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PubMed2002

Effect of protein kinase C on multidrug resistance of multidrug-resistant colorectal cancer LoVo/Adr cells.

OBJECTIVE: To observe the effect of protein kinase C (PKC) on the multidrug resistance of multidrug-resistant colorectal cancer LoVo/Adr cells and explore the mechanism. METHODS: The changes of PKC activity in LoVo/Adr cells in response to treatment with staurosporine (SP) and phorbol-12-myristate-13-acetate (PMA) were detected by way of 32P incorporation. The effect of PKC on adriamycin uptake in LoVo/Adr cells was detected by flow cytometry. Reverse transcriptase-PCR was utilized to observe the effect of PKC on mdr1 gene expression. RESULTS: PMA evinced bi-directional regulation of PKC activity in LoVo/Adr cells, and SP significantly inhibited membrane and cytosol fraction of PKC activity. Preincubation with PMA for 30 min caused the uptake of adriamycin to decrease significantly, but when the preincubation was prolonged to 24 h, significant increase occurred in adriamycin uptake. Neither PMA nor SP, however, could affect the expression of mdr1 gene. CONCLUSION: PKC regulates multidrug resistance of the cells through mechanisms other than regulation of mRNA level of mdr1 gene.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Probenecid reverses multidrug resistance in multidrug resistance-associated protein-overexpressing HL60/AR and H69/AR cells but not in P-glycoprotein-overexpressing HL60/Tax and P388/ADR cells.

PURPOSE: To determine whether probenecid, an inhibitor of organic anion transport, is able to reverse multidrug resistance (MDR) through modulation of the drug transport function of MDR-associated protein (MRP) and P-glycoprotein (P-gP). METHODS: Two MRP-overexpressing cell lines (HL60/AR and H69/AR) and two P-gP-overexpressing cell lines (HL60/Tax and P388/ADR) were cultured with different concentrations of daunorubicin (DNR) or vincristine (VCR) in the presence or absence of various concentrations of probenecid (0.01-10 mM). Drug sensitivity was determined using an MTT assay. DNR accumulation and subcellular distribution were determined by flow cytometry and confocal microscopy respectively. VCR accumulation was determined by scintillation spectrometry. RESULTS: Probenecid, in a concentration-dependent manner, reversed resistance to DNR and VCR in HL60/AR and H69/AR tumor cell lines. This effect of probenecid on MDR was associated with an increased accumulation of DNR and VCR and correction of the altered subcellular distribution of DNR. The concentrations of probenecid that reversed MDR are clinically achievable in vivo. In contrast, probenecid did not reverse MDR in either HL60/Tax or P388/ADR tumor cell lines that overexpress P-gP. CONCLUSION: These results suggest that probenecid is an effective chemosensitizer of MRP-associated MDR tumor cells and is a potential candidate for clinical use to reverse MDR.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is one of the main obstacles in tumor chemotherapy. A promising approach to solving this problem is to utilize a nontoxic and potent modulator able to reverse MDR, which in combination with anticancer drugs increases the anticancer effect. Experiments were carried out to examine the potential of tetrandrine (Tet) as a MDR-reversing agent. Survival of cells incubated with Tet at 2.5 micromol/l for 72 h was over 90%. Tet at 2.5 micromol/l almost completely reversed resistance to vincristine (VCR) in KBv200 cells. Tet at a concentration as low as 0.625 micromol/l produced a 7.6-fold reversal of MDR, but showed no effect on the sensitivity of drug-sensitive KB cells in vitro. In the KBv200 cell xenograft model in nude mice, neither Tet nor VCR inhibited tumor growth. However, VCR and Tet combined inhibited tumor growth by 45.7%, 61.2% and 55.7% in three independent experimental settings. In the KB cell xenograft model in nude mice, Tet did not inhibit tumor growth, but VCR and the combination of VCR and Tet inhibited tumor growth by 40.6% and 41.6%, respectively. Mechanism studies showed that Tet inhibited [(3)H]azidopine photoaffinity labeling of P-gp and increased accumulation of VCR in MDR KBv200 cells in a concentration-dependent manner. The results suggest that Tet is a potent MDR-reversing agent in vitro and in vivo. Its mechanism of action is via directly binding to P-gp and increasing intracellular VCR accumulation.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed1990

Structural characteristics of compounds that modulate P-glycoprotein-associated multidrug resistance.

Multidrug resistance is mediated by a membrane-bound protein, P-gp, that functions as an energy dependent efflux system to reduce the intracellular concentration of anticancer drugs by binding to these drugs and actively exporting them from the cell. Compounds that interact with P-gp and compete with anticancer drug binding modulate the degree of drug resistance and therefore enhance the cytotoxicity of anticancer drugs against the resistant cell. Effective modulators share certain physical and chemical properties including octanol/water partitioning and molecular size, but the physical properties of size and shape seem to correlate best with modulator effectiveness. Using a photoactivatable analog of vinblastine as a probe, together with a semi-synthetic series of structurally homologous reserpine and yohimbine analogs, the need for two planar aromatic domains and a basic nitrogen atom was established within the structural context of these compounds. The use of three-dimensional comparisons was extended to examine important structural features in other modulator types such as the condensed-ring aromatics. This approach indicates that structural similarities between different classes of compounds are present in compounds recognized by the MDR phenotype. These studies emphasize the importance of a ligand-receptor relationship for modulators of MDR, and begin to define the P-gp-binding pharmacophore. It is likely that this approach will be useful in directing the de novo synthesis of compounds that modulate MDR and help to further define the requirements for molecular recognition by this system.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

The multidrug resistance phenotype confers immunological resistance.

Multidrug resistance (MDR), which is due, in part, to the overexpression of P-glycoprotein, confers resistance to a variety of natural product chemotherapeutic agents such as daunorubicin, vincristine, and colchicine. RV+ cells are a P-glycoprotein overexpressing variant of the HL60 myeloid leukemia cell line. In addition to classic MDR, RV+ cells displayed relative resistance to complement-mediated cytotoxicity with both immunoglobulin G and M antibodies against different cell surface antigens, but not to antibody-dependent cellular cytotoxicity and lymphokine-activated killing. Complement resistance was reversed both by treatment with verapamil and with specific monoclonal antibodies (mAbs) capable of binding to P-glycoprotein and blocking its function. To further confirm that the resistance of RV+ cells was not a consequence of the selection of the cells on vincristine, a second system involving P-glycoprotein infectants was also investigated. K562 cells infected with the MDR1 gene, which were never selected on chemotherapeutic drugs, also displayed relative resistance to complement-mediated cytotoxicity. This MDR1 infection-induced resistance was also reversed by mAbs that bind to P-glycoprotein. Therefore, the MDR phenotype as mediated by P-glycoprotein provides resistance to complement-mediated cytotoxicity. The increased intracellular pH and the decreased membrane potential due to the MDR phenotype may result in abnormal membrane attack complex function. This observation may have implications for the possible mechanisms of action of P-glycoprotein and for a possible physiologic role for P-glycoprotein in protection against complement-mediated autolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1996

Are altered pHi and membrane potential in hu MDR 1 transfectants sufficient to cause MDR protein-mediated multidrug resistance?

Multidrug resistance (MDR) mediated by overexpression of the MDR protein (P-glycoprotein) has been associated with intracellular alkalinization, membrane depolarization, and other cellular alterations. However, virtually all MDR cell lines studied in detail have been created via protocols that involve growth on chemotherapeutic drugs, which can alter cells in many ways. Thus it is not clear which phenotypic alterations are explicitly due to MDR protein overexpression alone. To more precisely define the MDR phenotype mediated by hu MDR 1 protein, we co-transfected hu MDR 1 cDNA and a neomycin resistance marker into LR73 Chinese hamster ovary fibroblasts and selected stable G418 (geneticin) resistant transfectants. Several clones expressing different levels of hu MDR 1 protein were isolated. Unlike previous work with hu MDR 1 transfectants, the clones were not further selected with, or maintained on, chemotherapeutic drugs. These clones were analyzed for chemotherapeutic drug resistance, intracellular pH (pHi), membrane electrical potential (Vm), and stability of MDR 1 protein overexpression. LR73/hu MDR 1 clones exhibit elevated pHi and are depolarized, consistent with previous work with LR73/mu MDR 1 transfectants (Luz, J.G. L.Y. Wei, S. Basu, and P.D. Roepe. 1994. Biochemistry. 33:7239-7249). The extent of these perturbations is related to the level of hu MDR 1 protein that is expressed. Cytotoxicity experiments with untransfected LR73 cells with elevated pHi due to manipulating percent CO2 show that the pHi perturbations in the MDR 1 clones can account for much of the measured drug resistance. Membrane depolarization in the absence of MDR protein expression is also found to confer mild drug resistance, and we find that the pHi and Vm changes can conceivably account for the altered drug accumulation measured for representative clones. These data indicate that the MDR phenotype unequivocally mediated by MDR 1 protein overexpression alone can be fully explained by the perturbations in Vm and pHi that accompany this overexpression. In addition, MDR mediated by MDR protein overexpression alone differs significantly from that observed for MDR cell lines expressing similar levels of MDR protein but also exposed to chemotherapeutic drugs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

The effect of fatty acids and analogues upon intracellular levels of doxorubicin in cells displaying P-glycoprotein mediated multidrug resistance.

Multidrug resistance mediated by overexpression of P-glycoprotein (P-gp) is a major obstacle in the chemotherapeutic management of cancer. The objectives of the current work were to examine if fatty acids affect the intracellular transport and dynamics of doxorubicin in drug-resistant cancer cell lines, and to assess if such effects were mediated through modulation of P-gp efflux pump activity. Among the range of fatty acids tested in this study, eicosapentaenoic acid diester (EPADI) increased doxorubicin accumulation [A] to 137% and retention [R] to 212% in doxorubicin-resistant MCF-7/ADR breast carcinoma cells, and [A] to 147% and [R] to 163% in vinblastine-resistant KBVI nasopharyngeal carcinoma cells. Consistent with EPADI-induced increases in intracellular doxorubicin concentrations, EPADI (10 microg/ml) sensitized MCF-7/ADR cells to the cytotoxic effects of doxorubicin (1 microg/ml) as assessed by MTT assay (viability < 50% of control), while EPADI itself displayed no cytotoxicity. The combination of EPADI (10 microg/ml) with verapamil (1 microM) resulted in a considerable increase in the [A] and [R] of the model P-gp substrate rhodamine-123 within drug-resistant cells compared to when either agent were used alone. KBV1 cells treated with combination of EPADI (10 microg/ml) and verapamil (1 microM) achieved 160% and 1120% greater [A] and [R] of rhodamine-123, respectively, compared to untreated cells. The P-gp modulatory effects of EPADI either alone, or as part of a combination with more potent inhibitors, should be further investigated.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2000

HMBA induces activation of a caspase-independent cell death pathway to overcome P-glycoprotein-mediated multidrug resistance.

Multidrug resistance (MDR) is often characterized by the expression of P-glycoprotein (P-gp), a 170-kd ATP-dependent drug efflux protein. As well as effluxing xenotoxins, functional P-gp can confer resistance to caspase-dependent apoptosis induced by a range of different stimuli, including Fas ligand, tumor necrosis factor, UV irradiation, and serum starvation. However, P-gp-positive cells remain sensitive to caspase-independent death induced by cytotoxic T-cell granule proteins, perforin, and granzyme B. It is, therefore, possible that agents that induce cell death in a caspase-independent manner might circumvent P-gp-mediated MDR. We demonstrated here that hexamethylene bisacetamide (HMBA) induced equivalent caspase-independent cell death in both P-gp-positive and -negative cell lines at concentrations of 10 mmol/L and above. The HMBA-induced death pathway was marked by release of cytochrome c from the mitochondria and reduction of Bcl-2 protein levels. In addition, we show that functional P-gp specifically inhibits the activation of particular caspases, such as caspases-8 and -3, whereas others, such as caspase-9, remain unaffected. These studies greatly enhance our understanding of the molecular cell death events that can be regulated by functional P-gp and highlight the potential clinical use of drugs that function via a caspase-independent pathway for the treatment of MDR tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Immunotoxin resistance in multidrug resistant cells.

Multidrug resistance (MDR) can be mediated, in part, by overexpression of P-glycoprotein (P-gp) and is characterized by broad resistance to several structurally, chemically, and pharmacologically distinct chemotherapeutic compounds. It has been hypothesized that immunological approaches to cytolysis may be used to overcome drug resistance. RV+ is a P-gp-expressing variant of the human myeloid leukemic cell line HL60 that displays a typical MDR phenotype. MDR RV+ cells displayed relative resistance to the immunotoxin (IT) HuM195-gelonin and to free rGelonin. K562 leukemia cells retrovirally infected to overexpress P-gp are also resistant to HuM195-gelonin. In addition, a monoclonal antibody capable of inhibiting the function of P-gp was able to partially reverse resistance to the IT. These data indicated that the expression of P-gp may contribute to IT resistance in RV+. Resistance to the IT was not mediated through decreased binding to cells, nor reduced internalization into the cell because the IT displayed similar kinetics of binding and internalization for both the parental HL60 and MDR RV+ cell lines. Comparison of the cytotoxicity of other ribosome-inactivating toxins indicated that RV+ cells were not universally resistant to toxins: RV+ cells were sensitive to the actions of ricin A chain, which acts on precisely the same RNase target as gelonin. Sensitivity of the MDR RV+ cells to the protein synthesis inhibitor cycloheximide, saponin, and Pseudomonas exotoxin A additionally confirmed that the resistance was not mediated through the ribosome and that pathways downstream from the inactivation of protein synthesis leading to cell death were not substantially perturbed in the MDR cells. Resistance could be partially abrogated by bafilomycin A, which inhibits lysosomal function. Moreover, direct visualization by confocal microscopy of the intracellular trafficking route of the IT showed that the IT accumulated preferentially in the lysosome in MDR RV+ cells but not in sensitive cells. These observations implicated the process of increased lysosomal degradation as the most likely basis for resistance. Such pathways of resistance may be important in the therapeutic applications of ITs, now becoming available for human use.

Cell Survival↗

PubMed1995

[Use of rhodamine 123 for the detection of multidrug resistance].

Multidrug resistance (MDR) is characterized by the overexpression of P-glycoprotein (Pgp), which is responsible for decreasing drug uptake and/or increasing drug efflux in resistant cells. Although Pgp has a broad-spectrum specificity, this protein seems to react preferentially with amphiphilic and cationic molecules. Rhodamine 123 (R123) is widely used as a marker for mitochondria in living cells and its uptake is dependent on plasma and mitochondrial membrane potential. More recently, cross-resistance to R123 in cells resistant to adriamycin has been demonstrated and a correlation between expression of Pgp and reduced intracellular accumulation of R123 has been shown. The measurement of R123 uptake or efflux allows the characterization of cells displaying a MDR phenotype with overexpression of Pgp, even with low levels of resistance. Other proteins have now been identified which play a role in resistance and in drug transport, including MRP. For this reason we need to determine if R123 is transported only by Pgp or if R123 is a substrate for transport by other drug resistance proteins as well. We also discuss the possibilities of using several techniques based on fluorescence with R123 in order to fully characterize cells by measuring both Pgp activity and its presence/localization.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Non P-glycoprotein novel proteins involved in human cancer multidrug resistance.

Multidrug resistance of cancer cells is a serious problem in the treatment of tumors and is the leading cause of the frequent failure of chemotherapy. Cancer cell chemoresistance is based on the development of several mechanisms among which one of the most important concerns the overexpression of membrane proteins to remove cytotoxic compounds from the cytoplasm. The leading archetype of these proteins is the P-glycoprotein, a member of the ATP-binding cassette (ABC) superfamily of transporters, or traffic ATPases. In the recent past years, new non P-glycoprotein membrane proteins, several of which being members of the ABC superfamily of transporters, and new genes, have been discovered in cancer cells with a multiple drug resistance phenotype. In this article, we briefly review these newly discovered entities.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2003

Comparative analysis of multidrug-resistant, non-multidrug-resistant, and archaic methicillin-resistant Staphylococcus aureus isolates from Central Sydney, Australia.

In this study, the phenotypic and genotypic characteristics of 50 methicillin-resistant Staphylococcus aureus (MRSA) isolates (43 contemporary and 7 archaic strains from the mid-1960s) from four Sydney hospitals in the central Sydney area were compared. Phenotypic analysis based on antibiotic profiles and phage typing patterns categorized the MRSA isolates into three major groups: multidrug resistant (mMRSA), non-multidrug resistant (nmMRSA), and archaic. The nmMRSA isolates could be further subdivided into nmMRSA group 1, which was phage typeable and similar to the archaic group; nmMRSA group 2, which was non-phage typeable and only resistant to ciprofloxacin; and nmMRSA group 3, which was also nontypeable and generally resistant to other antibiotics. The characterization of all five phenotypic groups was then extended by genetic analysis. Restriction fragment length polymorphism (RFLP) analysis showed the 50 isolates could be sorted into 20 group-specific pulsotypes. mecI gene deletions and mutations at various percentages among the five MRSA groups were detected by sequencing. Several mec promoter mutations were also found. The overall findings indicated that nmMRSA strains may have independently acquired mec DNA and are more likely to be newly emergent strains than nmMRSA variants.

Anti-Bacterial Agents↗

PubMed1999

[Expression and clinical study of multidrug resistance gene and multidrug resistance associated protein gene in acute leukemia].

OBJECTIVE: To evaluate the relationship between the expression of multidrug resistance gene (mdr1) or multidrug resistance-associated protein gene (MRP) and the prognosis in patients with acute leukemia (AL). METHODS: The expression of mdr1 and MRP were measured in 55 patients with AL by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: The mdr1 and MRP gene expression levels in the relapsed AL and the blastic phase of CML group (0.735 +/- 0.249, 1.157 +/- 0.447) were significantly higher than those in the untreated group (0.408 +/- 0.186, 0.465 +/- 0.253) (P < 0.01). The complete remission (CR) rate in high mdr1 and MRP expression group was significantly lower than that in low mdr1 and MRP expression group (P < 0.01) in a follow up of 40 AL patients. CONCLUSION: Increased expression of mdr1 and MRP gene might be an important factor for predicting drug resistance, relapse and unfavorable prognosis in AL patients.

Acute Disease↗

PubMed2004

Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells.

Multidrug resistance (MDR) is one of the main obstacles limiting the efficacy of chemotherapy treatment of tumors. Parent acridones 1A and 1B were prepared by the Ullmann reaction followed by cyclization and N-alkylation. N-(omega-Chloroalkyl) analogues were subjected to iodide catalyzed nucleophilic substitution reaction with secondary amines to get the compounds 3A-13A and 3B-13B, which enhanced the uptake of vinblastine in KBChR-8-5 cells to a greater extent (2.6-13.1-fold relative to control) than verapamil. The study on the structure-activity relationship revealed that substitution of -H at position C-4 in acridone nucleus by -OCH3 increased the cytotoxic and anti-MDR activities. The ability of acridones to inhibit calmodulin dependent cyclic AMP phosphodiesterase has been determined and the results have shown a strong positive correlation between anti-calmodulin activity and cytotoxicity in KBChR-8-5 cells or anti-MDR activity.

Acridines↗

PubMed1999

Reversal of resistance in multidrug resistance protein (MRP1)-overexpressing cells by LY329146.

The benzothiophene LY329146 reverses the drug resistance phenotype in multidrug resistance protein (MRP1)-overexpressing cells when dosed in combination with MRP1-associated oncolytics doxorubicin and vincristine. Additionally, LY329146 inhibited MRP1-mediated uptake of the MRP1 substrate LTC4 into membrane vesicles prepared from MRP1-overexpressing cells.

ATP-Binding Cassette Transporters↗

PubMed2002

Discovery and biological evaluation of a new family of potent modulators of multidrug resistance: reversal of multidrug resistance of mouse lymphoma cells by new natural jatrophane diterpenoids isolated from Euphorbia species.

The effects of 15 jatrophane diterpene polyesters (1-3 and 5-16) isolated from lipophilic extracts of Euphorbia serrulata, E. esula, E. salicifolia, and E. peplus (Euphorbiaceae) on the reversion of multidrug resistance of mouse lymphoma cells were examined. The structures of five new compounds (1-5) were elucidated by spectroscopic methods, including HRFABMS, ESIMS, (1)H-(1)H homonuclear and (1)H-(13)C heteronuclear correlations, long-range correlation spectra, and NOESY experiments. The stereochemistry and absolute configuration of one compound (3) were determined by X-ray crystallography. The structure-activity relationship is discussed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

[Expression of ATP binding cassette superfamily (multidrug resistance-1, multidrug resistance-associated protein, human canalicular multispecific organ anion transporter) mRNA in etoposide and m-AMSA resistant cell lines].

The efficacy of all chemotherapeutic agents is limited by the occurrence of drug resistance. To further understand resistance to topoisomerase (topo) II inhibitors, 50 sublines were isolated as single clones from parental cells by exposure to etoposide or m-AMSA. Subsequently, a population of cells from each sublines was exposed to three-fold higher drug concentrations allowing 16 stable sublines to be established at higher extracellular drug concentration. Quantitative aspects of MRP and C-MOAT were studied by Northern blotting in 66 resistant cell lines. Increased MRP mRNA was observed in 48.5% of resistant cell lines (64.7% of etoposide resistant cells and 31.3% of m-AMSA resistant cell lines). Increased C-MOAT mRNA was also observed in 39.4% of resistant cell lines (41.2% in etoposide resistant cell lines and 37.5% in m-AMSA resistant cell lines). To characterize the function of C-MOAT, cellular accumulation assay for 3H-etoposide was performed in three resistant cell lines which overexpress C-MOAT but do not express MRP. Accumulation of etoposide was reduced in the cell lines. Our findings suggest that increased MRP and O-MOAT mRNA seems to be an important mechanism of resistance to topo II inhibitors.

ATP-Binding Cassette Transporters↗

PubMed2002

Synthesis and chemical characterization of 2-methoxy-N(10)-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells.

In an attempt to find clinically useful modulators of multidrug resistance (MDR), a series of 19 N(10)-substituted-2-methoxyacridone analogues has been synthesized. 2-Methoxyacridone and its derivatives (1-19) were synthesized. Compound 1 was prepared by the Ullmann condensation of o-chlorobenzoic acid and p-anisidine followed by cyclization using polyphosphoric acid. This compound undergoes N-alkylation in the presence of phase transfer catalyst (PTC). Stirring of 2-methoxy acridone with 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane in a two-phase system consisting of organic phase (tetrahydrofuran) and 6N potassium hydroxide in the presence of tetrabutylammonium bromide leads to the formation of compounds 2 and 11 in good yield. N-(omega-Chloroalkyl) analogues were found to undergo iodide catalyzed nucleophilic substitution reaction with various secondary amines. Products were characterized by UV, IR, 1H and 13C NMR, mass-spectral data and elemental analysis. The lipophilicity expressed in log(10) P and pK(a) of compounds have been determined. All compounds were examined for their ability to increase the uptake of vinblastine (VLB) in MDR KBCh(R)-8-5 cells and the results showed that the compounds 7, 10, 12, and 15-19 at 100 microM caused a 1.05- to 1.7-fold greater accumulation of vinblastine than did a similar concentration of the standard modulator, verapamil (VRP). However, the effects on VLB uptake were specific because these derivatives had little effect in the parental drug sensitive line KB-3-1. Steady state accumulation of VLB, a substrate for P-glycoprotein (P-gp) mediated efflux, was studied in the MDR cell line KBCh(R)-8-5 in the presence and absence of novel MDR modulators. Results of the efflux experiment showed that VRP and each of the modulators (1-19) significantly inhibited the efflux of VLB, suggesting that they may be competitors for P-gp. From among the compounds examined, 14 except 1, 2, 4, 8, and 11, exhibited greater efflux inhibiting activity than VRP. All the 19 compounds effectively compete with [(3)H] azidopine for binding to P-gp, pointed out this transport membrane protein as their likely site of action. Cytotoxicity has been determined and the IC(50) values lie in the range 8.00-18.50 microM for propyl and 4-15 microM for butyl derivatives against KBCh(R)-8-5 cells suggesting that the antiproliferative activity increases as chain length increases from 3 to 4 carbons at N(10)-position. Compounds at IC(10) were evaluated for their efficacy to modulate the cytotoxicity of VLB in KBCh(R)-8-5 cells and found that the modulators enhanced the cytotoxicity of VLB by 5- to 35-fold. Modulators 12, 14-16, and 19 like VRP, were able to completely reverse the 24-fold resistance of KBCh(R)-8-5 cells to VLB. Examination of the relationship between lipophilicity and antagonism of MDR showed a reasonable correlation suggesting that hydrophobicity is one of the determinants of potency for anti-MDR activity of 2-methoxyacridones.

Acridines↗