title: Reversal of bone cancer pain by HSV-1-mediated silencing of CNTF in an afferent area of the spinal cord associated with AKT-ERK signal inhibition.
abstract: Pain induced by bone metastases has a strong impact on the quality of life of patients with cancer, but current therapies for bone cancer pain cannot attain a satisfactory therapeutic goal because of various adverse reactions. Currently, advanced monitoring is required to clarify pathogenic mechanisms, so as to develop more effective treatments. We constructed herpes simplex virus carrying small interference RNA for CNTF (HSV-siCNTF) and established cancer-induced bone cancer pain models with intra-tibial injection of MRMT-1 cells. At different time points after treatment, sensory function indicated by thermal hyperalgesia and mechanical allodynia was measured. The mechanism underlying sensory function regulated by CNTF was also determined. There was apparent mechanical and thermal hyperalgesia in rats injected with bone cancer cells. Bone destruction was detected in the area of tibia injected with tumor cells by the plain radiography. MRMT-1 cells and the increased number of osteoclasts were found in tibia sections stained with hematoxylin and eosin. Intrathecal injection of morphine or HSV-siCNTF significantly reduced the mechanical allodynia and thermal hyperalgesia, which was accompanied by astrocyte hypertrophy. The number of nerve fibers positive for substance P (SP) and calcitonin gene related peptide (CGRP) was significantly decreased, which was consistent with the decrease of CNTF, ERK/pERK, AKT/pAKT and c-fos expression. These results demonstrate that the HSV-siCNTF gene therapy appears beneficial for the treatment of pain induced by bone cancer via blocking the AKT-ERK signaling pathway. Our data suggest that CNTF interference may be considered a new target to develop an effective management for bone cancer pain.
authors: Xu
authors: X
authors: Yang
authors: Jia
authors: J
authors: Liu
authors: Zun-Jing
authors: ZJ
authors: Liu
authors: Qing-Jie
authors: QJ
authors: Xia
authors: Mu
authors: M
authors: He
authors: Ran
authors: R
authors: Liu
authors: Wei
authors: W
authors: Liu
authors: Wei
authors: W
authors: Wang
authors: Jin
authors: J
authors: Liu
authors: Xin-Fu
authors: XF
authors: Zhou
authors: Yun-Hui
authors: YH
authors: Zhang
authors: Department of Anesthesiology and Institute of Neurological Disease, Translation Neuroscience Center, State Key Lab of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. tinghua_neuron@263.net.
authors: Ting-Hua
authors: TH
authors: Wang
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000150:complications* / Q000473:pathology; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000037:antagonists & inhibitors* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D005822:Genetic Vectors / Q000008:administration & dosage / Q000627:therapeutic use; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006930:Hyperalgesia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007278:Injections, Spinal; D008297:Male; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
chemical_list: D020934:Ciliary Neurotrophic Factor; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051057:Proto-Oncogene Proteins c-akt; D048052:Mitogen-Activated Protein Kinase 3