RESUMEN
Cancer is a leading cause of death worldwide. Recent research studies have revealed that GM3 derivatives have considerable promise as potential therapeutic agents for cancer. To discover novel GM3 derivatives as potential antitumor agents, a one-pot enzymatic synthesis was established, yielding 14 GM3 derivatives in high total yields (22-41%). Subsequently, the inhibitory activities of GM3 derivatives were assessed by wound-healing assays and Transwell assays and tumor-bearing animal models. Among all the GM3 derivatives, N-12 showed excellent migration and invasion inhibitory effects in cells and marked antitumor activity in C57BL/6 mice. The subsequent analysis of cancer tissues and serum samples revealed that N-12 induces tumor inhibition, which was closely related to immune response. Taken together, N-12 can be further developed as an effective therapeutic for the treatment of cancer. An RNA-sequencing (RNA-seq) analysis was then performed and indicated that the antitumor mechanism of N-12 involved focal adhesion and ECM-receptor interaction signaling pathways.
Asunto(s)
Antineoplásicos/uso terapéutico , Gangliósido G(M3)/análogos & derivados , Gangliósido G(M3)/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Citocinas/metabolismo , Gangliósido G(M3)/síntesis química , Gangliósido G(M3)/farmacocinética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad/efectos de los fármacos , Inmunoterapia , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , Necrosis/inducido químicamente , Transducción de Señal/efectos de los fármacosRESUMEN
Serum kinetics and organ distribution of [14C]-sialic acid-GM3 and [3H]-sphingosine-GM1, administered as an intravenous bolus, were analysed in Wistar rats. [3H]-GM1 and [14C]-GM3 had serum half-lives of 1.4 hours and 1.8 hours, respectively. Three hours after injection 75% of the GM1- and 38% of the GM3-associated label were present in the liver. Smaller yet significant amounts of label were present in the central nervous system, kidneys and lung. In vitro studies showed that [14C]-GM3 and [3H]-GM1 incubated with serum were predominantly bound to the High Density Lipoprotein and the Low Density Lipoprotein fractions. These results suggest a rapid serum clearance of exogenous gangliosides by the liver in rats.