MDR modulators

S9788. Comparison with 11 other MDR-modulating agents in a model of doxorubicin-resistant rat glioblastoma cells, Eur. J. Cancer 1993, 30, 1377-1383. 

Results Indicating no Influence of Phorbol Esters in MDR Modulation... 

It has been demonstrated that cis- (76) and frarcs-flupentixol (75) (see Fig. 5) inhibited the photo affinity labeling of P-gp by substrate analogues [173] Binding of several MDR modulators, among them TFP (5), to P-gp was shown by means of fluorescence quenching of the MIANS probe [174] or P-gp tryptophan fluorescence [175]. CPZ (9) is likely a P-gp substrate, as was shown in studies of its transport in membrane vesicles obtained from multidrug-resistant CCRF-CEM cells [176], and therefore it was used as a competitive inhibitor of drug transport mediated by P-gp [177]. 

Tsakovska [194] used methods of molecular modeling to investigate a group of 25 phenothiazines and structurally related compounds. The role of hydrophobicity of modulators and hydrogen-bond acceptor interactions in MDR reversal were revealed. The piperazine moiety with a tertiary nitrogen was identified as the most favorable type of side chain for effective MDR modulators. 

The choice of a cell line to study MDR modulator potency was very important for future potential application in human cancer treatment. PhM (12) that were quite effective in resistant mouse lymphoma cells were only slightly active in drug-resistant human sarcoma cell line MES-SA/Dx5 [198]. The drug-sensitive human sarcoma cell line MES-SA and its multidrug-resistant counterpart MES-SA/Dx5 were applied as a model system for evaluation of MDR modulator activities. Examination performed by the flow cytometric Rhl23 accumulation test demonstrated that the well-known P-gp modulators verapamil (79) and TFP (5) reduced MDR in MES-SA/Dx5 cells. In resistant MES-SA/Dx5 cells, verapamil (79) and TFP (5) restored the drug accumulation pattern which was typical for sensitive cells. However, the effectiveness of PhM (12) was very low. The most active compounds were derivatives with an H atom at position 2 of the phenothiazine ring, followed by Cl-substituted and CF3-substituted compounds. 

Flavonoids are now regarded as a class of MDR modulators that directly interact with nucleotide and steroid binding domains of P-gp. However, the molecular mechanism leading to inhibition of MRP1 transport activity by these compounds is still far from being fully understood. Apart from interaction with NBD or substrate binding sites, the stimulation of GSH transport carried by MRP1 and depletion of cellular GSH was also proposed as a possible mechanism of MRPl-mediated resistance reversal by flavonoids [223]. 

This model has provided important results regarding the influence of MDR modulators on hepatobiliary disposition of chemotherapeutic agents (426,427). 

Wilisch A, Haussermann K, Noller A, et al. MDR modulating and antineoplastic effects of B859-035, the (—)isomer of niguldipine. J Cancer Res Clin Oncol 1991 117 S110. 

However, contradictory results on the MDR-modulating activity of the flavonoid polyphenols kaempferol and quercetin have been reported that... 

In our experiments, kaempferol was ineffective in P-gp inhibition however, chrysin had a significant inhibitory effect. The rotenoid derivatives, amorphigenin and rotenone, had their MDR-modulating activity because of their structural difference of a hydroxyl (-OH) group at the position of C-8. The concentrations of flavonoids tested in this study had greater effects on the experimental results, then, a low concentration of quercetin activated the activity of P-gp, whereas a high concentration of quercetin inhibited the Pgp. A similar biphasic effect has been found for kaempferol. 

Actinomycin D has been clinically used for the treatment of many cancers and is known to be a DNA intercalator. The structure of actinomycin D is based on a phenoxazine ring bound to two cyclic pentapeptides [33]. The presence of the phenoxazine ring in the structure of actinomycin D suggests that phenoxazine derivatives may possess anticancer activity. Phenoxazine derivatives are known to be effective multidrug resistance (MDR) modulators in cancer cells [34], potent inhibitors of Akt signaling in cells [35], inhibitors of human plasma cholinesterase [36], and photo-chemotherapeutic agents in cancer cells [37]. Recent studies also show that the relatively water-soluble phenox-azines, such as 2-amino-4,4a-dihydro-4a,7-dimethyl-2H-phenoxazine-3-one and 2-aminophenoxazine-3-one, exert antitumor effects on various cancer cells in vitro and in vivo. [38]. We have investigated 24 phenoxazines [23,39] (Fig. 4). 

In order to put the MDR substrates in their medical and pharmacological context, we present some of the key molecules in separate figures. Figure 3 shows anticancer drugs, which are, unfortunately for the patients, also MDR substrates. Figure 4 shows the chemical MDR modulators used experimen-... 

Fig. 4 Venn-diagram for selected compounds interacting with the key MDR-related ABC transporters. MDR-Modulating agents. Abbreviations CSA cyclosporin A, VERAP verapamil STAURO staurosporine, ECON econazole, PRAZ prazosine, FTC fumitremor-gin C, PROB probenecide, BBR benzbromarone, SUPYR sulfinpyrazone, INDOM in-domethacin, GENIS genistein, PGA2 prostaglandin A2, CCCP chlorocarbonyl cyanide phenylhydrazine. (Reproduced from [4])...

The MDR modulators according to their chemical structures includes the arylalkylamines including verapamil and its analogs (verapamil (1), de-... 

In the derivatives bearing a stereogenic center at C-4, such as nicardipine, nimodipine, nitrendipine (42), felodipine (43), isradipine (44) and niguldip-ine (45), both stereoisomers differ markedly in their potencies as calcium channel blockers but they are about equally effective as MDR reversal mod-ulatores [80,81]. This has led to use of the R isomers as MDR modulators, as in the case of dexniguldipine (45). 

A systematic study of N-alkylaled DHPs as MDR modulators has shown that the derivatives with an arylalkyl substituent on the nitrogen atom were more active than verapamil in potentiating the anticancer activity of vincristine in in vitro, but not in in vivo. However, the additional introduction of basic substituents in the C-3 ester group led to DHPs with in vivo activity [89] (e.g. 20 (50)). 

A series of N-substituted cage dimeric 1,4-DHPs was also evaluated as inhibitors of membrane efflux pump Pgp in MDR cancer cells. Some of the reported 1,4-DHPs have MDR modulating effect on Pgp, significantly superior to that of verapamil. The most active 1,4-DHPs are lipophilic substituted N-bcnzyl and -phenyloxycarbonyl derivatives 3b (105) and 3e (106). Some P-gp... 

Krishna R, Mayer LD (2000) Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Fur J Pharm Sci 11 265-283... 

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