Polyphenol-rich fraction of Bergenia ligulata regresses colon and breast cancer metastasis by cell-type specific mechanism.

[BACKGROUND] Colon and breast cancer are among the leading causes of mortality worldwide. The limited efficacy of current treatments highlighted an urgent need for improved therapeutic options. Bergenia ligulata, known for its anticancer properties in Indian traditional and folk medicine, has shown promise. However, the molecular basis of its effects, particularly its anti-metastatic properties, remains poorly understood. Anti-prostate cancer activity of a polyphenol-rich fraction from Bergenia ligulata (PFBL) rhizome extract, defined by LC-MS, has already demonstrated promising results in preclinical models.

[PURPOSE] The present study aims to investigate the anticancer activity and anti-metastatic potential of PFBL against colon and breast cancers in both in vitro and preclinical settings.

[STUDY DESIGN AND METHODS] PFBL was tested in CT26 and 4T1-inducedsubcutaneous/solid tumors in BALB/c mice, alone or in combination with standard chemotherapeutic drugs. Its effect was analyzed based on changes in tumor mass and levels of various molecular markers. The anti-metastatic potential of PFBL was evaluated in CT26 and 4T1 lung metastasis models in mice, focusing on the number of lung nodules and lung size.

[RESULTS] Our results demonstrated that PFBL efficiently regressed both CT26 and 4T1-induced subcutaneous/solid tumors, both alone and in combination with 5-FU/doxorubicin, without adversely affecting the health of the normal host. Notably, PFBL suppressed the lung metastasis of 4T1 and CT26 cells in mice with great efficacy. Analysis of tumor and cell extracts suggested that colon cancer cells underwent autophagy-mediated death, while breast cancer cells mainly died by caspase-dependent apoptosis. PFBL's actions involved AMPK-dependent inhibition of mTORC1, and subsequent increase in LC3II, PARP1, CDK4, and Cyclin D1 levels in HCT116 and MCF7 cells. Elevated intracellular ROS levels were identified as the major cause of death in both cancer types. PFBL treatment also reversed the expression of EMT markers in vivo and in vitro.

[CONCLUSION] PFBL regressed colon and breast cancer metastasis through distinct mechanisms with little effect on healthy mice. The present study highlights PFBL as a novel anti-tumor and anti-metastasis candidate, warranting further evaluation in clinical settings.