ABSTRACT
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.
Subject(s)
Intestinal Diseases/drug therapy , MicroRNAs/metabolism , Pentoxifylline/therapeutic use , Platelet Aggregation Inhibitors/therapeutic use , Radiation Injuries/drug therapy , Radiation-Protective Agents/therapeutic use , Antioxidants/therapeutic use , Cells, Cultured/drug effects , Cells, Cultured/metabolism , Drug Therapy, Combination , Fibrosis/drug therapy , Fibrosis/metabolism , Humans , Hypoxia/metabolism , Intestinal Diseases/metabolism , MicroRNAs/antagonists & inhibitors , Molecular Targeted Therapy/methods , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , RNA/metabolism , RNA, Mitochondrial , Radiation Injuries/metabolism , Radiotherapy/adverse effects , alpha-Tocopherol/therapeutic useABSTRACT
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.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cisplatin/pharmacology , DNA Damage , Lung Neoplasms/drug therapy , Receptor, IGF Type 1/antagonists & inhibitors , Small Cell Lung Carcinoma/drug therapy , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal, Humanized , Cell Proliferation/drug effects , Cisplatin/administration & dosage , Down-Regulation , Female , Humans , Immunohistochemistry , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Mice , Mice, Nude , Molecular Targeted Therapy , Proto-Oncogene Proteins c-akt/metabolism , Receptor, IGF Type 1/immunology , Receptor, IGF Type 1/metabolism , Signal Transduction , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/metabolism , Survival Analysis , Xenograft Model Antitumor AssaysABSTRACT
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.
ABSTRACT
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.
