RESUMEN
In a search for potential cancer chemopreventive agents from natural resources, stevioside (1), a sweetener, and six related compounds, including two aglycones steviol (6) and isosteviol (7), were screened in an in vitro assay for inhibitory effects on Epstein-Barr virus early antigen activation. Compounds 1, 6 and 7 showed significant activity in this assay and also exhibited strong inhibitory effects in a two-stage carcinogenesis test using mouse skin induced by 7,12-dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA). The inhibitory effects of these three compounds were greater than that of glycyrrhizin. Furthermore, these three compounds significantly inhibited mouse skin carcinogenesis initiated by peroxynitrite and promoted by TPA. Their activities were comparable to that of curcumin. These results suggested that 1, as well as 6 and 7, could be valuable as chemopreventive agents for chemical carcinogenesis.
Asunto(s)
Antineoplásicos/química , Diterpenos de Tipo Kaurano/química , Diterpenos de Tipo Kaurano/farmacología , Glucósidos/química , Glucósidos/farmacología , Animales , Antineoplásicos/farmacología , Pruebas de Carcinogenicidad , Quimioprevención/métodos , Curcumina , Ácido Glicirrínico , Herpesvirus Humano 4/efectos de los fármacos , Ratones , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/prevención & controlRESUMEN
The oxidation potentials of fifteen flavonoids in phosphate buffer at pH 7.2 were determined by cyclic voltammetry. A good correlation was found between these oxidation potentials and the ability of flavonoids to inhibit Epstein-Barr virus early antigen (EBV-EA) activation. Furthermore, multiple regression analysis revealed that the solvent-accessible surface area (SASA) was a useful parameter for estimating the inhibitory effects of flavonoids on EBV-EA activation.
Asunto(s)
Flavonoides/farmacocinética , Herpesvirus Humano 4/fisiología , Electroquímica , Oxidación-ReducciónRESUMEN
Because heat shock proteins (Hsps) are involved in protecting cells and in the pathophysiology of diseases such as inflammation, cancer, and neurodegenerative disorders, the use of regulators of the expression of Hsps in mammalian cells seems to be useful as a potential therapeutic modality. To identify compounds that modulate the response to heat shock, we analyzed several natural products using a mammalian cell line containing an hsp promoterregulated reporter gene. In this study, we found that an extract from Fructus Arctii markedly suppressed the expression of Hsp induced by heat shock. A component of the extract arctigenin, but not the component arctiin, suppressed the response at the level of the activation of heat shock transcription factor, the induction of mRNA, and the synthesis and accumulation of Hsp. Furthermore, arctigenin inhibited the acquisition of thermotolerance in mammalian cells, including cancer cells. Thus, arctigenin seemed to be a new suppressive regulator of heat shock response in mammalian cells, and may be useful for hyperthermia cancer therapy.
Asunto(s)
Arctium/química , Furanos/farmacología , Calor , Lignanos/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Células HeLa , Factores de Transcripción del Choque Térmico , Humanos , Ratones , Temperatura , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción Genética/efectos de los fármacosRESUMEN
Achyranthes aspera leaves have been assessed for chemopreventive activity. The MeOH extract, alkaloid, non-alkaloid and saponin fractions exhibited significant inhibitory effects (concentration 100 microg) on the Epstein-Barr virus early antigen activation induced by the tumor promotor 12-O-tetradecanoylphorbol-13-acetate in Raji cells. In this in vitro assay the non-alkaloid fraction containing mainly non-polar compounds showed the most significant inhibitory activity (96.9%; 60% viability). In the in vivo two-stage mouse skin carcinogenesis test the total methanolic extract possessed a pronounced anticarcinogenic effect (76%). The present study suggests that A. aspera leaf extract and the non-alkaloid fraction are valuable antitumor promotors in carcinogenesis.
Asunto(s)
Achyranthes/química , Antineoplásicos/farmacología , Herpesvirus Humano 4/crecimiento & desarrollo , Papiloma/prevención & control , Extractos Vegetales/farmacología , Neoplasias Cutáneas/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Femenino , Ratones , Ratones Endogámicos ICR , Papiloma/inducido químicamente , Papiloma/virología , Hojas de la Planta/metabolismo , Preparaciones de Plantas/farmacología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/virología , Acetato de Tetradecanoilforbol/toxicidad , Células Tumorales Cultivadas , Activación Viral/efectos de los fármacosRESUMEN
To search for cancer chemopreventive agents from natural resources, many phytochemicals and food additives have been screened. Consequently, two natural sweeteners, mogroside V and 11-oxo-mogroside V isolated from the fruits of Momordica grosvenori, exhibited strong inhibitory effect on the primary screening test indicated by the induction of Epstein-Barr virus early antigen (EBV-EA) by a tumor promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA). These sweet glycosides, having cucurbitane triterpenoid aglycon, exhibited the significant inhibitory effects on the two-stage carcinogenesis test of mouse skin tumors induced by peroxynitrite (ONOO-) as an initiator and TPA as a promoter. Further, 11-oxo-mogroside V also exhibited the remarkable inhibitory effect on two-stage carcinogenesis test of mouse skin tumor induced by 7,12-dimethylbenz[a]anthracene (DMBA) as an initiator and TPA as a promoter.
Asunto(s)
Anticarcinógenos/farmacología , Momordica/química , Edulcorantes/farmacología , Triterpenos/farmacología , 9,10-Dimetil-1,2-benzantraceno , Animales , Células Cultivadas , Cocarcinogénesis , Femenino , Linfocitos , Ratones , Ratones Endogámicos ICR , Ácido Peroxinitroso/farmacología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/prevención & control , Acetato de TetradecanoilforbolRESUMEN
Labdane-type diterpenes, called excoecarins S, T1, and T2 were isolated from the resinous wood of Excoecaria agallocha, along with three known compounds, ent-12-oxo-2,3-secobeyer-15-ene-2,3-dioic acid, agallochin H, and ent-15-epoxy-beyerane-3alpha-ol. Their structures were elucidated on the basis of spectroscopic data, chemical evidence, and X-ray analysis.
Asunto(s)
Diterpenos/química , Diterpenos/aislamiento & purificación , Euphorbiaceae/química , Cristalografía por Rayos X , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , MaderaRESUMEN
Grandinal, a new dimeric phloroglucinol compound, was isolated from Eucalyptus grandis and characterized by spectral techniques. Tautomeric structures 1, 2, and 3 were assigned to grandinal. Biogenetically, 1 is proposed to be formed from intermediates derived from grandinol and jensenone.
RESUMEN
In continuation of our studies with chemoprevention potential of plant-derived naphthoquinone derivatives, leaf powder of the medicinal plant Lawsonia inermis L, commonly known as 'henna', was evaluated by its inhibition of the Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells. Lawsone (2-hydroxy- 1,4-naphthoquinone), the reddish orange pigment artifact formed during the extraction or preparation of the dye from henna leaves and believed to be the active component, was also assessed in this in vitro assay. Both showed a profound inhibition (>88%) of EBV-EA activation. In the in vivo two-stage mouse skin carcinogenesis study using UV-B radiation for initiation and TPA for tumor promotion, oral feeding of henna (0.0025%) in drinking water ad libitum decreased tumor incidence by 66% and multiplicity by 40% when compared to the positive control at 10 weeks of treatment. Similarly, in the above mouse model, orally fed lawsone (0.0025%) decreased tumor incidence by 72% and multiplicity by 50%. The tumor inhibitory trend continued throughout the 20-week test period. Similar antitumor activities were observed when henna (0.5 mg/ml) was applied topically on the back skin in the UV-B initiated, TPA promoted and peroxynitrite initiated, TPA promoted mouse skin carcinogenesis models. Topically applied lawsone (0.015 mg/ml) also exhibited similar protection against tumor formation in the 7,12-dimtehylbenz(a)anthracene induced and TPA promoted skin cancer in mice. Also, there was a delay of 1 to 2 weeks in tumor appearance in both henna and lawsone treated groups compared to control in all three test models. This study ascertains the skin cancer chemopreventive activity of henna leaf powder and lawsone when administered by either oral (through drinking water) or topical (by application on the back skin) routes. Further, it emphasizes the need for the evaluation of these henna-derived green chemopreventive candidates in combination with currently used sunscreen agents for complementary anticancer potential against UV-induced skin carcinogenesis.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Carcinogénesis/efectos de los fármacos , Lawsonia (Planta)/química , Naftoquinonas/administración & dosificación , Papiloma/prevención & control , Extractos Vegetales/administración & dosificación , Hojas de la Planta/química , Neoplasias Cutáneas/prevención & control , 9,10-Dimetil-1,2-benzantraceno/toxicidad , Administración Cutánea , Administración Oral , Animales , Antígenos Virales/biosíntesis , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Linfocitos B/efectos de los fármacos , Linfocitos B/patología , Linfocitos B/virología , Carcinogénesis/patología , Línea Celular Tumoral , Femenino , Herpesvirus Humano 4/efectos de los fármacos , Herpesvirus Humano 4/fisiología , Humanos , Masculino , Naftoquinonas/química , Naftoquinonas/aislamiento & purificación , Papiloma/inducido químicamente , Papiloma/patología , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/patología , Acetato de Tetradecanoilforbol/farmacología , Rayos UltravioletaRESUMEN
BACKGROUND: Sunscreen compounds with added benefit of skin cancer prevention have both public and commercial interests. Our earlier study using the Epstein-Barr virus early antigen in vitro assay reported on skin cancer chemoprevention potential of benzophenone sunscreens. We now report the in vivo antitumor activity of two of the benzophenone sunscreens which tested positively in the in vitro assay, octabenzone (UV-1) and dioxybenzone (UV-2), in the two-stage mouse skin carcinogenesis model using (±)-(E)-4-methyl-2-[-(E)-hydroxyamino]-5-nitro-6-methoxy-3-hexanamide (NOR-1) as inducer and 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter. MATERIALS AND METHODS: Pathogen-free, female hairless mice of HOS:HR-1 strain, 15 animals per control and test groups, were used. Skin tumors were induced by a single dose of NOR-1 (390 nmol in 100 µl of acetone). One week later, TPA (1.7 nmol in 100 µl of acetone) was applied to skin twice weekly for 20 weeks as tumor a promoter. The test compounds UV-I or UV-2 were administered at 0.0025% to mice through drinking water ad libitum, starting one week prior to and stopping one week after tumor initiation. All animals were examined weekly for the development of skin papillomas. RESULTS: In both UV-1- and UV-2-treated mice, a two-week delay in tumor appearance, and significant inhibition (p<0.001) of tumor incidence (50% and 60%, respectively) and tumor burden (papilloma inhibition/mouse, 50% and 70%, respectively) were observed when compared to the positive control group. UV-2 (dihydroxy derivative) was a more potent inhibitor of skin tumor than UV-1 (monohydroxy derivative), which followed their antioxidant activity ranking. CONCLUSION: The results affirm the skin cancer chemoprevention potential of orally-ingested benzophenone sunscreens in mice and warrant studies in humans to validate synergistic protection achievable by complementation of oral and topical sunscreen usage.
Asunto(s)
Anticarcinógenos/administración & dosificación , Benzofenonas/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/prevención & control , Protectores Solares/administración & dosificación , Animales , Anticarcinógenos/uso terapéutico , Benzofenonas/uso terapéutico , Transformación Celular Neoplásica , Agua Potable , Femenino , Ratones , Ratones Pelados , Protectores Solares/uso terapéuticoRESUMEN
As part of a project aimed at obtaining compounds capable of inhibiting tumor promotion, new 6-amino-6-deoxyglycoglycerolipids (AGGLs) derived from 2-O-ß-D-glucopyranosyl-sn-glycerol were synthesized and tested for their anti-tumor-promoting activity using a short-term in vitro assay of the inhibition of Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). The corresponding 6-amino-6-deoxy-ß-D-octylglucosides were also prepared as simplified aminoglycolipid models and tested. Comparison with the activity of a series of previously studied glycoglycerolipids showed that replacing the 6-oxygen of the glucose moiety by a nitrogen atom greatly reduced the in vitro activity of the compounds. A two-stage mouse skin carcinogenesis test of two representative aminoglycoglycerolipids confirmed their reduced activity also in this in vivo model.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Glucósidos/química , Glucolípidos/química , Glucolípidos/farmacología , Animales , Antígenos Virales , Antineoplásicos/síntesis química , Ensayos de Selección de Medicamentos Antitumorales/métodos , Femenino , Humanos , Ratones , Estructura Molecular , Neoplasias Nasofaríngeas/tratamiento farmacológico , Neoplasias Nasofaríngeas/virología , Nitrógeno/química , Oxígeno/química , Papiloma/inducido químicamente , Papiloma/tratamiento farmacológico , Papiloma/patología , Neoplasias Cutáneas/inducido químicamente , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Relación Estructura-Actividad , Acetato de Tetradecanoilforbol/efectos adversos , Células Tumorales CultivadasRESUMEN
Umbelliprenin is a prenylated compound, which belongs to the class of sesquiterpene coumarins. In continuation of our earlier in-vitro finding, we determined to assess the cancer chemopreventive activity of umbelliprenin in vivo by using a two-stage carcinogenesis assay of mouse skin tumors induced by peroxynitrite as an initiator and TPA (12-O-tetradecanoylphorbol-13-acetate) as a promoter. In this assay, treatment with umbelliprenin along with peroxynitrite/TPA delayed the formation of papillomas up to week 9, and approximately 33.3 and 86.6% of the mice bore papillomas after 11 and 20 weeks of promotion, respectively. Umbelliprenin reduced the number of tumors per mouse by 45% after 20 weeks of promotion compared with the control group. Interestingly, this is equal to the corresponding value (45%) for curcumin, used as a reference standard compound in our study. In addition, the pattern of tumor promotion was slower in mice treated with umbelliprenin compared with the curcumin. Therefore, umbelliprenin might be valuable as a cancer chemopreventive agent.
Asunto(s)
Anticarcinógenos/uso terapéutico , Papiloma/prevención & control , Neoplasias Cutáneas/prevención & control , Umbeliferonas/uso terapéutico , Animales , Carcinógenos , Modelos Animales de Enfermedad , Femenino , Ratones , Papiloma/inducido químicamente , Ácido Peroxinitroso , Neoplasias Cutáneas/inducido químicamenteRESUMEN
A new complex tannin, cowaniin (1) was isolated from the leaves and stems of Cowania mexicana (Rosaceae), and its structure was characterized as novel C-glucosidic tannin dimer linked through (+)-catechin on the basis of spectral and chemical evidence. The inhibitory effect on activation of the Epstein-Barr virus early antigen was assessed for cowaniin. Six known polyphenols and related compounds, including a nitrile glucoside, purshianin, were also characterized.
Asunto(s)
Catequina/química , Rosaceae/química , Taninos/química , Estructura Molecular , Componentes Aéreos de las Plantas/químicaRESUMEN
From a MeOH extract of the aerial part of Piper futokadsura, the tetrahydrofuran lignans, futokadsurin A [(7S,8S,7'S,8'R)-3,4,3'-trimethoxy-4'-hydroxy-7,7'-epoxylignan], futokadsurin B [(7R,8R,7'R,8'S)-3,4-dimethoxy-3',4'-methylenedioxy-7,7'-epoxylignan], and futokadsurin C [(7R,8R,7'S,8'S)-3,4-methylenedioxy-3',4'-dimethoxy-7,7'-epoxylignan] were isolated, together with nine known neolignans. In addition, L-tryptophan, pellitorine, phytol, elemicin, and 1,2,4-trimethoxyphenyl-5-aldehyde were isolated. The structures of the new compounds were elucidated using spectroscopic methods. These lignans inhibited nitric oxide production by a murine macrophage-like cell line (RAW 264.7), which was activated by lipopolysaccharide and interferon-gamma.
Asunto(s)
Lignanos/aislamiento & purificación , Lignanos/farmacología , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico/biosíntesis , Piper , Animales , Línea Celular , Lignanos/química , Ratones , Componentes Aéreos de las Plantas , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacologíaRESUMEN
Six new chromones, 6-methoxy-2-[2-(3-methoxy-4-hydroxyphenyl)ethyllchromone (2), 6,8-dihydroxy-2-(2-phenylethyl)chromone (3), 6-hydroxy-2-[2-(4-hydroxyphenyl)ethyl]chromone (4), 6-hydroxy-2-[2-(2-hydroxyphenyl)ethyl]chromone (5), 7-hydroxy-2-(2-phenylethyl)chromone (6), and 6-hydroxy-7-methoxy-2-(2-phenylethyl)chromone (7) were isolated from the ether extract of agarwood in addition to a known compound, 2-(2-phenylethyl)chromone or flidersiachromone (1). Their structures were determined by spectroscopic methods including UV, IR, and NMR spectral data and comparisons with the calculated values using the hydroxyl and methoxyl substituent increments of the chromone ring.
Asunto(s)
Cromonas/aislamiento & purificación , Plantas/química , Cromonas/química , Análisis EspectralRESUMEN
Three new diterpenoids, excoecarins V1-V3 (1-3) and a new flavanone glycoside (7) were isolated from the fresh stem of Excoecaria agallocha L. Their structures were elucidated as: 2alpha,3alpha,18-trihydroxy-3beta,20-epoxybeyer-15-ene (1), ent-2,3-secokaur-16-en-2,3-dioic acid (2), ent-3,4-seco-16alpha-hydroxyatis-4(19)-en-3-oic acid (3), and 3,5,7,3',5'-pentahydroxy-2R,3R-flavanonol 3-O-alpha-L-rhamnopyranoside (7) on the basis of spectroscopic data, chemical evidence, and/or X-ray analysis.
Asunto(s)
Diterpenos/química , Euphorbiaceae/química , Flavanonas/química , Glicósidos/química , Diterpenos/aislamiento & purificación , Flavanonas/aislamiento & purificación , Glicósidos/aislamiento & purificación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Tallos de la PlantaRESUMEN
The MeOH extract of the roots of Inula helenium showed a high inhibitory activity for cell growth against MK-1, HeLa and B16F10 cell lines. Significant activity was found in the hexane-soluble fraction. From the hexane-soluble fraction, seven sesquiterpenes, namely, one germacrane (4beta,5alpha-epoxy-1(10),11(13)-germacradiene-8,12-olide), one elemane (igalane), and five eudesmanes (alantolactone, isoalantolactone, 11alpha,13-dihydroalantolactone, 11alpha,13-dihydro-isoalantolactone, 5-epoxyalantolactone) were isolated. In vitro antiproliferative activities of the isolates against MK-1, HeLa and B16F10 cells are reported.
Asunto(s)
Inhibidores de Crecimiento/farmacología , Inula/química , Lactonas/farmacología , Sesquiterpenos/farmacología , Animales , Antineoplásicos/aislamiento & purificación , Antineoplásicos/farmacología , Inhibidores de Crecimiento/química , Inhibidores de Crecimiento/aislamiento & purificación , Células HeLa , Humanos , Lactonas/química , Lactonas/aislamiento & purificación , Melanoma Experimental , Ratones , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Raíces de Plantas , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificación , Células Tumorales CultivadasRESUMEN
Two new bis-secolabdane diterpenoids, excoecarins R1 (1) and R2 (2), were isolated from the resinous wood of Excoecaria agallocha. The structures of 1 and 2 were established on the basis of spectroscopic data interpretation and chemical evidence.
Asunto(s)
Diterpenos/aislamiento & purificación , Euphorbiaceae/química , Plantas Medicinales/química , Diterpenos/química , Hidrólisis , Japón , Estructura Molecular , Oxidación-Reducción , Corteza de la Planta/química , Estereoisomerismo , MaderaRESUMEN
Five new euglobals possessing the phloroglucinol-monoterpene structure, euglobals G8-G12, together with a known euglobal-IIc were isolated from the hexane fraction of the methanol extract of the leaves of Eucalyptus grandis. Euglobal-G8 is an adduct of formyl-isovaleroyl-phloroglucinol and gamma-terpinene whereas -G9, -G10 and -G11 have the same phloroglucinol moiety fused with alpha-terpinene, while Euglobal-G12 has terpinolene fused with the same phloroglucinol moiety. The structures of these compounds were elucidated on the basis of spectral evidences. Biomimetic synthesis of euglobals suggests that these compounds are derived biogenetically by the Diels-Alder type cycloaddition of the corresponding terpenes with an ortho-quinone methide generated from grandinol.
RESUMEN
Resveratrol, sesamol, sesame oil and sunflower oil are known natural dietary components with intrinsic cancer chemopreventive potentials. As a part of our study of dietary constituents as potential cancer chemopreventive agents, we have assessed the anti-cancer potentials of these products in the promotion stage of cancer development employing the in vitro Epstein-Barr virus early antigen activation assay induced by the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA). Further, we studied the activities of these compounds in the brine shrimp cytotoxicity assay as well as on the stable 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging bioassay with a view to comparing some of the mechanisms of their anti-cancer activity. Finally, we compared the observed chemoprotective capabilities of the four products in the in vivo 7,12 dimethylbenz(a)anthracene initiated and TPA-promoted mouse skin two-stage carcinogenesis protocols. All the products tested showed a profound inhibitory effect on the Epstein-Barr virus early antigen induction using Raji cells. Comparatively, sesame oil was the most potent followed by sesamol and then resveratrol. Only sesamol and resveratrol showed a remarkable cytotoxic activity in the brine shrimp lethality assays as well as profound free radical scavenging activity in the DPPH bioassay. In both test systems, sesamol exhibited a more remarkable activity than resveratrol while sesame oil and sunflower oil did not exhibit any appreciable activity even at the highest concentrations tested (4000 microg ml(-1) ). In our in vivo assay at a 50-fold molar ratio to TPA, sesamol offered 50% reduction in mouse skin papillomas at 20 weeks after promotion with TPA. Under an identical molar ratio to TPA, resveratrol offered a 60% reduction in the papillomas in mouse at 20 weeks. Thus sesamol seems to be an almost equally potent chemopreventive agent. Sesame oil and sunflower oil offered 20 and 40% protection, respectively, in the mouse skin tumor model. The anti-oxidant capabilities of these compounds could not solely explain the observed anti-cancer characteristics. Resveratrol is present in grapes. Sesamol, a constituent of sesame oil and sunflower oil are regularly consumed dietary natural products. The observed chemopreventive effect of these products particularly warrants more attention since they already exist in the population with no known adverse effects.
Asunto(s)
Antígenos Virales/biosíntesis , Antineoplásicos Fitogénicos/farmacología , Artemia/efectos de los fármacos , Depuradores de Radicales Libres/farmacología , Herpesvirus Humano 4/fisiología , Neoplasias Cutáneas/prevención & control , Activación Viral/efectos de los fármacos , 9,10-Dimetil-1,2-benzantraceno , Animales , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad , Benzodioxoles , Compuestos de Bifenilo , Cocarcinogénesis , Femenino , Depuradores de Radicales Libres/uso terapéutico , Depuradores de Radicales Libres/toxicidad , Herpesvirus Humano 4/inmunología , Dosificación Letal Mediana , Ratones , Ratones Endogámicos ICR , Fenoles/farmacología , Fenoles/uso terapéutico , Fenoles/toxicidad , Picratos , Aceites de Plantas/farmacología , Aceites de Plantas/uso terapéutico , Aceites de Plantas/toxicidad , Resveratrol , Aceite de Sésamo/farmacología , Aceite de Sésamo/uso terapéutico , Aceite de Sésamo/toxicidad , Neoplasias Cutáneas/inducido químicamente , Estilbenos/farmacología , Estilbenos/uso terapéutico , Estilbenos/toxicidad , Aceite de Girasol , Acetato de Tetradecanoilforbol , Células Tumorales CultivadasRESUMEN
In continuation of our search for novel agents, we have investigated 29 phenothiazines and related tri-heterocyclic compounds as potential cancer chemopreventive agents in a short-term in vitro assay of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the evaluated compounds, chlorpromazine, phenoxazine, ethylpropazine, 9-oxo-9H-thioxanthene-3-carbonitrile-10,10-dioxide, thiothixene and phenothiazine showed profound inhibition of EBV-EA in the in vitro assay. This activity was influenced by a modification of the phenothiazine ring. Replacement of nitrogen in the phenothiazine ring with sulfur atoms decreased the anti-tumor activity. Overall analysis showed that the simple tri-cyclic compound phenoxazine was the most active anti-tumor promoting compound in the test system. Therefore, we assessed the anti-tumor promoting effect of phenoxazine in vivo in two different chemical carcinogen-induced-promotion experimental models in mice namely the 7,12-dimethylbenz(a)anthracene (DMBA) initiated and TPA-promoted ICR mouse skin two-stage carcinogenesis protocol and the peroxynitrite (PN)-induced and TPA-promoted skin carcinogenesis in HOS:HR-1 mouse. Following tumor initiation with DMBA, topical application of 0.0025% phenoxazine to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The compound exhibited remarkable inhibitory effects on the mouse skin tumor promotion in terms of a reduction in tumor multiplicity (>50%) and incidence, accompanied by an extension of the tumor latency. In the PN-induced and TPA-promoted two-stage mouse skin carcinogenesis, oral administration of phenoxazine (0.0025%) for 2 weeks showed profound decrease in both the tumor incidence and burden by more than 20 and 80%, respectively, at 10 weeks of treatment. This was also accompanied by a 20% delay in the tumor latency period. In all the treatment groups, there was no toxicity due to phenoxazine in the treatment groups as compared to the control animals. These significant anti-tumor potentials of phenoxazine either via topical or oral administration might be due to the inherent cytotoxicity of these classes of compounds, which can be utilized in the prevention of development of overt tumors, immunopotentiation, induction of differentiation and apoptosis. In addition, since phenoxazine derivatives and other related phenothiazine compounds in use, as anti-psychotic agents without any reported adverse effect are known to pass the blood-brain barrier, they represent a new class of cancer chemopreventive agents with greater implication in the prevention of brain cancers.