Myricetin 3-rhamnoside retards the proliferation of hormone-independent breast cancer cells by targeting hyaluronidase

Abstract

Breast cancer is the second-leading cause of cancer-related death in women and the most often diagnosed malignancy. As the majority of chemotherapeutic medications are associated with recurrence, drug resistance, and side effects, scientists are shifting to beneficial agents for prevention and treatment, such as natural molecules. Myricetin 3-rhamnoside, a natural flavonol glycoside is known for diverse pharmacological activities but fewer reports describe the antiproliferative ability. The study aims to investigate the antiproliferative efficacy and target [hyaluronidase (HYAL) and ornithine decarboxylase (ODC), two poor breast cancer prognostic markers] modulatory potential of myricetin 3-rhamnoside on breast cancer cell lines using cytotoxicity assays and in silico docking, molecular dynamics analysis, cell-free and cell-based test methods. Myricetin 3-rhamnoside significantly retard the growth of MDA-MB-231 cells in SRB (IC50 88.64 ± 7.14 µM) and MTT (56.26 ± 8.50 µM) assay. It suppressed the transition of cells to the S-phase by inducing arrest in the G0/G1 phase with a fold change of 1.10. It shows robust binding interaction with ODC (-7.90 kcal/mol) and HYAL (-9.46 kcal/mol) and inhibits ODC (15.22 ± 2.61 µM) and HYAL (11.92 ± 2.89 µM) activity, but in a cell-based assay, the prominent response was observed against HYAL (21.46 ± 4.03 µM). Besides, it shows a 1.38 fold-down regulation of HYAL and forms a stable complex with HYAL. The binding pocket for myricetin 3-rhamnoside and the simulation pocket during the simulation are identical, indicating that myricetin 3-rhamnoside is actively blocking hyaluronidase. The computational prediction suggests it is a safe molecule. These observations imply that myricetin 3-rhamnoside could be used as a pharmacophore to design and synthesize a novel and safe agent for managing hormone-independent breast cancer. Communicated by Ramaswamy H. Sarma