Abstract
Patients with tumors that metastasize to bone frequently suffer from debilitating pain, and effective therapies for treating bone cancer are lacking. This study employed a novel strategy in which herpes simplex virus (HSV) carrying a small interfering RNA (siRNA) targeting platelet-derived growth factor (PDGF) was used to alleviate bone cancer pain. HSV carrying PDGF siRNA was established and intrathecally injected into the cavum subarachnoidale of animals suffering from bone cancer pain and animals in the negative group. Sensory function was assessed by measuring thermal and mechanical hyperalgesia. The mechanism by which PDGF regulates pain was also investigated by comparing the differential expression of pPDGFRα/β and phosphorylated ERK and AKT. Thermal and mechanical hyperalgesia developed in the rats with bone cancer pain, and these effects were accompanied by bone destruction in the tibia. Intrathecal injection of PDGF siRNA and morphine reversed thermal and mechanical hyperalgesia in rats with bone cancer pain. In addition, we observed attenuated astrocyte hypertrophy, down-regulated pPDGFRα/β levels, reduced levels of the neurochemical SP, a reduction in CGRP fibers and changes in pERK/ERK and pAKT/AKT ratios. These results demonstrate that PDGF siRNA can effectively treat pain induced by bone cancer by blocking the AKT-ERK signaling pathway.
Highlights
Cancer patients with bone metastases suffer from debilitating pain that severely reduces their quality of life[1,2]
Hematoxylin and eosin (H&E) staining 28 days after injection demonstrated that the bone matrix in the bone marrow of these animals was damaged and filled with tumor cells and osteoclasts; these features were not observed in the normal control rats (Fig. 1A)
To evaluate the development of pain-related behaviors induced by the intra-tibial injection of tumor cells, tail-flick latency (TL) and paw withdrawal threshold (PWT) were assessed at baseline and 1, 2, 3 and 4 weeks after tumor cell inoculation
Summary
Cancer patients with bone metastases suffer from debilitating pain that severely reduces their quality of life[1,2]. HSV-mediated gene therapy has been employed to correct genetic defects associated with proenkephalin, glutamic acid decarboxylase, anti-inflammatory peptides and glial cell-derived neurotrophic factor. An HSV vector carrying 2 artificial PDGF small interfering RNAs was intrathecally injected into the L4–6 spinal cord segments of animals with bone cancer pain. Immunofluorescence staining demonstrated that PDGF localized to microglia cells, astrocytes and neurons, cell types expected to be infected by HSV These data demonstrate that reducing PDGF expression using RNAi inhibits the expression of glial fibrillary acidic protein (GFAP), substance p (SP), calcitonin gene-related peptide (CGRP) and the phosphorylation of ERK and AKT and represents a novel strategy for treating bone cancer pain
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