Development of a New Animal Model and Treatment Strategies for Aromatase Inhibitor-Associated Arthralgia

Abstract

Background: Aromatase inhibitors (AIs) are widely used as the most effective adjuvant chemotherapy for postmenopausal women with breast cancer. Unfortunately, nearly half of women receiving AIs have reported AI-associated arthralgia (AIA), which may increase cancer-related mortality and non-adherence to the therapy. As of now, no clear biological mechanisms of AIA have been found partially due to a lack of relevant animal models, and consequently, few beneficial treatments have been developed for AIA. Purpose: The purpose of this dissertation is to establish a clinically relevant animal model of AIA, and to examine potential treatment strategies for attenuating AIA by focusing on anti-nociceptive properties of curcumin (turmeric) and physical exercise. Methods: To mimic the clinical condition of AIA, female immune-deficient mice underwent tumor transplantation on flanks, surgical removal of grown tumors (~300 mm3) and ovaries, and subcutaneous injections of letrozole (10µg/day for 8 weeks). Mice weekly received behavior assays of musculoskeletal pain and physical function at pre-tumor baseline, post-tumor removal, and during AI treatment. To test effects of curcumin or physical exercise on AIA, letrozole-treated mice were given either 45 mg/kg curcumin or peanut oil (vehicle) orally, or they were housed either in cages with free voluntary running wheels or cages with locked wheels for five weeks, respectively. Following the interventions, protein expression levels of brain-derived neurotrophic factor (BDNF), a critical molecular moderator of pain behavior, were evaluated in the spinal dorsal horn. Results: Eight weeks of letrozole injections significantly induced mechanical allodynia, thermal (cold) allodynia, joint hypersensitivity, decreased grip strength, worsened motor coordination, and anteroposterior weight shift. Curcumin administration improved almost all deteriorated nocifensive behavior and neuromuscular function except for mechanical allodynia. Physical exercise enhanced the deteriorated nocifensive behavior but did not rescue neuromuscular dysfunction. BDNF protein expression levels were down-regulated following curcumin administration and physical exercise. Conclusion: This animal model is clinically relevant to AIA with face validity. It will provide an important platform to better understand progression and characteristics of AIA and allow examination of factors that cause AIA symptoms. Curcumin and physical exercise could be considered as effective interventions to reduce AIA symptoms and warrant studies in humans.