RESUMEN
BACKGROUND: Cetuximab, an inhibitor targeting EGFR, is widely applied in clinical management of colorectal cancer (CRC). Nevertheless, drug resistance induced by KRAS-mutations limits cetuximab's anti-cancer effectiveness. Furthermore, the persistent activation of EGFR-independent AKT is another significant factor in cetuximab resistance. Nevertheless, the mechanism that EGFR-independent AKT drives cetuximab resistance remains unclear. Thus, highlighting the need to optimize therapies to overcome cetuximab resistance and also to explore the underlying mechanism. PURPOSE: This work aimed to investigate whether and how andrographolide enhance the therapeutic efficacy of cetuximab in KRAS-mutant CRC cells by modulating AKT. METHODS: The viabilities of CRC cell lines were analyzed by CCK-8. The intracellular proteins phosphorylation levels were investigated by Human Phospho-kinase Antibody Array analysis. Knockdown and transfection of PDGFRß were used to evaluate the role of andrographolide on PDGFRß. The western blotting was used to investigate Wnt/ß-catenin pathways, PI3K/AKT, and EMT in KRAS-mutant CRC cells. The animal models including subcutaneous tumor and lung metastasis were performed to assess tumor response to therapy in vivo. RESULTS: Andrographolide was demonstrated to decrease the expression of PI3K and AKT through targeting PDGFRß and EGFR, and it enhanced cetuximab effect on KRAS-mutant CRC cells by this mechanism. Meanwhile, andrographolide helped cetuximab to inhibit Wnt/ß-catenin, CRC cell migration and reduced Vimentin expression, while increasing that of E-cadherin. Lastly, co-treatment with cetuximab and andrographolide reduced the growth of KRAS-mutant tumors and pulmonary metastases in vivo. CONCLUSIONS: Our findings suggest that andrographolide can overcome the KRAS-mutant CRC cells' resistance to cetuximab through inhibiting the EGFR/PI3K/AKT and PDGFRß /AKT signaling pathways. This research provided a possible theory that andrographolide sensitizes KRAS-mutant tumor to EGFR TKI.
Asunto(s)
Neoplasias Colorrectales , Diterpenos , Proteínas Proto-Oncogénicas c-akt , Animales , Humanos , Cetuximab/farmacología , Cetuximab/genética , Cetuximab/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , beta Catenina/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Receptores ErbB/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Resistencia a Antineoplásicos , Línea Celular Tumoral , Vía de Señalización Wnt , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , MutaciónRESUMEN
Three new iridal-type triterpenoids (1-3) featuring a rearranged homofarnesylside chain were isolated from the rhizomes of Iris tectorum. Compounds 2 and 3 were found to be a pair of epimers. Their structures were elucidated on the basis of comprehensive spectroscopic analysis. A possible biosynthetic pathway for them was postulated. Moreover, the mixture of compounds 2 and 3 exhibited moderate neuroprotective activity against serum deprivation-induced PC12 cell death.
Asunto(s)
Género Iris/química , Fármacos Neuroprotectores/farmacología , Triterpenos/farmacología , Animales , China , Estructura Molecular , Fármacos Neuroprotectores/aislamiento & purificación , Células PC12 , Fitoquímicos/aislamiento & purificación , Fitoquímicos/farmacología , Ratas , Rizoma/química , Triterpenos/aislamiento & purificaciónRESUMEN
Heliosterpenoids A and B (1 and 2), two unprecedented jatrophane-derived diterpenoid esters with a novel 5/6/4/6-fused tetracyclic ring skeleton, were isolated from the whole plants of Euphorbia helioscopia. The structures of 1 and 2 were elucidated by extensive spectroscopic methods and electronic circular dichroism (ECD) analyses. The plausible biogenetic pathways of 1 and 2 were postulated. 1 and 2 were found to be potent inhibitors of P-glycoprotein (ABCB1) and 1 also exhibited cytotoxicity against MDA-MB-231 cell lines.
Asunto(s)
Antineoplásicos Fitogénicos/química , Diterpenos/química , Euphorbia/química , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ciclosporina/farmacología , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Doxorrubicina/farmacología , Expresión Génica , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Extractos Vegetales/químicaRESUMEN
Ten new clerodane diterpenoid glucosides (1-10) and three known analogues (11-13) were isolated from an EtOAc extract of the stems of Tinospora sinensis. Spectroscopic analyses and chemical methods were used to elucidate the structures of these isolates. The absolute configurations of tinosinenosides A-C (1-3) were established by using experimental and calculated ECD data. Their cytotoxicity against the human epithelioid cervical carcinoma (HeLa) cell line and the nitric oxide production inhibitory activity of lipopolysaccharide-activated N9 microglial cells were tested. 1-Deacetyltinosposide A (12) exhibited mild cytotoxicity against HeLa cells, with an IC50 value of 8.35 ± 0.60 µM.
Asunto(s)
Antiinflamatorios no Esteroideos/aislamiento & purificación , Diterpenos de Tipo Clerodano/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Glucósidos/aislamiento & purificación , Tallos de la Planta/química , Tinospora/química , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Diterpenos/farmacología , Diterpenos de Tipo Clerodano/química , Diterpenos de Tipo Clerodano/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Glucósidos/química , Glucósidos/farmacología , Glicósidos/farmacología , Células HeLa , Humanos , Concentración 50 Inhibidora , Lipopolisacáridos/farmacología , Macrófagos/efectos de los fármacos , Ratones , Estructura Molecular , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear BiomolecularRESUMEN
Four new aristolochic acid derivatives aristchamic A (1), aristchamic B (2), aristochamic C (3a), aristchamic D (3b) and one new aristolactam aristolactam-CV (4), together with 10 known compounds (5-14), were isolated from the rhizomes of Aristolochia championii. Their structures were assigned by detailed analysis of MS and NMR spectroscopic data. All of the isolated compounds were evaluated for their cytotoxic activities against HCT-116, HepG2, BGC-823, NCI-H1650, and A2780 cell. Compound 1 exhibited significant cytotoxic activity against HCT-116, HepG2, BGC-823, and NCI-H1650, with IC50 values of 0.50, 7.37, 2.66, and 0.75µM, respectively.
Asunto(s)
Aristolochia/química , Ácidos Aristolóquicos/química , Rizoma/química , Ácidos Aristolóquicos/aislamiento & purificación , Línea Celular Tumoral , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura MolecularRESUMEN
Phytochemical investigation of the rhizomes of Iris tectorum resulted in the isolation and characterization of three new apocynin derivatives, apocynin-4-O-ß-D-(6'-O-syringyl)glucopyranoside (1), scrophenoside C-7-ethyl ether (2, 3), together with a new naturally occurring compound but known by synthesis, apocynin-4-O-ß-D-xylopyranoside (4), and five known ones (5-9). Their structures were elucidated on the basis of spectroscopic data interpretation.
Asunto(s)
Acetofenonas/aislamiento & purificación , Género Iris/química , Acetofenonas/química , Glicósidos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Extractos Vegetales/química , Rizoma/químicaRESUMEN
Six new iridal-type triterpenoids containing an unprecedented cyclopentane ring, polycycloiridals E-J (1-6), were isolated from a large-scale re-extraction of Iris tectorum. A possible biosynthesis pathway is postulated. The known spirioiridotectal D (7) was also obtained in the current investigation, and its structure was unequivocally defined using X-ray diffraction data. Compound 7 suppressed LPS-activated NO production in the BV2 cell line with an IC50 value of 0.54 µM.
Asunto(s)
Ciclopentanos/aislamiento & purificación , Género Iris/química , Rizoma/química , Triterpenos/aislamiento & purificación , Ciclopentanos/química , Ciclopentanos/farmacología , Estructura Molecular , Extractos Vegetales/química , Triterpenos/química , Triterpenos/farmacología , Difracción de Rayos XRESUMEN
Three new flavonoid glycosides (1-3) and one new aristololactam N-glycoside (4) were isolated from the rhizome of Aristolochia championii. The structures of compounds 1-4 were elucidated on the basis of their spectroscopic data and chemical evidence (UV, IR, HR-ESI-MS, 1D and 2D NMR). Their structures were determined as 8-(5-formyl-2-furanmethyl)-isorhamentin 3-O-robinobioside (1), 8-(5-methyl-2-furanoyl)-isorhamentin 3-O-robinobioside (2), 8-formylisorhamentin 3-O-robinobioside (3), and N-ß-D-glucopyranosylaristololactam V (4), respectively.
Asunto(s)
Aristolochia/química , Flavonoides/aislamiento & purificación , Glicósidos/aislamiento & purificación , Rizoma/química , Medicamentos Herbarios Chinos/química , Flavonoides/química , Glicósidos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Phytochemical investigation on the whole plants of Iris japonica led to the isolation of four new aromatic glycosides. Their structures including the absolute configurations were determined by spectroscopic and chemical methods as (-)-4-hydroxy-3-methoxy acetophenone 4-O-ß-d-{6-O-[4-O-(7R,8S)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (1), (-)-4-hydroxy-3-methoxy acetophenone 4-O-ß-d-{6-O-[4-O-(7S,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (2), (-)-4-hydroxy-3-methoxy acetophenone 4-O-ß-d-{6-O-[4-O-(7R,8R)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (3), (-)-4-hydroxy-3-methoxy acetophenone 4-O-ß-d-{6-O-[4-O-(7S,8S)-(4-hydroxy-3-methoxyphenylglycerol-8-yl)-3-methoxybenzoyl]}-glucopyranoside (4), respectively.
Asunto(s)
Medicamentos Herbarios Chinos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Género Iris/química , Acetofenonas/química , Medicamentos Herbarios Chinos/química , Glicósidos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Nine new compounds, together with 16 known analogs, were isolated from the whole plants of Rehmannia chingii. The structures of compounds 1-9 were elucidated on the basis of their spectroscopic data and chemical evidence. In addition, the new compounds were tested for their hepatoprotective activities against APAP-induced HepG2 cell damage and their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line. Compounds 2 and 5 exhibited pronounced hepatoprotective activities against APAP-induced HepG2 cell damage at a concentration of 10 µM, and compounds 4 and 9 showed moderate inhibitory activity against microglial inflammation factor with IC50 values of 3.51 and 7.11 µM, respectively.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/aislamiento & purificación , Medicamentos Herbarios Chinos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Rehmannia/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Glicósidos/química , Glicósidos/farmacología , Células Hep G2 , Humanos , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Estructura Molecular , Óxido Nítrico/biosíntesisRESUMEN
Nine new iridoid glycosides, rehmachingiiosides A-I (1-9), together with 16 known analogues, were isolated from the whole plants of Rehmannia chingii. The structures of compounds 1-9 were elucidated on the basis of spectroscopic data analysis and from chemical evidence. Furthermore, in two vitro assays, compounds 5 and 10 showed an inhibitory effect on LPS-induced NO production with IC50 values of 2.5 and 7.3 µM, and compounds 4, 6, and 10-12 (when evaluated at 10 µM) exhibited evidence of hepatoprotective effects against APAP-induced HepG2 cell damage.
Asunto(s)
Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Glicósidos Iridoides/aislamiento & purificación , Glicósidos Iridoides/farmacología , Rehmannia/química , Acetaminofén/farmacología , Animales , Medicamentos Herbarios Chinos/química , Células Hep G2 , Humanos , Concentración 50 Inhibidora , Glicósidos Iridoides/química , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Estructura Molecular , Óxido Nítrico/biosíntesis , Resonancia Magnética Nuclear BiomolecularRESUMEN
Chemical examination of the ethanol extract of rhizomes of Iris tectorum led to the isolation and characterization of three new lignans, (7R,7'R,8S,8'S)-5'-methoxy-neo-olivil (1a), (7S,7'S,8R,8'R) -5'-methoxy-neo-olivil (1b), (7S,7'R,8S,8'S)-neo-olivil (2a), (7R,7'S,8R,8'R)-neo-olivil (2b), (7R,7'R,8S,8'S,7''S,8''S)-threo-neo-olivil-4'-O-8-guaiacylglycerol ether (3), together with six known ones (4-9). Among them, compounds 1 and 2 were found to be racemic mixtures, respectively, which were verified by chiral HPLC analysis, compound 3 was a new sesquineolignan. The structures were elucidated on the basis of extensive spectroscopic analysis. To our knowledge, this is the first report of lignan constituents isolated from I. tectorum. All compounds were evaluated for their cytotoxicity against five human tumor cell lines and none of them displayed significant toxicity in tested cell lines at a concentration of 10 µM.
Asunto(s)
Género Iris/química , Lignanos/química , Extractos Vegetales/química , Rizoma/química , Línea Celular Tumoral , Humanos , Lignanos/aislamiento & purificación , Estructura MolecularRESUMEN
Eleven flavonol glycosides were isolated from the ethanol extract of Lysimachia clethroides by a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, and reversed-phase HPLC. Their structures were identified as astragalin (1), isoquercitrin (2), isorhamnetin-3-O-ß-D-glucopyranoside (3), quercetin-3-O-ß-D-6"-acetylglucopyranoside (4), quercetin-7-O-ß-D-glucopyranoside (5), prunin (6), 2-hydroxynaringin-5-O-ß-D-glucopyranoside (7), kaempferol-3-O-rutinonoside (8), kaempferol-3-O-robinobioside (9), rutin (10) and kaempferol-3,7-di-O-ß-D-glucopyranoside (11). Among them, compounds 4, 7 and 11 were obtained from the Lysimachia genus for the first time, while compounds 3, 5 and 9 were firstly reported from this plant. In the preliminary assays, compounds 2, 6 and 8 possessed significant inhibition against aldose reduc- tase, with IC50 values of 2.69, 1.00, 1.80 µmol · L(-1), respectively; none of compounds 1-11 exhibited obvious cytotoxic activity (IC50 > 10 µmol · L(-1)).
Asunto(s)
Medicamentos Herbarios Chinos/química , Flavonoles/química , Glicósidos/química , Primulaceae/química , Estructura Molecular , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
Six novel iridal-type triterpenoids with a previously unreported 3,6-dihydro-2H-pyran moiety, named spirioiridotectals A-F (1-6), were isolated from the ethanol extract of the rhizomes of Iris tectorum. Their structures were elucidated on the basis of extensive spectroscopic analysis. Furthermore, in in vitro bioactivity assays, compounds 1, 2, and 6 exhibited neuroprotective activities against serum-deprivation-induced PC12 cell damage.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Iridaceae/química , Fármacos Neuroprotectores/aislamiento & purificación , Fármacos Neuroprotectores/farmacología , Triterpenos/aislamiento & purificación , Triterpenos/farmacología , Animales , Antineoplásicos Fitogénicos/química , Medicamentos Herbarios Chinos/química , Estructura Molecular , Fármacos Neuroprotectores/química , Resonancia Magnética Nuclear Biomolecular , Células PC12 , Ratas , Rizoma/química , Triterpenos/químicaRESUMEN
Four new ionone and ionone glycosides (1-4), and a new monoterpene (5), together with 10 known analogues (6-15), were isolated from the air-dried roots of Rehmannia glutinosa. The structures of these compounds were elucidated on the basis of spectroscopic data analysis. Furthermore, in in vitro assays, compound 3 (10 µM) exhibited moderate hepatoprotective activities against d-galactosamine-induced HL-7702 cell damage.
Asunto(s)
Medicamentos Herbarios Chinos/aislamiento & purificación , Glicósidos/aislamiento & purificación , Hepatocitos/efectos de los fármacos , Norisoprenoides/aislamiento & purificación , Rehmannia/química , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Galactosamina/farmacología , Glicósidos/química , Glicósidos/farmacología , Humanos , Estructura Molecular , Norisoprenoides/química , Norisoprenoides/farmacología , Resonancia Magnética Nuclear Biomolecular , Raíces de Plantas/químicaRESUMEN
Seven new triterpenoid saponins, schekwangsiensides A-G (1-7), and a new triterpenoid, schekwangsienin (8), together with nine known triterpenoids and saponins (9-17), were isolated from the aerial parts of Schefflera kwangsiensis. The structures of these compounds were elucidated on the basis of spectroscopic data analysis and chemical evidence. Furthermore, in in vitro assays, compounds 4, 8, 9, and 15 (10 µM) exhibited moderate hepatoprotective activities against D-galactosamine-induced HL-7702 cell damage.
Asunto(s)
Araliaceae/química , Sustancias Protectoras/farmacología , Saponinas/farmacología , Triterpenos/farmacología , Línea Celular , Galactosamina/toxicidad , Hígado/efectos de los fármacos , Resonancia Magnética Nuclear Biomolecular , Sustancias Protectoras/química , Sustancias Protectoras/aislamiento & purificación , Saponinas/química , Saponinas/aislamiento & purificación , Triterpenos/química , Triterpenos/aislamiento & purificaciónRESUMEN
Six new carboxylic acids (1-6), together with 11 known ones (7-17), were isolated from the aerial parts of Lysimachia clethroides. Their structures were elucidated on the basis of spectroscopic analysis and chemical evidence. Five new carboxylic acids (1 and 3-6) were evaluated for their in vitro inhibitory activity against aldose reductase.
Asunto(s)
Aldehído Reductasa/antagonistas & inhibidores , Ácidos Carboxílicos/aislamiento & purificación , Ácidos Carboxílicos/farmacología , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Primulaceae/química , Ácidos Carboxílicos/química , Medicamentos Herbarios Chinos/química , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Relación Estructura-ActividadRESUMEN
Eight new sesquiterpenes (1-8) and one new norsesquiterpene (9) named calamusins A-I were isolated from the ethanol extract of Acorus calamus rhizomes. The absolute configuration of compound 8 was determined by comparing its experimental and calculated ECD spectra. The absolute configurations of the other compounds were determined from their CD spectra. Furthermore, in in vitro assays, compounds 3, 4, 7, and 9 (10 µM) exhibited weak hepatoprotective activities against APAP-induced HepG2 cell damage.
Asunto(s)
Acorus/química , Medicamentos Herbarios Chinos/aislamiento & purificación , Sesquiterpenos/aislamiento & purificación , Acetaminofén/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Rizoma/química , Sesquiterpenos/química , Sesquiterpenos/farmacologíaRESUMEN
Catalpol is a active component in Rehmannia Root, and its pharmacological effects are extensive. In this paper its effects and chemical changes were summarized. This will offer the reference for further research work catalpol.