Abstract 3687: Analgesic effects of capsazepine on a mouse model of bone cancer pain

Abstract

Breast cancer has the highest incidence rate in women, accounting for more than 22% of all cancers and possessing a strong disposition to metastasize to bone. Discovered in 70% of advanced breast cancer patients and over 90% prevalence in patients who die from breast cancer, the affinity of this disease to metastasize bone has become overwhelming. These skeletal metastases become a significant cause of morbidity and mortality in patients with the primary symptom being pain. Pain is a major concern in determining a patient's quality of life and there have been many attempts to understand and control bone pain with little success. Capsazepine was identified during a high throughput screen to be a potent inhibitor of breast cancer cell-mediated glutamate release, a neurotransmitter with known associations in both neural communication and pain. This drug also has antagonistic effects on transient receptor potential vanilloid type 1 (TRPV-1) receptors which act as key players in both heat and vanilloid-induced nociception. Studies have shown that glutamate plays a role in bone cancer pain, with an excess in free glutamate able to cause pain either directly through excitotoxic pathways or indirectly though the dysregulation of osteoclasts and osteoblasts, causing bone dysregulation. TRPV-1 receptors have also has been implicated in the mechanisms of bone cancer pain, as osteoclasts release protons during bone remodeling which can elicit a TRPV-1-related nociceptive response from neurons in the surrounding periosteum. These findings suggest that Capsazepine may provide a powerful multi-pronged approach to treating cancer pain. A model of breast cancer-induced bone pain has been established using human MDA-MB-231 breast adenocarcinoma cells injected into the femurs of BALB/c nude mice. Behavioural tests are then preformed using the dynamic plantar aesthesiometer (DPA) and the dynamic weight bearing (DWB) devices on the affected limb for both movement-evoked and spontaneous pain-related behaviours. Using Capsazepine, delivered intraperitoneally via mini-osmotic drug pumps (5kg/mg and 10kg/mg), we demonstrate a dose-dependent attenuation of pain behaviours in vivo. While confirming tumour presence using immunohistochemistry (IHC) we show that TRPV-1 and glutamate play an important role in the onset and severity of bone cancer pain. The use of Capsazepine was able to attenuate these pain-related behaviours without the side effects of common analgesics. (This work is supported by the Canadian Institutes of Health Research (CIHR)) Citation Format: Matthew D. Balenko, Eric Seidlitz, Gurmit Singh. Analgesic effects of capsazepine on a mouse model of bone cancer pain. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3687. doi:10.1158/1538-7445.AM2014-3687