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PubMed1985

Antirespiratory and antiproliferative activity of anthralin in cultured human keratinocytes.

The effect of anthralin and its oxidation products, anthralin-dimer and anthralin-quinone, on protein content and thymidine incorporation as well as CO2 production from glucose and glutamine has been studied in transformed human keratinocytes in vitro. Anthralin exhibited the strongest inhibition, the dimer was generally less active and the quinone inactive. Respiration and thymidine incorporation were the most sensitive cellular functions showing 50% inhibition at about 1 and 3 microM anthralin, respectively. Comparison of the inhibition kinetics of anthralin with those of antimycin A and mitomycin C showed that anthralin behaved as an inhibitor of mitochondrial function rather than of DNA replication. The biologic effects were triggered in the first minutes of exposure to the cells when anthralin became rapidly associated with the cell membranes. Labeling experiments with [14C]anthralin revealed that the manifestation of the biologic response occurring after a latency phase of some hours coincided with the accumulation of radioactivity in the intracellular particulate fraction. The cytosol remained essentially unlabeled.

Anthracenes↗
PubMed1990

The antipsoriatic compound anthralin influences bioenergetic parameters and redox properties of energy transducing membranes.

Bioenergetic parameters and redox properties of energy transducing membranes in rat liver mitochondria and cyanobacteria were investigated in the presence of the antipsoriatic compound anthralin (1,8-dihydroxy-9-anthrone). Transmembrane pH and electrical gradients were determined using electron paramagnetic resonance spectroscopy. In mitochondria, ubiquinones 9,10 and other redox components of the electron transport chain are reduced by anthralin; the proton motive force is increased. In the absence of ADP, anthralin slightly stimulates mitochondrial cyanide-insensitive oxygen consumption. It is suggested that increased cyanide-insensitive respiration is due to enhanced autoxidation of mitochondrial components and/or catalyzed oxidation of anthralin. In the presence of ADP mitochondrial respiration is decreased, and ATP synthesis is inhibited. Uncoupler-induced mitochondrial respiration is also decreased by anthralin, indicating inhibition of the electron transport chain. In the cyanobacterium Synechococcus PCC 6311 anthralin increases the pH gradient and decreases ATP levels. Thus, anthralin acts as an electron donor to membrane associated redox components and inhibits ATP synthesis in two different biologic systems. In human keratinocytes oxygen metabolism is influenced by anthralin in a similar pattern as in isolated mitochondria, and ATP content is decreased. Because anthralin reacts with redox components in different biologic membranes, alterations of subcellular/cellular redox status and energy metabolism might contribute significantly to its antiproliferative activity.

Animals↗
PubMed2001

Cornified envelope formation by anthralin, simple analogues, and related anthracenones.

The ability of the antipsoriatic anthralin to induce HaCaT keratinocyte differentiation was investigated and correlated with its potency to inhibit proliferation of keratinocytes. To determine the structural requirements for this effect, anthralin and seventeen simple analogues or related anthracenones were examined for their ability to induce the formation of cornified envelope as a marker of terminal differentiation. Covalently cross-linked protein was measured as a key feature of this process. Induction of keratinocyte differentiation was significant at a concentration of 0.5 microM anthralin after 48 h exposure. The presence of the 1,8-dihydroxy groups is a critical determinant of cross-linking activity, since removing or exchanging these groups prevented the induction of keratinocyte differentiation. Furthermore, at least one hydrogen atom at the 10-position of anthralin is required. Moreover, anthralin, anthralin dimer, and anthralin triacetate exhibited antiproliferative and antirespiratory activity at concentrations required to induce keratinocyte differentiation, suggesting a causality between these effects. In addition, cornified envelope formation was observed for a number of related anthracenones at concentrations as low as 1-5 microM. In general, compounds containing benzoyl substituents, independent of the position in the anthralin nucleus, were more potent than those having benzyl substituents. Only marginal differences in cross-linking potency were observed within a number of phenylpropionyl substituted analogues, suggesting that the ability to induce keratinocyte differentiation is independent of the nature of substituents at the side chain.

Administration, Topical↗
PubMed1982

Anthralin: chemical instability and glucose-6-phosphate dehydrogenase inhibition.

The chemical stability of the antipsoriatic drug, anthralin (1,8-dihydroxy-9-anthrone), in solution has been studied using high-performance liquid chromatographic analysis. The time course for decomposition in solution has been correlated with that of the inhibition of glucose-6-phosphate dehydrogenase, one of the most widely documented biochemical properties associated with anthralin. Solutions of anthralin in aqueous buffer (37 degrees, pH 7.5, under light protection) completely within 4 hr giving the 10,10'-dimer (40%), no detectable 1,8-dihydroxy-9,10-anthraquinone, and a greatly increased potency of inhibition of glucose-6-phosphate dehydrogenase. This increased inhibitory potency could not be explained by formation of the dimer which, like anthralin and its quinone, were shown to be only weak inhibitors of the enzyme. In acetone solution exposed to light and air, anthralin decomposed completely within 4 days, in part via the dimer as intermediate. The final solution had the characteristic color of anthralin-brown, contained the quinone (20%), and like decomposed aqueous solutions of anthralin, completely inhibited glucose-6-phosphate dehydrogenase. The results show that neither anthralin, nor either of its two identified decomposition products, is the potent toxic species against glucose-6-phosphate dehydrogenase.

Acetone↗
PubMed2000

Anti-psoriatic drug anthralin activates JNK via lipid peroxidation: mononuclear cells are more sensitive than keratinocytes.

Anthralin is a widely used, topical therapy for psoriasis. Anti-proliferative and anti-inflammatory properties of anthralin have been identified. Little is known, however, about differential sensitivities of targeted cell types and specific mechanisms of signaling pathway activation. We demonstrate that anthralin exerts potent effects on keratinocytes and mononuclear cells through strong induction of lipid peroxidation and JNK activation, a stress-induced signal transduction pathway. Lipid peroxidation was observed rapidly and half-maximal levels of lipid peroxidation were reached at a 10-fold lower concentration of anthralin for peripheral blood mononuclear cells vs normal keratinocytes. JNK activation was detected in peripheral blood mononuclear cells at a 40-fold lower anthralin dose compared with keratinocytes. For both cell types, selected inhibitors of lipid peroxidation prevented JNK activation. This study demonstrates that mononuclear leukocytes are markedly more sensitive than keratinocytes to anthralin-induced lipid peroxidation and JNK activation. We identify anthralin as a novel and potent inducer of JNK activation and demonstrate that this process is mediated, at least in part, by lipid peroxidation which is among the earliest and most proximate, membrane-related responses to anthralin yet described.

Administration, Topical↗
PubMed2005

The anti-psoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria.

Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.

Anthralin↗
PubMed1989

Investigations of anthralin free radicals in model systems and in skin of hairless mice.

The antipsoriatic compound anthralin (1.8-dihydroxy-9-anthrone) is converted in skin into several oxidized products, including persistent free radicals that are not well characterized. Anthralin oxidation was investigated by electron spin resonance spectroscopy in a biological system and in a chemical system. Free radical formation in the skin of hairless mice is reduced by the antioxidant tocopherol. The data indicate that tocopherol acts by interfering with free radical formation rather than by scavenging persistent anthralin radicals directly. The skin radicals do not correspond to 10-anthranyl, the initial paramagnetic anthralin oxidation product. Similar radicals obtained in skin are formed by anthralin exposed to ultraviolet light or alkaline solution and by mitochondria and microsomes. The pertinent skin radical is attributed to products derived from anthralin dark structures, the final oxidation products of anthralin. It is suggested that resonance stabilized, paramagnetic polycyclic hydrocarbons are the compounds detected. Their stability and low reactivity indicate a low potential for cutaneous irritation and tumor promotion. Reactive oxygen species, which have been reported to be formed concomitantly during oxidation of anthralin, and the initially formed highly reactive 10-anthranyl radical are more potent candidates for mediating tumor promotion and inflammation.

Animals↗
PubMed2005

Inhibition of the nuclear factor-kappaB signaling pathway by leflunomide or triptolide also inhibits the anthralin-induced inflammatory response but does not affect keratinocyte growth inhibition.

We performed this study to determine the relationship between activation of nuclear factor (NF)-kappaB and inhibition of keratinocyte growth by anthralin, which not only might be useful for a better understanding of the role of NF-kappaB in the pathogenesis of psoriasis, but also indicate whether the inflammatory reaction induced by anthralin is inseparable from its antipsoriatic activity. The involvement of NF-kappaB was assessed using the antipsoriatic drugs leflunomide and triptolide (T0) as effectors, since they can inhibit NF-kappaB activation induced by anthralin. The results showed that the inhibition of keratinocyte growth by anthralin was not related to the activation of NF-kappaB. Using sodium salicylate, a known NF-kappaB inhibitor, further confirmed this conclusion. Thus it might be possible to inhibit the inflammatory response induced by anthralin via repression of NF-kappaB activation. We found that leflunomide or T0 could significantly inhibit the mRNA overexpression of interleukin-8 and intercellular adhesion molecule-1 in keratinocytes induced by anthralin. Taken together, our data indicate that the growth inhibition of anthralin is related to the NF-kappaB-independent signaling pathway, and that leflunomide or T0 could control proinflammatory cytokine expression induced by anthralin via inhibiting the activation of NF-kappaB.

Anthralin↗
PubMed1991

Synergistic stimulation of prostaglandin E2 release by epidermal growth factor and a tumor promoter anthralin from primary cultures of mouse epidermal cells.

The tumor promoter anthralin stimulated prostaglandin E2 (PGE2) and arachidonic acid release from primary cultures of mouse epidermal cells. Epidermal growth factor (EGF) hardly stimulated PGE2 release by itself; however, a combination of anthralin and EGF synergistically stimulated PGE2 release. Neither anthralin, EGF nor EGF plus anthralin affected the incorporation of arachidonic acid into cellular phospholipids at least up to 2 hr after the stimulation by these agents. In the presence of EGF, however, [3H]arachidonic acid in the medium decreased substantially 4-8 hr after the addition of this agent, indicating that EGF suppresses [3H]arachidonic acid release and stimulates the incorporation of [3H]arachidonic acid into the cells during this time period. Cellular cyclooxygenase activity was increased by treating the cells either with anthralin or EGF, and it was synergistically increased by EGF plus anthralin. Both cycloheximide and actinomycin D inhibited the increase in cyclooxygenase activity caused by EGF plus anthralin. These results indicate that the synergistic stimulation of PGE2 release caused by EGF plus anthralin is due to a synergistic stimulation of arachidonic acid release (in the early phase of stimulation) and a synergistic increase in cyclooxygenase activity, probably a synergistic induction of cyclooxygenase, by these agents.

Animals↗
PubMed1988

Anthralin-corticosteroid combination therapy in the treatment of chronic plaque psoriasis.

A prospective randomized trial of anthralin in Lassar's paste compared with anthralin in 0.0125% clobetasol propionate in the treatment of chronic plaque psoriasis was undertaken. The psoriatic skin of patients treated with the corticosteroid-anthralin combination cleared significantly more quickly than those treated with anthralin alone, with a mean time to clearance of 14.9 days compared with 18.5 days, and with lower concentrations of anthralin. No significant difference was found in the rate of relapse of the two treatment groups, with relapse occurring in over 80% of patients within one year. Anthralin in 0.0125% clobetasol propionate was found to be an effective agent in the treatment of chronic plaque psoriasis, and one that was cosmetically acceptable to patients and nursing staff. An important disadvantage, however, was the development of a staphylococcal folliculitis in four of the 35 patients in which it was used. Because of this, anthralin in Lassar's paste remains our standard inpatient therapy, although the ease of use and cosmetic acceptability of anthralin in clobetasol propionate make it a useful remedy for outpatient use.

Adolescent↗
PubMed1982

[Combined 1-hour therapy of psoriasis using anthralin and UV light].

Fifty-one patients with psoriasis were treated with 1% anthralin for 1 h (1-h treatment) and UV-light. Seven of 11 out-patients treated with anthralin and UV-B showed a good response. In 40 in-patients the 1-h regimen was administered in right-left side comparison to evaluate (1) whether UV-A or UV-B combined with anthralin was more effective than anthralin alone and (2) whether anthralin was photoactivated by UV-A or UV-B. As to the latter, one body side of the patients was exposed to UV radiation before and the other body side after application of anthralin. In in-patients the response to therapy was monitored by a defined score system. We did not find any significant differences in the paired comparisons. We therefore summarized the different treatment regimens and rated 42% with very good or good, 26% with fair, and 32% with poor. The results show that the 1-h treatment with 1% anthralin seems to be advantageous especially for the treatment of out-patients with circumscribed chronic psoriatic lesions. UV-light did not improve considerably the therapeutic effect of anthralin in the regimen of this study.

Adult↗
PubMed1997

Anthralin (dithranol) in vitro inhibits human monocytes to secrete IL-6, IL-8 and TNF-alpha, but not IL-1.

Anthralin is a most widely used compound for topical treatment of psoriasis. Whereas numerous studies have ascertained anthralin as a safe and effective drug its mode of action still remains unclear. Previous studies demonstrated dose-dependent inhibition of a number of pro-inflammatory functions in human neutrophils and monocytes (MO). The aim of the present study was to investigate in stimulated MO the effect of anthralin on the secretion of cytokines which are of known importance for the psoriatic tissue reaction. Highly purified MO were incubated with anthralin (0.01-1.0 microgram/ml), its clinically inactive derivative danthrone (0.1 and 10 micrograms/ml), the solvent acetone, or medium alone. Culture supernatants were analysed for immunoreactivity for interleukin-1 beta, and -8 (IL-1 beta, IL-8), and tumour necrosis factor alpha (TNF-alpha) by specific ELISA. IL-6 bioactivity was determined using the B9-bioassay. Additionally, IL-1 bioactivity was measured by the D10[N4]M-bioassay. The results show a dose-dependent inhibition of MO IL-6, IL-8, and TNF-alpha release with a half-maximal inhibitory concentration of 0.25-0.6 microgram/ml of anthralin. There was no effect of danthrone or acetone on the secretion of these cytokines from MO. Secretion of IL-1 beta immunoreactivity measured by ELISA as well as determination of biological activity of IL-1 using the D10[N4]M-bioassay revealed a slight increase in IL-1 secretion with a maximum at an anthralin concentration of 0.1 microgram/ml. Danthrone at a concentration of 10 micrograms/ml and acetone (0.1%) similarly enhanced IL-1 secretion from human MO measured by both methods. Our results demonstrate a differential, dose-dependent inhibition of cytokine secretion from human MO by anthralin. The present data provide evidence that the anti-inflammatory and anti-proliferative activity of anthralin may at least in part be due to its inhibitory effect on pro-inflammatory cytokine secretion by MO.

Administration, Topical↗
PubMed1998

Anthralin stimulates keratinocyte-derived proinflammatory cytokines via generation of reactive oxygen species.

OBJECTIVE AND DESIGN: Topical application of anthralin, used in the treatment of psoriasis, is often accompanied by severe skin inflammation, presumably due to free radical products of the drug. The role of inflammatory cytokines and their induction by anthralin-derived reactive oxygen species were studied in cultures of normal human keratinocytes (NHKs). MATERIALS AND METHODS: Anthralin was added to cultures of NHKs in the presence or absence of various antioxidants, including superoxide dismutase, tetramethylthiourea, N-acetylcysteine and vitamin E and relative changes in cytokine secretion and in the number of mRNA transcripts were examined. In addition, NHKs were either treated with neutralizing antibodies to tumor necrosis factor (TNF)-alpha or transfected with a CAT-linked IL-8 promoter to establish the direct effects of anthralin on chemokine synthesis. RESULTS: Anthralin, at concentrations between 5 microM and 25 microM, caused a marked increase in granulocyte macrophage-colony stimulating factor (GM-CSF), interleukin (IL)-6, IL-8 and TNFalpha synthesis that was selectively inhibited by specific antioxidants. Furthermore, anthralin induced chemokine secretion without the need of primary cytokines. CONCLUSIONS: Taken together, these studies suggest that oxygen radicals generated from anthralin are responsible for the induction of inflammatory cytokines which, in turn contributes to their dermal toxicity.

Acetylcysteine↗
PubMed1995

Short-contact anthralin treatment augments therapeutic efficacy of cyclosporine in psoriasis: a clinical and pathologic study.

BACKGROUND: Psoriasis is characterized by immune activation and increased epidermal proliferation. Cyclosporine acts by reducing T lymphocyte numbers and lymphokine production. Anthralin inhibits keratinocyte proliferation. OBJECTIVE: We investigated whether topical anthralin would augment clearing of psoriasis produced by systemic cyclosporine. METHODS: Twelve patients with psoriasis were treated with cyclosporine (5 mg/kg per day). Patients applied anthralin only to plaques on half of their body. They were treated until a remission or maximum benefit was achieved. Disease activity was assessed by a severity index and quantitative histopathologic markers. RESULTS: Of the 12 patients, the skin of five cleared within 10 weeks irrespective of anthralin use. The other seven (slow responders) continued treatment for a mean of 18 weeks. Slow responders had a significantly lower severity index, a thinner epidermis, fewer CD8+ cells, and fewer proliferating keratinocytes on the anthralin-treated side than on the non-anthralin-treated side. CONCLUSION: The combination of cyclosporine and topical anthralin is effective in patients who are slow to respond to cyclosporine alone.

Administration, Cutaneous↗
PubMed1986

Effect of short-contact anthralin therapy on ultraviolet B irradiation of psoriasis.

The influence of short-contact anthralin on the therapeutic effect of ultraviolet B irradiation (Sylvania UV-21 tubes) was investigated with the half-body comparison method in fifteen outpatients with plaque-type psoriasis. The lesions on the right or left half of the body were exposed to one of the topically applied compounds (either anthralin and 2% salicylic acid in petrolatum or 2% salicylic acid in petrolatum alone) for 10 to 30 minutes daily. Of the fifteen patients, five (Group I) were given 0.3% anthralin and five (Group II) received increasing concentrations of anthralin (0.3, 1, 3%); the other five (Group III) were patients who had failed to respond to ultraviolet B therapy alone, and for them a new clearing treatment was started with the addition of anthralin in increasing concentrations (0.3%, 1%, 3%). Only two patients in Group I, one patient in Group II, and one in Group III showed a moderately better clearance of psoriasis on the short-contact anthralin side. Irritation of nonaffected skin by anthralin was common only during the first week of the treatment. Staining of clothes and bedding occurred.

Adolescent↗
PubMed2006

Anthralin: primary products of its redox reactions.

One-electron reduction significantly enhances the ability of anthralin, 1, to act as a hydrogen atom donor. On annealing of an MTHF glass in which the radical anion of anthralin, 1*-, is generated radiolytically, this species decays mainly by loss of H* to give the anthralyl anion, 2- . On the other hand, radicals formed on radiolysis of matrices that are suitable for the generation of radical anions or cations are capable to abstract H* from anthralin to give the anthralyl radical, 2* . Both 2- and 2* are obtained simultaneously by mesolytic cleavage of the radical anion of the anthralin dimer. Contrary to general assumptions, the anthralyl radical is found to be much more reactive toward oxygen than the anion. All intermediates are characterized spectroscopically and by reference to quantum chemical calculations. Attempts to generate the radical cation of anthralin by X-irradiation of an Ar matrix containing anthralin led also to significant formation of its radical anion, i.e., anthralin acts apparently as an efficient electron trap in such experiments.

Anions↗
PubMed1986

Anthralin (1,8-dihydroxyanthrone) is a potent inhibitor of leukotriene production and LTB4-omega oxidation by human neutrophils.

The effect of anthralin and its oxidation products danthrone and anthralin-dimer on the production of 5-lipoxygenase products (5-HETE, leukotriene B4, omega-oxidized LTB4) by Ca-ionophore A 23187-stimulated human neutrophils has been studied in vitro. Anthralin exhibited dose-dependent inhibitory activity showing 50% inhibition at 7 microM with 10(7) neutrophils. Inhibitory effects strongly depended upon cell densities and maximal inhibition occurred at low cell concentrations, whereas inhibitory rates of anthralin were low at high cell densities. Inhibition of leukotriene production persisted after washing of anthralin-treated neutrophils. Also, with increasing amounts of arachidonic acid as substrate only slight changes of inhibitory activity were detected, indicating a noncompetitive way of action. In addition to the inhibition of leukotriene-production, the formation of omega-OH-LTB4 from LTB4 as well as omega-COOH-LTB4 from omega-OH-LTB4 was inhibited with IC50 (half maximum inhibition concentration) near 4.4 microM and 2.2 microM, respectively. In contrast to anthralin, both metabolites--danthrone as well as anthralin-dimer--did not show any effect on leukotriene production and omega-oxidation even at high concentrations (up to 70 microM and 44 microM, respectively).

Anthralin↗
PubMed1982

Inhibition of DNA replication and repair by anthralin or danthron in cultured human cells.

The comparative effects of the tumor promoter anthralin and its analog, danthron, on semiconservative DNA replication and DNA repair synthesis were studied in cultured human cells. Bromodeoxyuridine was used as density label together with 3H-thymidine to distinguish replication from repair synthesis in isopycnic CsCl gradients. Anthralin at 1.1 microgram inhibited replication in T98G cells by 50%. In cells treated with 0.4 or 1.3 microM anthralin and additive effect was observed on the inhibition of replication by ultraviolet light (254 nm). In cells irradiated with 20 J/m2, 2.3 microM anthralin was required to inhibit repair synthesis by 50%. Thus there was no selective inhibitory effect of anthralin on repair synthesis. Danthron exhibited no detectable effect on either semiconservative replication or repair synthesis at concentrations below about 5.0 microM. Neither compound stimulated repair synthesis in the absence of ultraviolet irradiation. Thus, anthralin and danthron do not appear to react with DNA to form adducts that are subject to excision repair. Although both compounds appear to intercalate into supercoiled DNA in vitro to a limited extent, the degree of unwinding introduced by the respective drugs does not correlate with their relative effects on DNA synthesis in vivo. Therefore the inhibitory effect of anthralin on DNA replication and repair synthesis in T98G cells does not appear to result from the direct interaction of the drug with DNA.

Anthracenes↗