 are fatty acid ester surfactants and are proven modulators of MDR [57]. We have carried out preliminary experiments with the clinically metronidazoleresistant line B7268 and shown that inclusion of Cremophor EL (0.05% -0.2%) or Solutol (874 M) in metronidazole susceptibility assays reduces the MIC from 50 M to 12.5 M. Addition of 100-200 M verapamil also reduces the MIC restoring susceptibility to around 6 m M. This is suggestive of a classical MDR pathway operating in the clinically metronidazole-resistant line, B7268, and we are undertaking further work using other clinically resistant lines and other modulators to resolve the questions regarding the mechanisms of metronidazole resistance in clinical isolates.…”

Section: Multiple Drug Resistancementioning

confidence: 99%

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

et al. 2003

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Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged.

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Reversal of Multidrug-Resistance Phenotype by Surfactants: Relationship to Membrane Lipid Fluidity

Cited by 137 publications

References 0 publications

The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

The combined use of paclitaxel-loaded nanoparticles with a low-molecular-weight copolymer inhibitor of P-glycoprotein to overcome drug resistance

Effects of bile salts on the lovastatin pharmacokinetics following oral administration to rats

Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis

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