New Purines and Purine Analogs as Modulators of Multidrug Resistance

Dhainaut, A.; Regnier, G.; Tizot, André; Pierre, Alain St.; Léonce, Stéphane; Guilbaud, Nicolas; Kraus‐Berthier, Laurence; Atassi, Ghanem

doi:10.1021/jm960361i

Cited by 43 publications

(19 citation statements)

References 15 publications

(34 reference statements)

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“…Since P-gp transports substrates out of the cell, P-gp substrates show lower accumulation in P-gp expressing cells than in the P-gp deficient cells. Similarly, drug accumulation is increased under conditions where P-gp is inhibited, such that the difference in accumulation in parental cells and Pgp over-expressing cells becomes insignificant (196).…”

Section: Accumulation/efflux Assaymentioning

confidence: 99%

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Bansal¹,

Jaggi²,

Khar³

et al. 2009

J Pharm Pharm Sci

212

161

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Chemotherapy forms the mainstay of cancer treatment particularly for patients who do not respond to local excision or radiation treatment. However, cancer treatment by drugs is seriously limited by P-glycoprotein (P-gp) associated multi-drug resistance (MDR) in various tumor cells. On the other hand, it is now widely recognized that P-gp also influences drug transport across various biological membranes. P-gp transporter is widely present in the luminal surface of enterocytes, biliary canalicular surface of hepatocytes, apical surface of proximal tubular cells of kidney, endothelial cells of blood brain barrier, etc. thus affecting absorption, distribution, metabolism and excretion of xenobiotics. Clinical significance of above mentioned carrier is appreciated from the fact that more than fifty percent of existing anti-cancer drugs undergo inhibitable and saturable P-gp mediated efflux. Consequently, there is an increasing trend to optimize pharmacokinetics, enhance antitumour activity and reduce systemic toxicity of existing anti-cancer drugs by inhibiting P-gp mediated transport. Although a wide variety of P-gp inhibitors have been discovered, research efforts are underway to identify the most appropriate one. Flavonoids (polyphenolic herbal constituents) form the third generation, non-pharmaceutical category of P-gp inhibitors. The effects produced by some of these components are found to be comparable to those of well-known P-gp inhibitors verapamil and cyclosporine. Identification of effective P-gp modulator among herbal compounds have an added advantage of being safe, thereby making them ideal candidates for bioavailability enhancement, tissue-penetration (e.g. blood brain barrier (BBB)), decreasing biliary excretion and multi-drug resistance modulating agents. The dual effects, i.e. P-gp modulation and antitumor activity, of these herbal derivatives may synergistically act in cancer chemotherapy. This paper presents an overview of the investigations on the feasibility and application of flavonoids as P-gp modulators for improved efficacy of anti-cancer drugs like taxanes, anthracyclines, epipodophyllotoxins, camptothecins and vinca alkaloids. The review also focuses on flavonoid-drug interactions as well as the reversal activity of flavonoids useful against MDR. In addition, the experimental models which could be used for investigation on P-gp mediated efflux are also discussed.

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Section: Accumulation/efflux Assaymentioning

confidence: 99%

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Bansal¹,

Jaggi²,

Khar³

et al. 2009

J Pharm Pharm Sci

212

161

View full text Add to dashboard Cite

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“…Advances have been mostly achieved in vitro: they include the use of the calcium channel inhibitor verapamil, of the immunosuppressive drug cyclosporin A, and of quinoline derivatives such as the antimicrobial agent difloxacin, all reported to compete with the binding of antineoplastic drug for the active P-glycoprotein pump site. Yet, clinical use of these compounds is limited by their toxicities (Lehnert, 1993;Huet et al, 1993;Tsuruo and Tomida, 1995;Dhainaut et al, 1996;Bouffard et al, 1996). Monoclonal antibodies have also proven to be able to reverse MDR and, in addition, may contribute to the immune response (Tsuruo and Tomida, 1995).…”

Section: Number Of Cells (%)mentioning

confidence: 99%

The anticancer agent PB-100, selectively active on malignant cells, inhibits multiplication of sixteen malignant cell lines, even multidrug resistant

Beljanski¹

2000

Genet. Mol. Biol.

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The plant-derived anticancer agent PB-100 selectively destroys cancer cells, even when multidrug resistant; yet, it does not inhibit normal (non-malignant) cell multiplication. Testing of PB-100 on sixteen malignant cell lines, several multidrug resistant, as well as on five normal cell lines, confirmed our previous results. Flavopereirine and dihydroflavopereirine, the active principles of PB-100, were chemically synthesized and displayed the same selectivity for tumor cells as the purified plant extract, being active at even lower concentrations.
O agente anticancerígeno de origem vegetal PB-100 destrói seletivamente as células cancerosas, mesmo quando elas são resistentes a múltiplas drogas; no entanto, ele não inibe a multiplicação de células normais (não malignas). O teste do PB-100 em 16 linhagens de células malignas, assim como em 5 linhagens de células normais, confirmou nosso resultados prévios. Flavopereirine e dihidroflavopereirine, os princípios ativos do PB-100, foram sintetizados quimicamente e mostraram a mesma seletividade para as células tumorais que o extrato purificado da planta, sendo ativos em concentrações ainda menores

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“…36 purine derivatives were selected and used in QSAR analysis ( Table 1) [29]. These compounds were divided into two sets: the training set and the test set.…”

Section: P-glycoprotein Ligandsmentioning

confidence: 99%

Some substrates of P-glycoprotein targeting <i>β</i>-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis

Zhu¹,

Chen²,

Yang³

2013

ABB

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The pathogenesis of Alzheimer's disease (AD) putatively involves a compromised blood-brain barrier (BBB). In particular, the importance of brain-to-blood transport of brain-derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as AD, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly β-amyloid (Aβ), a neuropathological hallmark of AD. P-glycoprotein (P-gp), a major component of the BBB, plays a role in the etiology of AD through Aβ clearance from the brain. Our QSAR models on a series of purine-type and propafenone-type substrates of P-gp showed that the interaction between P-gp and its modulators depended on Molar Refractivity, LogP, and Shape Attribute of drugs it transports. Meanwhile, another model on BBB partitioning of some compounds revealed that BBB partitioning relied upon the polar surface area, LogP, Balaban Index, the strength of a molecule combined with the membrane-water complex, and the changeability of the structure of a solute-membranewater complex. The predictive model on BBB partitioning contributes to the discovery of some molecules through BBB as potential AD therapeutic drugs. Moreover, the interaction model of P-gp and modulators for treatment of multidrug resistance (MDR) indicates the discovery of some molecules to increase Aβ clearance from the brain and reduce Aβ brain accumulation by regulating BBB P-gp in the early stages of AD. The mechanism provides a new insight into the therapeutic strategy for AD.

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New Purines and Purine Analogs as Modulators of Multidrug Resistance

Cited by 43 publications

References 15 publications

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

The anticancer agent PB-100, selectively active on malignant cells, inhibits multiplication of sixteen malignant cell lines, even multidrug resistant

Some substrates of P-glycoprotein targeting <i>β</i>-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis

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New Purines and Purine Analogs as Modulators of Multidrug Resistance

Cited by 43 publications

References 15 publications

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy

The anticancer agent PB-100, selectively active on malignant cells, inhibits multiplication of sixteen malignant cell lines, even multidrug resistant

Some substrates of P-glycoprotein targeting &lt;i&gt;β&lt;/i&gt;-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis

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Product

Resources

About

Some substrates of P-glycoprotein targeting <i>β</i>-amyloid clearance by quantitative structure-activity relationship (QSAR)/membrane-interaction (MI)-QSAR analysis