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PubMed2004

Hepatocellular bioactivation and cytotoxicity of the synthetic endoperoxide antimalarial arteflene.

Arteflene is a synthetic endoperoxide antimalarial. Its peroxide bridge undergoes iron(II)-mediated reduction in vitro which yields a carbon-centered cyclohexyl radical and a mixture of cis- and trans-alpha,beta-unsaturated ketones (enones). The enones are biliary metabolites in rats and therefore surrogate markers of bioactivation. Arteflene is reported to be more cytotoxic to primary rat hepatocytes than some non-endoperoxide antimalarials. Hepatic metabolism of arteflene was investigated in recirculating isolated perfused rat livers, and the drug's metabolism and cytotoxicity were compared using hepatocytes from male rats. Both preparations metabolized [(14)C]arteflene to cis- and trans-[(14)C]enone, 8-hydroxyarteflene glucuronide and an unassigned isomeric glucuronide. During a 2 h liver perfusion, the cis- and trans-enones recovered in bile represented 8.1 +/- 3.4 and 11.3 +/- 4.6% (mean +/- S.D., N=6), respectively, of the [(14)C]arteflene (52 microM) added to the perfusate. After a 3 h incubation of [(14)C]arteflene (10 microM) with hepatocytes in suspension, the cis- and trans-enones comprised, respectively, 14.8 +/- 7.1 and 2.1 +/- 1.0% (N = 4) of the recovered radioactivity; the corresponding data for cultured hepatocytes being 18.6 +/- 6.9 and 3.3 +/- 2.2%. Arteflene was significantly (P < 0.05) toxic to isolated hepatocytes with reference to extramitochondrial reductase activity (tetrazolium reduction) but not enzyme leakage when the cells were exposed to drug concentrations > or =50 microM for 24 h. Cellular glutathione was depleted under these conditions. Therefore arteflene was acutely cytotoxic, though only at relatively high concentrations, when it was metabolized via a pathway which generates carbon-centered radicals.

Animals↗

PubMed1993

Anti-proliferative effects of the arotinoid Ro 40-8757 on human cancer cell lines in vitro.

A novel arotinoid with a morpholine structure in the polar end group Ro 40-8757 (4-[2-[p-[(E)-2(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2- naphthyl)propenyl]phenoxy]ethyl]-morpholine) was tested for its anti-proliferative activity against nine human cancer cell lines in vitro. The lines included two estrogen receptor positive breast cancer lines (MCF-7 and ZR-75-1), two estrogen receptor negative breast cancer lines (MDA-MB-231 and BT-20), one cervix carcinoma line (KB-3-1), two lung adenocarcinoma lines (A549 and HLC-1), one large cell lung cancer line (LXFL 529) and two colorectal lines (CXF 243 and CXF 280). Proliferation of all the lines, except the two lung adenocarcinoma lines, was inhibited by lower concentrations of Ro 40-8757 than those of all-trans retinoic acid (RA) or 13-cis RA giving the same level of inhibition. The degree of inhibition of RO 40-8757 was concentration and time dependent. The arotinoid was not cytotoxic and morphological signs by differentiation were not evident in cultures treated with Ro 40-8757 for up to 2 weeks. Because this compound is active on cells such as KB-3-1 that are not inhibited by all-trans RA and because it does not bind to nuclear retinoic acid receptors, it may represent a novel class of anti-proliferative agents.

Adenocarcinoma↗

PubMedDate not supplied

Decrease in toxic potential of mixed tensides maintained below the critical micelle concentration: an in vitro study.

Sodium lauryl sulphate (SLS) is an anionic tenside widely utilized in commercial topical preparations that may cause skin irritation. It has been shown that the barrier damage caused by SLS in vivo is lower when SLS is used in combination with other tensides which are able to reduce the critical micelle concentration (CMC). The aim of our study was to evaluate if the cytotoxic effect of SLS is reduced by the association with different tensides also at concentrations well below the CMC. Normal human keratinocytes from plastic surgery were grown in serum-free medium. At subconfluency, the cells were treated with SLS at a dose of 0.0025% in combination with cocamidopropyl betaine, Tween 20 and Tween 80 at the minimum toxic dose. Following tenside treatment, the culture medium was changed, and after 24 h the cells were collected for (3)H-thymidine incorporation, the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay and neutral red (NR) uptake. The cytotoxic effect on normal human keratinocytes, as evaluated by (3)H-thymidine incorporation, MTT assay and NR uptake, was significantly decreased by the combination with all the tested tensides. The correlation between cytotoxicity and physical properties was also studied by a conductimetric assay to investigate the mechanism involved in this toxicity reduction.

Betaine↗

PubMed2006

MZ3 induces apoptosis in human leukemia cells.

PURPOSE: 4-(4-Bromophenyl)-2,3-dihydro-N,3-bis(3,4,5-trimethoxyphenyl)-2-oxoidmi-dazole-1-carboxamide (MZ3) is one of the synthesized combretastatin-A-4 analogues and has been reported that it displayed a promising specific activity against leukemia cell lines. Our purpose was to investigate the mechanism of MZ3's cytotoxicity. METHODS: Cytotoxicity was measured by MTT method, apoptosis was measured by flow cytometry. DNA fragmentation was tested by agarose gel electrophoresis. Mitochondrial membrane potential (DeltaPsim) was detected by JC1 staining and flow cytometry, while intracellular reactive oxygen species (ROS) was detected by 5-(and-6)-carboxy-2'-7'-dichlorofluorescin diacetate staining and flow cytometry. Protein expression was analyzed by western blotting. In vivo activity of MZ3 was assayed through severe combined immunodeficiency (SCID) mice model of human leukemia engrafts. RESULTS: MZ3 exhibited high anti-cancer activity in six leukemia cell lines, including two drug-resistant cell lines. MZ3 induced DNA fragmentation, and caused an elevation of ROS and a loss of DeltaPsim in HL60 cells. MZ3 also induced the activation of caspase-3, influenced the expression of Bcl-2 family members, MAPKs and other proteins relative to mitochondria-induced apoptosis. In addition, N-acetylcysteine cannot inhibit HL60 cell apoptosis caused by MZ3. Furthermore, a prolonged survival time was observed after treatment with MZ3 in SCID mice model of human leukemia engrafts. CONCLUSIONS: MZ3 is a potent compound against leukemia cell lines both in vitro and in vivo, and the mitochondrial pathway mediated by Bcl-2 protein family and MAPKs might be involved in signaling MZ3-induced apoptosis.

Animals↗

PubMed1989

Nucleic acid hybridization assays employing dA-tailed capture probes. II. Advanced multiple capture methods.

A fourth capture is added to the reversible target capture procedure of the preceding paper. This results in an improved radioisotopic detection limit of 7.3 x 10(-21) mol of target. In addition, the standard triple capture method is converted into a nonradioactive format with a detection limit of under 1 amol of target. The principal advantage of nonradioactive detection is that the entire assay can be performed in about 1 h. Nucleic acids are released from cells in the presence of the ('capture probe') which contains a 3'-poly(dA) sequence and the ('labeled probe') which contains a detectable nonradioactive moiety such as biotin. After a brief hybridization in solution, the target is captured on oligo(dT) magnetic particles. The target is further purified from sample impurities and excess labeled probe by recapture either once or twice more on fresh magnetic particles. The highly purified target is then concentrated to 200 nl by recapture onto a poly(dT) nitrocellulose filter and rapidly detected with streptavidin-alkaline phosphatase using bromochloroindolyl phosphate and nitroblue tetrazolium. Using this procedure, as little as 0.25 amol of a target plasmid has been detected nonradioactively in crude samples in just 1 h without prior purification of the DNA and RNA. Finally, a new procedure called background capture is introduced to complement the background-reducing power of RTC.

Biotin↗

PubMed1997

Proliferation and differentiation of cultured human keratinocytes is modulated by 1,25(OH)2D3 and synthetic vitamin D3 analogues in a cell density-, calcium- and serum-dependent manner.

The natural form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) decreases proliferation and promotes terminal differentiation of cultured human epidermal keratinocytes. The purpose of this study was to find out to what extent the culture conditions determine the sensitivity of keratinocytes to 1,25(OH)2D3 and synthetic vitamin D analogues. Human keratinocytes were grown in microplates. Cell proliferation (MTT-assay) and differentiation (quantity of transglutaminase type I) were measured consecutively in the same monolayer. When vitamin D3 analogues were added to 50-60% confluent keratinocytes grown in serum-free keratinocyte growth medium with 0.09 mM Ca2+, stimulation of the proliferation was either minimal or non-existent, while differentiation was unaffected or slightly inhibited. There was no difference in the sensitivity to 1,25(OH)2D3 and the vitamin D3 analogues. When 1,25(OH)2D3 was added to less confluent keratinocytes (30%) a marked antiproliferative effect was observed. Addition of 3% charcoal stripped foetal calf serum further enhanced the antiproliferative effect of 1,25(OH)2D3, and a difference in the sensitivity of the vitamin D3 analogues was noted. If, finally, the Ca2+ concentration was raised to 0.3 mM, 1,25(OH)2D3 and the vitamin D3 analogues stimulated differentiation. Also, a biphasic effect on proliferation occurred: stimulation at low vitamin D concentrations and inhibition at higher concentrations. Furthermore, keratinocytes became more sensitive to the synthetic vitamin D3 analogues than to 1,25(OH)2D3: KH1060 > EB1089 > GS1500 > or = EB1213 > calcipotriol > 1,25(OH)2D3. For all compounds tested differentiation occurred at concentrations 10 to 30 times lower than for proliferation. These results indicate that the sensitivity to vitamin D3 analogues as well as the direction of the response to vitamin D3 analogues is dependent on the keratinocyte density, the availability of serum and Ca2+ concentrations.

Antibodies, Monoclonal↗

PubMed1999

The MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay is a fast and reliable method for colorimetric determination of fungal cell densities.

The entomopathogenic fungus Neozygites parvispora (Entomophthorales: Zygomycetes) grows in vitro as irregularly rod-shaped hyphal bodies in a complex medium. In order to simplify the medium composition and determine growth-promoting compounds for the cultivation of this fungus, we were looking for a rapid and quantitative method to estimate the number of living cells in small volumes of liquid culture. A colorimetric method for the determination of cell densities using MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] proved to be more accurate and timesaving than conventional hemocytometer counting.

Colony Count, Microbial↗

PubMed2005

Gymnasterkoreayne G, a new inhibitory polyacetylene against NFAT transcription factor from Gymnaster koraiensis.

A new polyacetylene, gymnasterkoreayne G (1) and seven known (2--8) constituents were isolated from the leaves of Gymnaster koraiensis. Base on extensive 1D and 2D NMR spectroscopic data, the structure of the new compound was identified as erythro-8(S)-9(Z),16-heptadecadiene-4,6-diyne-2,3,8-triol. Isolated compounds were evaluated for their ability to inhibit NFAT transcription factor. While other components did not show activity, most of polyacetylene components markedly inhibit NFAT transcription factor. Of these compounds, gymnasterkoreayne B (3) was the most potent (IC(50) 1.44+/-0.59 microM). In term of the isomers, compound 1 (IC(50) 43.9+/-2.24 microM) with an erythro-configuration showed less inhibition than 2 (IC(50) 7.24+/-0.42 microM) with a threo-configuration.

Acetylene↗

PubMed1983

[Immunopharmacological actions of 6-amidino-2-naphthyl-4-guanidinobenzoate (FUT-175). 2. Effect of FUT-175 on immunological reactions in man].

FUT-175 is a new anti-complemental drug which strongly inhibits complement-mediated allergic reactions in animals. It was reported that FUT-175 does not affect both antibody formation and host defense to bacterial infection in mice. The present study was undertaken to examine the effects of FUT-175 on various immunological reactions in humans. FUT-175 dose-dependently decreased the antigen-induced anaphylactic histamine release from leukocytes of atopic patients. However, i.d. treatment of FUT-175 neither inhibited antigen- or compound 48/80-induced immediate type skin reactions in atopic patients nor antigen-induced early, late or delayed type skin reactions in Candida-sensitive patients. FUT-175 also did not inhibit the PPD-mediated delayed type skin reaction in healthy subjects. FUT-175 at a dose of 10(-4)M but not at 10(-8) to 10(-5)M significantly decreased the proliferation of human atopic peripheral blood lymphocytes (PBL) caused by mite antigen, concanavalin A or pokeweed mitogen. 51Cr release from human PBL was slightly enhanced by FUT-175 at a dose range of 10(-6) to 10(-4)M. FUT-175 did not change the number of SIg receptors or C3 receptors on human B cells. FUT-175 hardly affected the nitroblue tetrazolium reduction test and Escherichia coli-mediated chemotaxis in human neutrophils. These results strongly suggest that FUT-175 does not affect immunological functions and host defense in humans.

Benzamidines↗

PubMed1991

Dithranol-induced cytotoxicity in primary cultures of rat epidermal keratinocytes. I. The role of reactive oxygen species.

Primary cultured rat epidermal keratinocytes were used as an experimental model to detect oxidant-mediated adverse effects of dithranol (anthralin), a widely used antipsoriasis drug with tumor-promoting and skin-irritating properties. Keratinocytes were isolated and prepared from the skin of neonatal rats by a trypsin flotation method. Highly proliferative monolayer cells cultured in a serum-free medium were exposed to the test compound at concentrations (5-100 microM) used therapeutically for the treatment of skin disorders. Cytotoxicity was evaluated by changes in plasma membrane integrity (lactate dehydrogenase leakage), lysosomal function (neutral red uptake), and mitochondrial metabolic activity (reduction of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, MTT). Exposure of keratinocytes to dithranol produced time- and concentration-related toxic responses. MTT reduction was found to be a more sensitive endpoint of cytotoxicity, showing significant toxic effects at 2 hr, while significant leakage of lactate dehydrogenase did not result until 6 hr. Oxygen consumption in keratinocytes and isolated mitochondria showed a similar pattern after exposure to dithranol. Increased cyanide-insensitive respiration was also noted. Oxidative stress, measured by superoxide anion-dependent reduction of nitroblue tetrazolium, occurred before dithranol produced cytotoxicity in the keratinocyte cultures. Superoxide formation, which increased with time after dithranol exposure, was detected both extracellularly and intracellularly and was inhibited by the addition of superoxide dismutase. Dithranol-induced cell injury was partially prevented by treatment with superoxide dismutase, and greater protection was shown by concurrent treatment with superoxide dismutase plus catalase. These findings suggest that the superoxide anion and hydrogen peroxide may be involved in the cytotoxicity of dithranol and that a culture system of rat keratinocytes may be useful in evaluating the mechanism of toxicity of dermatotoxicants.

Animals↗

PubMed1996

An in vitro study of m-dinitrobenzene toxicity on the cellular components of the blood-brain barrier, astrocytes and endothelial cells.

We have studied the effects of an industrial compound, m-dinitrobenzene (DNB), on cultured astrocytes and brain capillary endothelial cells in an in vitro blood-brain barrier (BBB) model. In single cultures, the threshold DNB concentration that induced cell death, as assessed by morphology and lactose dehydrogenase leakage into the culture medium, was 1 mM for both cell types after 1 day of incubation. In cocultures, astrocytes showed a dose-response curve similar to that obtained in single cultures, while endothelial cells showed an increased sensitivity to DNB cytotoxicity. DNB induced a dose-dependent increase in glucose consumption and lactate production in both cell types in single cultures, although astrocytes appeared to be more sensitive than endothelial cells. The role of oxidative stress was also studied using the reduction of nitroblue tetrazolium as an index of generation of active oxygen species. A dose-dependent increase was observed for both cell types in single cultures, although this could not be prevented by the addition of superoxide dismutase to the culture medium. Addition of 0.3 mM carmustine to the culture medium increased the cytotoxicity of 0.5 mM DNB in both astrocytes and endothelial cells, indicating a role of oxidative stress in DNB-induced damage. Desferrioxamine (20 mm) completely protected endothelial cells from damage by 1 mM DNB, suggesting that hydroxyl radicals mediated at least part of the DNB neurotoxicity. However, astrocytic damage by 2 mM DNB was only partially prevented by desferrioxamine. We conclude that our in vitro model is suitable for studying interactions between astrocytes and endothelial cells in toxicological situations.

Analysis of Variance↗

PubMed1991

Dipyridamole and RA-642 inhibit the production of superoxide anion and free radical damage to rat lens.

We studied the effects of dipyridamole and RA-642 on the production of superoxide anions and on oxygen radicals-induced lipid peroxidation in lens tissue homogenates from normal rats and rats given dipyridamole or RA-642 intraperitoneally. Superoxide production was evaluated by phenazine methosulphate (PMS)-induced nitroblue tetrazolium (NBT) reduction and lipid peroxidation by ferrous sulfate and ascorbic acid (FeAs)-induced malondialdehyde (MDA) production. Dipyridamole and RA-642 showed an inhibitory effect on both assays in the experiments with lens tissue homogenates from untreated or treated rats. The extent of inhibition, however, was significantly higher in pyrimidopyrimidinic-treated rats (range of inhibition at different times of incubation was 18% versus 23-57% for dipyridamole and 14% versus 73-80% for RA-642 in the assay of MDA production, and 10% versus 33-37% for dipyridamole and 2.5% versus 11-32% for RA-642 in the assay of NBT reduction). Concentrations of dipyridamole and RA-642 in lens tissue from treated animals could not be determined (less than 0.001 micrograms/mg of tissue). Although both compounds inhibited lipid peroxidation induced by oxygen free radicals, the mechanism of action might include the role of adenosine as a mediator.

Animals↗

PubMed1990

Are the kinetics of technetium-99m methoxyisobutyl isonitrile affected by cell metabolism and viability?

To investigate the role of cell viability and metabolism on the myocardial kinetics of a new tracer, technetium-99m-methoxyisobutyl isonitrile (Tc-99m-MIBI), 250 microCi/l Tc-99m-MIBI was infused in isolated rat hearts under constant flow conditions. The hearts were studied after inducing irreversible damage by cytochrome c oxidase inhibitor sodium cyanide (n = 8) or sarcolemmal membrane detergent Triton X-100 (n = 8). The control hearts (n = 6) received no toxins. Mean Tc-99m-MIBI peak accumulation activity was significantly reduced after cyanide (51.1 +/- 44.2% of control, p less than 0.01) and Triton (13.8 +/- 2.7% of control, p less than 0.001) administration. Kinetic studies also showed marked reduction in accumulation rates and marked increase in clearance rates for cyanide (p less than 0.01) and Triton (p less than 0.01) groups compared with controls. Potential changes in regional flow distribution were assessed using microspheres. When peak accumulation activity was corrected for these changes, there remained significant differences between the groups. In the cyanide and Triton groups, irreversible cell injury was confirmed by creatine kinase and lactate dehydrogenase release, triphenyl tetrazolium chloride staining, and electron microscopy. All the cells were viable in the control group. We conclude that the accumulation and clearance kinetics of Tc-99m-MIBI are significantly affected by cell viability. Tc-99m-MIBI kinetics appear to be dependent on sarcolemmal integrity and to a lesser extent on aerobic metabolism.

Animals↗

PubMed1993

Modification of sulfhydryl groups of interleukin-8 (IL-8) receptor impairs binding of IL-8 and IL-8-mediated chemotactic response of human polymorphonuclear neutrophils.

Interleukin-8 (IL-8), a monocyte-derived neutrophil chemotactic agent, has a potential role in the regulation of inflammatory responses. The specific receptor for IL-8 has been identified and characterized on the surface of human neutrophils (Samanta, A. K., Oppenheim, J. J., and Matsushima, K. (1989) J. Exp. Med. 169, 1185-1189). The present study demonstrates that at least two sulfhydryl groups of this receptor from human neutrophils participate in the binding of IL-8. Incubation of neutrophils with sulfhydryl group-modifying reagents, N-ethylmaleimide and diazene dicarboxylic acid bis-N,N-dimethylamide (diamide), severely impaired the binding of 125I-IL-8 to neutrophils. Treatment with 0.8 mM N-ethylmaleimide and 0.4 mM diamide inhibit binding of 125I-IL-8 to the neutrophils by 62 and 60%, respectively. These inhibitory effects could be reversed by 84-87% by treatment with 2-4 mM dithiothreitol. The saturable amount of the ligand, IL-8, provided partial protection against the modifying reagents. N-Ethylmaleimide and diamide at a concentration of 0.4 mM reduced chemotactic migration of neutrophils in a Boyden chamber by 95 and 60%, respectively. At a concentration of 0.4 mM, N-ethylmaleimide reduced the IL-8-induced (10 micrograms/ml) release of myeloperoxidase by 50%. Under identical conditions, 0.4 mM diamide could reduce release of myeloperoxidase by 63%. Finally, N-ethylmaleimide severely affected the overall binding and total uptake of 125I-IL-8 to the neutrophils at 37 degrees C, a condition required for receptor-mediated internalization of the ligand and recycling of the receptor to the surface of neutrophils. Nitro blue tetrazolium reduction test of the lipopolysaccharide-stimulated neutrophils indicates that compared to control general metabolic functions of thiol-modified cells were markedly retained. These data suggest that at least two conformationally vicinal free reactive sulfhydryl groups are located in the binding domain of the receptor in neutrophils which are essential for IL-8-mediated biological responses.

Binding Sites↗

PubMed2006

Small interference RNA targeting heat-shock protein 27 inhibits the growth of prostatic cell lines and induces apoptosis via caspase-3 activation in vitro.

OBJECTIVES: To evaluate synthetic small interference RNA (siRNA) compounds targeting heat-shock protein 27 (Hsp27) as an alternative approach to Hsp27 'knockdown' in prostate cancer cells, as Hsp27 expression is highly up-regulated in prostate cancer cells after androgen withdrawal or chemotherapy, to become uniformly highly expressed in androgen-independent (AI) prostate cancer. MATERIALS AND METHODS: We recently showed that targeting Hsp27 by a 2'-methoxyethyl modified phosphorothioate antisense oligonucleotide, OGX-427, inhibits Hsp27 expression and enhances hormone- and chemotherapy in prostate cancer xenograft models. In the present study, a 'gene walk' screening different siRNAs was initially used in PC-3 and LNCaP cells to determine the most potent sequence to down-regulate Hsp27 mRNA and protein levels. The effects of Hsp27 silencing on in vitro growth rates were studied by tetrazolium-blue and crystal violet assays. Apoptosis was determined by single-stranded DNA nuclear and cleaved caspase-3 immunostaining, as well as flow cytometry. Spotted microarrays with 14,000 human oligonucleotides were used to examine changes in gene expression. RESULTS: Low concentrations of 1 nm siRNA decreased Hsp27 mRNA levels by 19-fold and suppressed protein expression to undetectable levels. Silencing of Hsp27 in prostate cancer cells by siRNA # 2 increased apoptotic rates 2.4-4 fold and caused 40-76% inhibition of cell growth in LNCaP and PC-3 cells. Characteristic cleavage of caspase-3 occurred after treatment with Hsp27 siRNA (1 nm). cDNA microarray analysis from LNCaP and PC-3 cell lines revealed differential gene expression profiles after Hsp27 down-regulation that could be used to identify various survival pathways involved in androgen-dependent and AI growth. CONCLUSIONS: These findings illustrate the potential utility of Hsp27-silencing therapy and highlight Hsp27 siRNA strategies as a novel and highly effective tool, with the potential for future targeted therapy in enhancing the efficacy of chemotherapy in advanced prostate cancer.

Apoptosis↗

PubMed2006

A new stilbene glucoside from the roots of Polygonum multiflorum Thunb.

One new stilbene glucoside (6), along with five known compounds (1-5), were isolated from the roots of Polygonum multiflorum Thumb., and their chemical structures established based on physicochemical and spectroscopic data. Of the compounds, compound 3 showed DNA topoisomerase I and II inhibitory activities.

Antineoplastic Agents, Phytogenic↗

PubMed2002

Structure-activity relationship of triterpenoids isolated from Mitragyna stipulosa on cytotoxicity.

Chromatographic separation of the stem bark extract of Mitragyna stipulosa afforded triterpene derivatives ursolic acid (1), quinovic acid (2), quinivic acid 3-O-beta-D-glucopyranoside (3, quinovin glycoside C), quinovic acid 3-O-[(2-O-sulfo)-beta-D-quinovopyranoside] (4, zygophyloside D) and quinovic acid 3-O-beta-D-quinovopyranosyl-27-O-beta-D-glucopyranosyl ester (5, zygophyloside B). These five compounds were subjected to the cytotoxicity on MTT assay system. Compound 1 among tested showed the most potent cytotoxicity. Quinovic acid showed less potent cytotoxicity than ursolic acid and sugar linkages to 2 decreased the cytotoxicity. Compound 4 more potent than 3 with indicate that the sulfonyl group significantly enhances the activity. This indicates that the glycosidic linkage in ursane-type triterpenoids has mainly negative effect on cytotoxicity unlike in oleanane-type glycosides.

Antineoplastic Agents, Phytogenic↗

PubMed2006

Novel tetrahydroisoquinolin-ethyl-phenylamine based multidrug resistance inhibitors with broad-spectrum modulating properties.

PURPOSE: The ATP-binding cassette transporters P-glycoprotein (Pgp) and BCRP are implicated in multidrug resistance (MDR) of many tumors. Multi-targeted inhibitors such as cyclosporin A, have been shown to circumvent MDR in clinical trials. Here, we present the characterization of a novel class of effective and multi-targeted tetrahydroisoquinolin-ethyl-phenylamine based MDR inhibitors. METHODS: The novel MDR inhibitors, XR9577, WK-X-34, WK-X-50 and WK-X-84 were examined for cellular toxicity in several cell lines. Chemosensitivity and inhibition of BCRP-mediated mitoxantrone efflux were analyzed in BCRP-overexpressing MCF7/mx cells. Chemosensitivity towards daunorubicin and inhibition of Pgp-mediated efflux of (99m)Tc-Sestamibi were examined in Pgp-overexpressing A2780/Adr cells. Potential MRP-interactions were evaluated with 5-CFDA efflux assays in selectively transfected MRP-1, -2 and -3 cell lines. RESULTS: All WK-X-compounds showed significant BCRP inhibition in the MCF7/mx cells resulting in significant increases in mitoxantrone intracellular accumulation and 200-300 fold increases in mitroxantrone cytotoxicity. WK-X-34 and XR9577 were also potent inhibitors of Pgp, increasing (99m)Tc-Sestamibi accumulation with IC(50) values in the nM range. Daunorubicin cytotoxicity was also increased seven to eight-fold in cells co-treated with XR9577 or WK-X-34 (10 muM). These compounds did not appear to interact with the MRP transporters. As compared to cyclosporin A, these compounds showed reduced cellular toxicity and increased potency of BCRP and Pgp inhibition. CONCLUSION: The novel MDR inhibitors WK-X-34 and XR9577 demonstrate superior effectiveness in Pgp and BCRP inhibition, in vitro tolerance and specificity over cyclosporin A. The novel compounds might be the promising candidates for a broad-spectrum based approach to the circumvention of MDR in resistant tumors.

ATP Binding Cassette Transporter, Subfamily B↗