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At least 19 recordsLinked to original sources
PubMed1992

Anthralin decreases keratinocyte TGF-alpha expression and EGF-receptor binding in vitro.

Anthralin is an effective topical treatment for active psoriasis; however, its mechanism of action is unknown. Both TGF-alpha and its receptor, the EGF receptor, are overexpressed in active psoriatic plaques and might, therefore, play a role in psoriatic epidermal hyperplasia. In order to assess whether anthralin might act via alteration of this growth factor pathway, we examined the in vitro effects of pharmacologic concentrations of anthralin on cultured normal human keratinocytes. Keratinocyte proliferation was inhibited by 98% at an anthralin concentration of 10 ng/ml. In contrast, lymphocyte proliferation was inhibited by only 50% at an anthralin concentration of 10 micrograms/ml. Anthralin treatment did not induce cell-cycle-specific growth arrest as assessed by flow-cytometric analysis of acridine-orange-stained keratinocytes. Northern analysis of anthralin-treated keratinocytes demonstrated a marked decrease in TGF-alpha mRNA expression. Anthralin-treated keratinocytes showed decreased binding of 125I-EGF and 125I-IGF-I to their respective receptors, but EGF receptor binding was inhibited to a greater extent. Anthralin decreased ligand-binding affinity and cell-surface numbers of EGF receptors as assessed by Scatchard analysis of 125I-EGF binding to anthralin-treated keratinocytes. These results indicate that anthralin alters components of the EGF receptor pathway in cultured keratinocytes and that these effects might contribute to the clinical efficacy of anthralin in the treatment of active psoriasis.

Anthralin↗
PubMed1992

Anthralin, a non-TPA type tumor promoter, synergistically enhances phorbol ester-caused prostaglandin E2 release from primary cultured mouse epidermal cells.

Primary cultures of mouse epidermal cells (i.e., target cells of skin tumor promotion) stimulated by 12-O-tetradecanoylphorbol-13-acetate (TPA) release prostaglandin E2 within 30 min. Anthralin, a non-TPA type tumor promoter, also stimulated PGE2 release; however, no release was detectable at least up to 4 hr after the addition of anthralin. When the cells were incubated with TPA plus anthralin, both PGE2 and arachidonic acid release were synergistically enhanced. Other non-TPA type tumor promoters, i.e., chrysarobin, 7-bromomethylbenz[a]anthracene, benzoylperoxide, okadaic acid and palytoxin, did not potentiate the TPA-caused PGE2 release. In protein kinase C-down regulated cells, the synergistic stimulation of PGE2 and arachidonic acid release by TPA plus anthralin were not detected. Anthralin plus TPA did not alter the incorporation of arachidonic acid into cellular phospholipids. Cellular cyclooxygenase activity was increased 2 hr after TPA stimulation. Anthralin-caused increase in cyclooxygenase activity was detected at 6 hr after the addition of anthralin. Cyclooxygenase activity was synergistically increased by treating the cells with TPA plus anthralin. Cycloheximide and actinomycin D inhibited the increase in cyclooxygenase activity caused by anthralin or TPA plus anthralin. These results indicate that anthralin synergistically stimulates TPA-caused PGE2 release by synergistically increasing arachidonic acid release and cellular cyclooxygenase activity.

Animals↗
PubMed1992

The antipsoriatic drug, anthralin, inhibits protein kinase C--implications for its mechanism of action.

In psoriatic patients, anthralin is known to attenuate lesional inflammation, but often generates perilesional dermatitis. This phenomenon is well reflected by the contrasting action of anthralin on human leukocytes. The release of reactive oxygen species (ROS) is inhibited by anthralin in phorbol ester-activated leukocytes, whereas anthralin directly induces this cellular response in unstimulated cells. In order to elaborate further the underlying mechanisms, we compared the kinetics of anthralin and different well-characterized stimuli, including the phorbol ester, phorbol-12-myristate-13-acetate, in this test system. Compared with standard stimuli, anthralin only marginally induced the release of ROS from human leukocytes and displayed different kinetics. Protein kinase C (PKC), the major cellular phorbol ester receptor, is considered to be involved in the regulation of this cellular response. Furthermore, its involvement in the pathophysiology of psoriasis has been suggested. Therefore, we also investigated the effects of anthralin on purified PKC. Anthralin was found to inhibit the enzyme activity in a dose-dependent manner but not to display any stimulatory effects. The present results provide first evidence that the therapeutic activity of anthralin, at least in part, might be mediated by inhibition of PKC.

Animals↗
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↗
PubMed1975

The effect of anthralin and its derivatives on epidermal cell kinetics.

An attempt was made to clarify the effect of anthralin on epidermal cell kinetics. Commercial anthralin powder was separated by column chromatography into three components: pure anthralin, 1,8-dihydroxyanthroquinotne, and anthralin dimer. The effect of these on the diurnal mitotic variation and the cell cycle of the hairless mouse epidermis was studied. Neither anthroquinone nor the anthralin dimer had any influence on these parameters. Both the chromatographically pure and commercial anthralins had similar effects. Mitotic activity was considerably reduced, although not to zero, with concomitant elimination of the diurnal peak. The G2 and S phases of the cell cycle were approximately doubled in length. Application of the pure and commercial anthralin also resulted in some irritation not seen with either the anthroquinone or dimer.

Acetates↗
PubMed1992

Inhibition of human monocyte functions by anthralin.

Anthralin is a well-established and widely used compound for topical treatment of psoriasis. In recent years attention has been focused on the anti-inflammatory properties of anthralin, with particular reference to psoriasis. In this study the effect of anthralin on human monocyte chemotaxis, superoxide-anion generation, and enzyme degranulation, were investigated. For comparison, the effect of the clinically inactive anthralin derivative danthrone and the solvent (acetone) were also studied. The results show that anthralin potently inhibits stimulated human monocyte superoxide-anion generation and enzyme degranulation, with a half-maximal inhibitory concentration (IC50) of as low as 0.02 micrograms/ml. Chemotactic migration of monocytes, however, was only affected when very high doses of anthralin (10 micrograms/ml) were used for pretreatment of the cells. Danthrone, up to a concentration of 10 micrograms/ml, or acetone alone (0.1%, v/v), did not inhibit the monocyte functions tested. Our results indicate that anthralin at pharmacological concentrations is a potent and selective inhibitor of human monocyte pro-inflammatory activities, by inhibiting respiratory burst activity (e.g. superoxide-anion generation) and enzyme degranulation, without affecting chemotactic migration.

Acetone↗
PubMed1992

Effect of H1-receptor blockade on anthralin inflammation.

The effect of terfenadine, an H1-receptor antagonist, on anthralin inflammation was studied in 12 subjects. Subjects were randomised to receive terfenadine 60 mg or placebo b.d. in a double-blind, cross-over study. Anthralin 5, 10 and 20 micrograms in 10 microliters chloroform was pipetted onto flexor forearm skin. Anthralin inflammatory oedema and erythema were measured using Harpenden calipers and a reflectance photometer, 48 h after anthralin application. After a 3-day washout period, placebo and terfenadine were restarted and the procedures repeated on the opposite arm. Anthralin erythema and oedema increased with dose but the dose-response curves showed no significant difference with or without terfenadine (p greater than 0.05). This study shows that H1-receptor blockade does not inhibit anthralin inflammation.

Adult↗
PubMed1991

Structure-function relationship of new anthralin derivatives assayed for growth inhibition and cytotoxicity in human keratinocyte cultures.

HaCaT keratinocyte cultures were exposed to twelve hydrophilic anthralin derivatives 1 to 12 with substituents at C-1 and C-8 of the anthrone skeleton, of one H at C-10 and of both H's at C-10 by lacton rings. After 3 microM treatment growth was determined by cellular protein content, 3H-thymidine- and 14C-amino-acid-uptake and cytotoxicity by the release of cytoplasmic LDH into the culture medium. In comparison to acetone control (100%) anthralin suppressed mean protein content, as well as DNA- and protein-synthesis to 33, 28, and 21%, respectively, and the drug revealed an enzyme release of 660%. In relation to the parent drug we found similar cell growth inhibitory effects of compounds 4, 6, 8, 9, 10, and 12. Deriv. 4, 8, and 10 were, however, to some extent less cytotoxic than anthralin, whereas deriv. 6, 9, and 12 were in the same range. An extreme suppression of growth parameters which differed from the anthralin effect by a factor 0.5-0.8 was caused by deriv. 11, showing the same cytotoxicity. Deriv. 1, 2, 3, 5, and 7 did not demonstrate any cytotoxicity. Concerning growth parameters, deriv. 2 induced a slight stimulation, deriv. 3 and 7 were completely ineffective, deriv. 1 and 5 induced slightly to moderately inhibited proliferation but both being much less effective than anthralin. These data indicate that the "minimum structure" concept by Krebs and Schaltegger--claiming 1-hydroxy-9-anthrone as a precondition for clinical antipsoriatic potency--is not valid at least in cell-biological tests and point toward possible usefulness of some experimental model compounds as alternative antipsoriatics.

Anthralin↗
PubMed1992

The effect of indomethacin on anthralin inflammation.

The effect of prostaglandin inhibition, using topical indomethacin, on anthralin inflammation was studied. Indomethacin gel and gel base were applied to opposite flexor forearm skin sites of 11 volunteers for 2 h and then washed off. Anthralin and UVB were then applied to the gel-treated skin and the anthralin- and UVB-induced erythema and oedema were measured at 2, 6, 24 and 48 h using Harpenden callipers and a reflectance erythrometer. Prostaglandin inhibition was demonstrated by a significant reduction of UVB erythema at the indomethacin-treated sites compared to the gel-base-treated sites. There was a small but significant reduction in anthralin erythema, but not oedema, at the indomethacin-treated sites compared to the gel-base sites. This study demonstrates that prostaglandins, and other inflammatory mediators because the inhibitory effect was small, are involved in anthralin inflammation.

Administration, Topical↗
PubMed1992

A semiempirical computational investigation of the antipsoriatic drug anthralin.

A series of computational studies was carried out, by using the highly successful Austin Model 1 (AM1) semiempirical method, to illuminate more completely the fundamental, molecular-level forces that affect the function and utility of the antipsoriatic drug anthralin. First, examination of the keto-enol tautomeric equilibrium by AM1 showed that the keto tautomer of the drug is 9.5 kcal/mol more stable than the enol form. Strong electrostatic forces involving the hydrogens on the hydroxy groups (a partial charge of +0.25 in both forms) and the keto oxygen (a partial charge of -0.40) apparently overcome the effects of the increased aromatic stabilization present in the enol form. Second, AM1 was applied to the degradation products of anthralin, 1,8-dihydroxy-9,10-anthraquinone, 1,8,1',8'-tetrahydroxy-10,10'-dianthrone, and a further oxidized form of the dimer. These molecules have been implicated in some of the unpleasant side effects of anthralin. Third, AM1 was used to predict the preferred site of ionization of anthralin.

Anthralin↗
PubMed1975

[Antipsoriatic effect of dithranol (anthralin). 1].

This review deals with the biochemical-pharmacological actions of anthralin (dithranol) and with the various possibilities of regulating the disturbed metabolism in psoriasis. A close relationship exists between enzyme inhibition, blocking of nucleic acid metabolism, and cytostatic-cytotoxic actions exerted by anthralin. Special reference is made of the inhibitory capacity on important enzymes of the pentose phosphate shunt the importance of which is briefly outlined. In vitro experiments with dithranol confirmed clinical observations such as the advantageous application of anthralin together with ultraviolet light or the decreased efficacy of anthralin incorporated in plain zinc paste.

Alkaline Phosphatase↗
PubMed1991

Effects of anthralin on mitochondrial bioenergetics.

Isolated mitochondria were used to determine what causes anthralin inhibition of oxidative phosphorylation. In good agreement with other results, the rate of oxygen consumption was not modified by anthralin when mitochondria were first uncoupled with FCCP, suggesting that only the last steps of the process leading to ATP phosphorylation are implicated. No effects were found at the level of the ATPase and the Pi carrier in contrast with a competitive inhibition of the ADP/ATP translocator. These experiments suggest an atractyloside-like effect to explain the action of anthralin on mitochondria.

Adenosine Triphosphatases↗
PubMed1977

A topical treatment program for psoriasis with low anthralin concentrations.

A treatment program for psoriasis in which 0.01--0.05% anthralin was used has been clinically evaluated. In such low concentrations it is possible to use anthralin if one simultaneously avoids exposing the skin to unnecessary external mechanical trauma, including the mechanical removal of the scales from the lesions. Applied in this fashion, anthralin then also becomes most suitable for use in ambulatory therapy. In these low concentrations it does not irritate either the involved or the non-involved psoriatic skin. No discoloration of the clothes, the skin, the hair or the nails was observed.

Administration, Topical↗
PubMed1975

Influence of ultraviolet light, various temperatures, and zinc ions on anthralin (dithranol). Biochemical and chemical investigations.

The changes of anthralin under various physical conditions (temperature, ultraviolet irradiation) were investigated by biochemical assay (inhibition of G-6-PDH activity), by oxygen monitor (increased oxygen consumption in the presence of zinc ions), and by recording the absorption spectra. Higher temperatures and exposure to ultraviolet light provoke the formation of a biochemically highly active compound within short periods of time. In clinical therapy, this compound may easily be formed when anthralin is used together with ultraviolet irradiation (Ingram method). Changes in the biochemical activity of anthralin are accompanied by changes in the absorption spectra. Oxidation (e.g. in the presence of zins ions) or inhibition of oxidation (e.g. in the presence of salicylic acid) may easily be detected by spectroscopic assay.

Absorption↗
PubMed1992

Anthralin is a potent inhibitor of pityrosporum orbiculare/ovale in vitro.

Two strains of Pityrosporum orbiculare/ovale were grown in a liquid medium and exposed to different concentrations of the imidazoles ketoconazole and clotrimazole as well as anthralin, liquor carbonis detergens and salicylic acid. With regard to growth inhibition of yeast cells, the efficacies of anthralin and the imidazoles were similar, a half-maximal inhibition being achieved with an anthralin concentration of 7 mg/l. Liquor carbonis detergens and salicylic acid also inhibited growth of Pityrosporum orbiculare/ovale, but only at much higher concentrations. The response to salicylic acid was mainly due to its acid pH.

Anthralin↗
PubMed1976

[PUVA and anthraline therapy of psoriasis, a clinical, histological and autoradiographic comparison].

Treatment of psoriasis with 8-Methoxypsoralen and long wave ultraviolet rays (UV-A) (PUVA) was carried out on 63 patients with severe psoriasis. 41 patients were given the medication orally, the other 22 had it applied locally. After 8.5 weeks, with an average of 25 radiations, about 54% of the patients were cleared of all symptoms or improved considerably. Histological and autoradiographical examinations were carried out to 10 of the orally treated patients. After three weeks of treatment we found a reduced H 3-thymidine-labelling-index (H 3-I) and a shortened DNA-synthesis-time (ts). The average cell cycle time (tc) was lengthened. The effect of PUVA is comparable to that of Anthralin therapy, but the clinical success and the length of treatment with the PUVA-method are inferior to those of the Anthralin-method. There we consider the Anthralin-method as used on in-patients at the Department of Dermatology at the University of Cologne, to be the more suitable method. The PUVA-method ist less complicated and its application easier for the physician as well for the patient, therefore we consider the PUVA-method more suitable for the treatment of out-patients.

Adult↗
PubMed1978

Structure and tumor-promoting activity of analogues of anthralin (1,8-dihydroxy-9-anthrone).

Seventeen analogues of the tumor-promoting agent anthralin were tested for the same biological property by repeated skin application on mouse skin using female ICR/Ha Swiss mice, after a single application of a subcarcinogenic dose of 7,12-dimethylbenz[a]anthracene. Seven of the compounds tested are new compounds. They are 1,8-diacetoxy-9-anthrone, 1,8-dimyristoyloxy-9-anthrone, 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1,8,10-trihydroxy-9-anthrone, 1,8-dihydroxy-9,10-dihydroanthracene, and myristoyljuglone. All compounds were used in pure form for the bioassays. Of the 17 test compounds four showed notable tumor-promoting activity. They are 1,8-dihydroxy-10-acetyl-9-anthrone, 1,8-dihydroxy-10-myristoyl-9-anthrone, 1-hydroxy-9-anthrone, and juglone. In order to determine whether there is any relationship between tumor-promoting activity and metal chelation in this series, the chelating abilities of anthralin and of its inactive analogue 1,8-dihydroxyanthraquinone were examined using the bivalent metal ions Cu(II), Zn(II), Mn(II), Mg(II), and Ca(II). No relationship between chelation and tumor-promoting ability was found.

Animals↗