RESUMEN
Tumor hypoxic stress after photodynamic therapy (PDT) will be inevitably exacerbated by the vascular blocking effects and oxygen consumption in the tumor microenvironment (TME) which usually leads to compromised efficacy and clinical performance. Increasing evidence links the hypoxia induced up-regulation of hypoxia inducible factor 1α (HIF-1α) with immunosuppressive TME, including the polarization of M2 phenotype tumor associated macrophages (TAMs), which promote the recurrence and metastasis. Here, we reported NIR-triggered core-satellite upconverting nanoparticles (CSNPs) with curcumin (Cur) embedded as a difunctional photosensitizer, which could realize PDT in deep tumors with long excitation wavelength (980 nm) and reverse the immunosuppressive TME induced by up-regulated HIF-1α at the same time. This Cur-loaded CSNPs (Cur-CSNPs)-mediated PDT could successfully induce the immunogenic cell death (ICD) of triple negative breast cancer (TNBC) cell lines (4T1 and MDA-MB-231) in vitro and repolarize the 4T1 cells co-cultured TAMs from pro-tumor M2 to the anti-tumor M1 phenotype. Furthermore, Cur-CSNPs-mediated PDT could suppress the 4T1 tumor growth in primary and distant sites through the synergistic immunotherapeutic effects in vivo by priming M1 type TAMs and CD4+/CD8+ T cells' infiltration. Our data highlight the novel application of CSNPs-embedded Cur as a difunctional photosensitizer to enhance the anti-tumor efficacy of PDT.
Asunto(s)
Curcumina , Nanopartículas , Fotoquimioterapia , Linfocitos T CD8-positivos , Línea Celular Tumoral , Curcumina/farmacologíaRESUMEN
Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Factor de Crecimiento del Tejido Conjuntivo/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Proteínas Oncogénicas/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genética , Ensayos Clínicos como Asunto , Factor de Crecimiento del Tejido Conjuntivo/genética , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Curcumina/farmacología , Curcumina/uso terapéutico , Progresión de la Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Matriz Extracelular/metabolismo , Regulación Neoplásica de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Neoplasias/genética , Neoplasias/mortalidad , Neoplasias/patología , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Pronóstico , Transducción de Señal/efectos de los fármacos , Tasa de Supervivencia , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
OBJECTIVE: To study the effects of triptolide-medicated serum on secretory function of adrenocortical cells isolated from rats. METHODS: Thirty SD rats were randomly divided into control group, prednisone group, and low-, medium- and high-dose triptolide groups. Rats were administered with normal saline, prednisone and low-, medium- and high-dose triptolide respectively by gastrogavage to prepare sera containing drugs. Primary adrenocortical cells were isolated from normal male rats and cultured with sera containing drug for 48 hours. Expression of proliferating cell nuclear antigen (PCNA) was observed by immunohistochemical method and number of PCNA-positive cells was counted. Ultrastructure of adrenocortical cells was observed under a transmission electron microscope. Content of corticosterone in supernatant of adrenocortical cell culture was detected by enzyme-linked immunosorbent assay, and real-time fluorescence quantitative polymerase chain reaction (PCR) was employed to investigate the expression of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) mRNA. RESULTS: As compared with the control group, content of corticosterone in supernatant of adrenocortical cell culture and expression of 3beta-HSD mRNA were significantly increased in the triptolide-treated groups, and the numbers of PCNA-positive cells were increased in the medium- and high-dose triptolide groups, however, they were decreased in the prednisone group. CONCLUSION: Triptolide-medicated serum can increase the secretion of corticosterone in rat adrenocortical cells in vitro.