Submission
| Title: | Peripheral Monoacylglycerol Lipase Inhibition Prevents Neuropathy While Enhancing Tumor-Killing Efficacy of Chemotherapeutic Treatment in a Mouse Breast Cancer Model |
| Presenter: | Jonah Wirt |
| Institution: | Indiana University Bloomington, Psychological & Brain Sciences Department |
| Authors: | Jonah Wirt1,2; Emily Fender-Sizemore1; Mirjam Huizenga3; Mario Van Der Stelt3; Andrea G. Hohmann1,2,4
1Dept. of Psychological and Brain Sciences, Indiana University, Bloomington, IN; 2Program in Neuroscience, Indiana University, Bloomington, IN; 3Department of Molecular Physiology, Leiden University & Oncode Institute, Netherlands. 4Gill Center for Biomolecular Science, Indiana University, Bloomington, IN |
Abstract
| Background/Significance/Rationale: | Chemotherapeutic treatment for breast cancer produces anti-cancer effects but also produces dose-limiting toxicities such as neuropathic pain [1-3]. Inhibition of the primary enzymes that degrade endogenous cannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) suppress neuropathic nociception in models of chemotherapy-induced peripheral neuropathy (CIPN) and show anti-cancer properties [4-7]. 2-AG is degraded by the enzyme monoacylglycerol lipase (MGL) whereas AEA is degraded by fatty-acid Amide Hydrolase (FAAH), respectively. In the current studies, we compared a CNS-impermeable MGL inhibitor LEI-515, global MGL inhibitor JZL184, and peripheral FAAH inhibitor URB937 in their abilities to suppress development of CIPN and reduce tumor size in a mouse model of breast cancer. |
| Methods: | LEI-515, JZL184, URB937, or vehicle were administered prophylactically before and during administration of chemotherapeutic agent paclitaxel to assess the development of paclitaxel-induced mechanical (assessed by von Frey) and cold (assessed by the acetone test) hypersensitivities in non-tumor bearing and 4T1 breast cancer tumor-bearing mice. Tumor volumes were measured daily. At the terminal endpoint, colonic content weights were assessed. |
| Results/Findings: | LEI-515 and URB937 prevented the development of paclitaxel-induced mechanical and cold hypersensitivity in non-tumor bearing mice, and only LEI-515 fully suppressed hypersensitivities in tumor-bearing mice. JZL184 did not prevent the development of mechanical or cold hypersensitivity; tolerance developed to antinociceptive effects of JZL184. Peripheral MGL inhibitor LEI-515 and Global MGL inhibitor JZL184 reduced tumor size compared to chemotherapy alone when combined with paclitaxel. Paclitaxel-treated mice that received LEI-515 showed reduced tumor weights. Colonic weights of all paclitaxel groups increased. |
| Conclusions/Discussion: | Peripheral MGL and FAAH inhibition hold therapeutic potential for suppressing development of CIPN in breast cancer patients. |
| Translational/Human Health Impact: | Finding therapeutic treatment options that improve cancer patient quality of life through CIPN suppression without sacrificing anti-cancer efficacy remains a clinical imperative. These studies provide a rationale for the use of peripheral endogenous cannabinoid enzyme inhibition for breast cancer patients. |
