RESUMEN
Three new minor oleanane triterpenoid saponins, cylindrosides B (1), C (2), and D (3), were isolated from the seed of Cylindrokelupha dalatensis using chromatographic method. Their structures were established on the basis of the chemical and spectroscopic evidences. They displayed significant antitumor activity in vitro against HL60 cancer cell lines and IC50 values were 7.15 ± 0.63, 10.07 ± 0.97, and 4.74 ± 0.57 µM, respectively, by MTT method.
Asunto(s)
Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Plantas Medicinales/química , Saponinas/química , Saponinas/farmacología , Triterpenos/química , Triterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos , Células HL-60 , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
All-trans retinoic acid (ATRA)-based cell differentiation therapy has been successful in treating acute promyelocytic leukemia, a unique subtype of acute myeloid leukemia (AML). However, other subtypes of AML display resistance to ATRA-based treatment. In this study, we screened natural, plant-derived vibsane-type diterpenoids for their ability to induce differentiation of myeloid leukemia cells, discovering that vibsanin A potently induced differentiation of AML cell lines and primary blasts. The differentiation-inducing activity of vibsanin A was mediated through direct interaction with and activation of protein kinase C (PKC). Consistent with these findings, pharmacological blockade of PKC activity suppressed vibsanin A-induced differentiation. Mechanistically, vibsanin A-mediated activation of PKC led to induction of the ERK pathway and decreased c-Myc expression. In mouse xenograft models of AML, vibsanin A administration prolonged host survival and inhibited PKC-mediated inflammatory responses correlated with promotion of skin tumors in mice. Collectively, our results offer a preclinical proof of concept for vibsanin A as a myeloid differentiation-inducing compound, with potential application as an antileukemic agent. Cancer Res; 76(9); 2698-709. ©2016 AACR.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Diferenciación Celular/efectos de los fármacos , Diterpenos/farmacología , Leucemia Mieloide/patología , Fitoterapia/métodos , Animales , Western Blotting , Activación Enzimática/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína Quinasa C/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la Polimerasa , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A new triterpenoid saponin, named cylindroside A (1), was isolated from the seeds of Cylindrokelupha dalatensis (Kosterm.) T.L. Wu by using chromatographic method. The structure of 1 was established by comprehensive spectroscopic analysis and chemical degradation. Compound 1 displayed significant antitumor activity in vitro against BCG and MCF-7 cancer cell lines and IC50 values were 4.17 ± 0.23 and 3.07 ± 0.66 µM by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, respectively.