Anti-rheumatic drug iguratimod protects against cancer-induced bone pain and bone destruction in a rat model

Abstract

The bone is one of the most common sites of metastasis in patients with cancer. Current treatments for bone metastases include bisphosphonates, denosumab, non-steroidal anti-inflammatory drugs and analgesics, but each of them has certain limitations. Cytokines and mediators released from various cells in the bone microenvironment may drive a vicious cycle of osteolytic bone metastases. Iguratimod (T-614), a novel disease-modifying anti-rheumatic drug, has demonstrated therapeutic effects by suppressing the production of inflammatory cytokines in rats and patients with rheumatoid arthritis. Therefore, the current study evaluated the hypothesis that iguratimod may protect against cancer-induced bone pain and bone metastasis in a rat model. For this purpose, rats inoculated with Walker 256 cells were treated with iguratimod from days 11–17 post-surgery. Mechanical paw withdrawal thresholds and expression levels of phosphorylated extracellular signal-related kinase (pERK) and c-Fos in the spinal cord were investigated to detect changes in bone pain. Bone destruction levels were detected using X-rays, hematoxylin and eosin and tartrate-resistant acid phosphatase staining. The results revealed that mechanical paw withdrawal thresholds and the expression levels of pERK and c-Fos declined in a dose-dependent manner in rats treated with iguratimod, and bone destruction severity was also reduced. These findings may provide important new insights into the treatment of bone metastasis symptoms.

Influence of Iguratimod on Bone Metabolism in Patients with Rheumatoid Arthritis: A Meta-analysis

“…Besides, some recent studies also have highlighted the potential benefits of IGU on bone metabolism in other clinical circumstances other than RA. For example, in vitro and in vivo studies have consistently showed that IGU could effectively protect against cancer-induced bone pain and bone destruction, probably via downregulating interleukin-6 production in a nuclear factor- κ B-dependent manner [ 54 , 55 ]. Moreover, an early study has also suggested a directly inhibitory role of IGU on osteoclast formation and function, which may also be a candidate mechanism underlying the preventative efficacy of IGU against bone destruction [ 56 ].…”

Iguratimod: a valuable remedy from the Asia Pacific region for ameliorating autoimmune diseases and protecting bone physiology

“…Recently, Sun et al reported the efficacy of iguratimod in a rat model of cancer-induced bone pain as analyzed by mechanical paw withdrawal and pERK and c-Fos measurements in the spinal cord. 63 In addition, bone destruction was detected by histopathology and X-ray (Fig. 5).…”

Establishment, optimization and characterization of a rat model of breast cancer induced bone pain

“…Importantly, the majority of studies in the literature that used the Walker 256 breast cancer cell-induced bone pain model in rats, used the hind "paw" as a location to test hypersensitivity to evoked pain such as that induced by the von Frey test, rather than spontaneous or movement evoked pain (Cheng et al, 2016, Yao et al, 2011, Sima et al, 2016, Luo et al, 2016, Shenoy et al, 2016. There are many different studies recently published in 2017 to date, that used Walker 256 cells to induce bone pain in rats that only used stimuli evoked behavioural measures such as von Frey paw withdrawal thresholds in the hindpaws, but not spontaneous movement evoked or weight bearing measures to assess pain hypersensitivities (Liu et al, 2017b, Liu et al, 2017a, Yao et al, 2017, Sun et al, 2017b, Sun et al, 2017a, Dai et al, 2017, Hou et al, 2017, Hang et al, 2017, Zhou et al, 2018. However, in the preclinical research field of cancer induced bone pain, pioneering efforts are being made to introduce novel methods to assess hypersensitivity, like application of stimulus directly to the tibia (Falk et al, 2015a) or assessment of grid climbing behaviours (Falk et al, 2017).…”