Old drugs, new uses: new perspectives for the repositioning of chemotherapy drugs and modulators of the extracellular matrix in breast cancer treatment.

DAIANA L. VITALE ; PAOLO ROSALES; ANTONELLA ICARDI ; CANDELA MORÁN ; INA SEVIC ; LAURA ALANIZ

Rosario

Congreso; SAIB 2023; 2023

Drug resistance is a major contributor to cancer recurrence. The tumor extracellular matrix (TECM) plays a significant role in drug resistance due to an imbalance in the synthesis and degradation of its components, including the glycosaminoglycan (GAG) hyaluronan (HA). This GAG accumulates in the TECM, impeding drug distribution and inducing pro-tumoral signals. UDP-glucuronic acid (UDP-GlcA) is synthesized by the UDP-glucose dehydrogenase (UGDH) enzyme. Together with N-acetyl-glucosamine, UDP-GlcA is involved in HA synthesis. Furthermore, this UDP-sugar plays a crucial role in the elimination of chemotherapeutic drugs as epirubicin (EPI). EPI is primarily metabolized through glucuronidation, involving a specific transferase called UGT2B7. Besides, candidate molecules proposed for drug repositioning include 4-methylumbelliferone (4MU), an orally approved dietary supplement derived from coumarins. 4MU specifically inhibits HA synthesis by binding to UDP-GlcA and depleting the cellular pool required for HA and other GAGs synthesis. The objective was to propose a combined treatment with EPI and 4MU in two breast cancer models to reduce EPI elimination and affect HA synthesis in TECM. To achieve this, 3D cultures (spheroids) of MDA-MB-231 and MCF-7 cells were established. After 5 days, spheroids were treated with EPI, 4MU, or EPI + 4MU for 3 days, completing 8 days of 3D culture under controlled conditions. Initially, it was determined that chemotherapeutic treatment with EPI was more effective in the presence of 4MU. Specifically, EPI + 4MU treatment reduced tumor cell viability (MTS) and increased early apoptosis (flow cytometry) in both breast cancer spheroids compared to control conditions (p