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

Authors
Yang X, Liu J, Liu ZJ, Xia QJ, He M, Liu R, Liu W, Wang W, Liu J, Zhou XF, Zhang YH, Wang TH

Lab
Department of Anesthesiology and Institute of Neurological Disease, Translation Neuroscience Center, State Key Lab of Biotherapy, West China Hospital, Sichuan University, Chengdu, China

Journal
Curr Gene Ther.

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.