Asunto(s)
Proliferación Celular/efectos de los fármacos , Diabetes Mellitus/tratamiento farmacológico , Células Secretoras de Insulina/efectos de los fármacos , Extractos Vegetales/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Swertia , Xantenos/farmacología , Animales , Humanos , Ratones , Quinasas DyrKRESUMEN
Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Inhibidores Enzimáticos/farmacología , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Physalis/química , Extractos Vegetales/farmacología , Witanólidos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Humanos , Isocitrato Deshidrogenasa/genética , Estructura Molecular , Mutación , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Relación Estructura-Actividad , Células Tumorales Cultivadas , Witanólidos/química , Witanólidos/aislamiento & purificaciónRESUMEN
Seven undescribed withanolides (1-7) and six artificial withanolides (8-13), along with 20 known compounds (14-33) were isolated from the aerial parts of Tubocapsicum anomalum. Their structures were confirmed by comprehensive spectroscopic analyses. The absolute configuration of compound 1 was defined by single-crystal X-ray crystallography. All isolates were evaluated for their antiproliferative effects against five human tumor cell lines (Hep3B, MDA-MB-231, SW480, HCT116 and A549), among which compound 24 (tubocapsanolide A) exhibited the highest activities against the MDA-MB-231 cells with an IC50 value of 1.89 ± 1.03 µM. Further studies showed that 24 exhibited significant damage to mitochondria in MDA-MB-231 cells, including excess reactive oxygen species, decreased mitochondrial membrane potential, and apoptosis initiation. In addition, compound 24 also inhibited cell migration. These findings show that tubocapsanolide A may be a promising molecule for triple-negative breast cancer treatment and merit further evaluation.