RESUMEN
A previously undescribed and robust miR210 overexpression is shown in intestinal samples obtained from patients with radiation enteropathy and fibrotic cultured cells. In addition, miR-210 overexpression is repressed by antifibrotic treatment combining pentoxifylline and α-tocopherol.
Asunto(s)
Enfermedades Intestinales/tratamiento farmacológico , MicroARNs/metabolismo , Pentoxifilina/uso terapéutico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Traumatismos por Radiación/tratamiento farmacológico , Protectores contra Radiación/uso terapéutico , Antioxidantes/uso terapéutico , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Quimioterapia Combinada , Fibrosis/tratamiento farmacológico , Fibrosis/metabolismo , Humanos , Hipoxia/metabolismo , Enfermedades Intestinales/metabolismo , MicroARNs/antagonistas & inhibidores , Terapia Molecular Dirigida/métodos , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , ARN/metabolismo , ARN Mitocondrial , Traumatismos por Radiación/metabolismo , Radioterapia/efectos adversos , alfa-Tocoferol/uso terapéuticoRESUMEN
Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146, and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 showed single-agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both cisplatin and IR in vitro. The triple combination R1507-cisplatin-IR led to a dramatic delay in tumor growth compared with cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis, and survival. Finally, we identified that the nucleotide excision repair pathway was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Cisplatino/farmacología , Daño del ADN , Neoplasias Pulmonares/tratamiento farmacológico , Receptor IGF Tipo 1/antagonistas & inhibidores , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Proliferación Celular/efectos de los fármacos , Cisplatino/administración & dosificación , Regulación hacia Abajo , Femenino , Humanos , Inmunohistoquímica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Ratones Desnudos , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor IGF Tipo 1/inmunología , Receptor IGF Tipo 1/metabolismo , Transducción de Señal , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/metabolismo , Análisis de Supervivencia , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Chronic toxicities of locoregional and systemic oncological treatments commonly develop in long-term cancer survivors. Amongst these toxicities, post-radiotherapeutic complications alter patient's quality of life. Reduction of exposure of normal tissues can be achieved by optimization of radiotherapy. Furthermore, understanding of the fibrogenic mechanisms has provided targets to prevent, mitigate, and reverse late radiation-induced damages. This mini-review shows how (i) global molecular studies using gene profiling can provide tools to develop new intervention strategies and (ii) how successful clinical trials, conducted in particular with combined pentoxifylline-vitamin E, can take benefice of biological and molecular evidences to improve our understanding of fibrogenic mechanisms, enhance the robustness of proposed treatments, and lead ultimately to better treatments for patient's benefice.
RESUMEN
BACKGROUND: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. METHODS: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-ß1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. RESULTS: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-ß1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-ß1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway. CONCLUSIONS: The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-ß1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.