The complementary anti-cancer and analgesic properties of the natural product barettin.

Abstract

e15129 Background: Chemotherapy induced peripheral neuropathy (CIPN) is one of the most common side effects of chemotherapy and a leading cause of chemotherapy dose reduction and treatment cessation. This means that CIPN is not only a source of significant patient morbidity but also increases patient mortality. Despite this importance, the available treatments for CIPN remain limited. The marine natural product Barettin has previously been described to have anti-inflammatory effects and cytotoxicity only at doses above 100 mg/mL or 238 µM. We thus chose to investigate Barettin to determine if it could be used as a novel treatment for CIPN. Methods: Von Frey filaments were used to measure if Barettin had antinociceptive effects in a mouse model of CIPN. To assess the anti-cancer properties of Barettin, a growth inhibition assay using PanC-1 cells was utilized. To investigate the underlying mechanism of Barettin, the PRESTO-Tango assay was used to determine activity at the mu opioid (MOR) and Serotonin 2A (5HT2AR) receptors, while a decatenation assay was used to assess effects on Topoisomerase 2a activity. Results: Barettin presented dose dependent antinociceptive properties in a mouse model of CIPN when administered via intraperitoneal injection over a dose range of 32-178 mg/kg. Interestingly, this effect was seen specifically in adult male mice, with female mice having no response at all tested doses. Over a 48-hour treatment durations, 1 µM Barettin significantly decreased PanC-1 cell proliferation by approximately 50%. When investigating the underlying mechanism of these effects, Barettin was determined to act as an inverse agonist at the 5HT2AR and an inhibitor of Topoisomerase 2a, while having no activity at the MOR across all tested concentrations. Conclusions: Barettin acts as inverse agonist at the 5HT2AR, which mediates its antinociceptive properties in male mice with CIPN. Interestingly, Barettin also acts as an inhibitor of Topoisomerase 2a which mediates its ability to inhibit PanC-1 cell proliferation while having no cytotoxicity in normal cells at similar dosing. The dual anti-cancer and antinociceptive activities of Barettin suggest it could be utilized in the future as a chemotherapeutic agent that also simultaneously treats CIPN, ultimately leading to increased treatment efficacy and improved patient quality of life.