RESUMEN
The extracellular matrix (ECM) is critical for drug resistance in colorectal cancer (CRC). The abundant collagen within the ECM significantly influences tumor progression and matrix-mediated drug resistance (MMDR) by binding to discoidin domain receptor 1 (DDR1), but the specific mechanisms by which tumor cells modulate ECM via DDR1 and ultimately regulate TME remain poorly understand. Furthermore, overcoming drug resistance by modulating the tumor ECM remains a challenge in CRC treatment. In this study, a novel mechanism is elucidated by which DDR1 mediates the interactions between tumor cells and collagen, enhances collagen barriers, inhibits immune infiltration, promotes drug efflux, and leads to MMDR in CRC. To address this issue, a multistage drug delivery system carrying DDR1-siRNA and chemotherapeutic agents is employed to disrupt collagen barriers by silencing DDR1 in tumor, enhancing chemotherapy drugs diffusion and facilitating immune infiltration. These findings not only revealed a novel role for collagen-rich matrix mediated by DDR1 in tumor resistance, but also introduced a promising CRC treatment strategy.
Asunto(s)
Colágeno , Neoplasias Colorrectales , Receptor con Dominio Discoidina 1 , Sistemas de Liberación de Medicamentos , Resistencia a Antineoplásicos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Receptor con Dominio Discoidina 1/genética , Receptor con Dominio Discoidina 1/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Colágeno/metabolismo , Ratones , Animales , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antineoplásicos/administración & dosificación , Matriz Extracelular/metabolismo , Modelos Animales de EnfermedadRESUMEN
Inducers of heat shock protein 70 (Hsp70) commonly promote cancer cell viability whereas inhibitors of Hsp90 reduce it. The anticancer agent celastrol, interferes with signal transduction pathways involving these heat shock proteins. The objective of this in vitro study was to silence inducible Hsp70 and to promote celastrol-induced tumor cell death. Hsp70 siRNA loaded chitosan-TPP carriers were prepared by ionic gelation and characterized by photon correlation spectroscopy and asymmetric flow field-flow fractionation combined with dynamic light scattering. Viability of human leukemia and glioblastoma cells and Hsp70 silencing was determined following treatment with chitosan-TPP-Hsp70 siRNA particles. The results showed that silencing of Hsp70 by chitosan-TPP-Hsp70 siRNA treatment significantly reduced cell viability, and enhanced antiproliferative effects of celastrol in leukemia and glioblastoma cells. In glioblastoma spheroids, higher concentrations of celastrol and Hsp70 siRNA in chitosan-TPP nanocarriers were necessary to induce cell death.