Phloretin suppresses metastasis by targeting protease and inhibits cancer stemness and angiogenesis in human cervical cancer cells.

Abstract

BACKGROUND:

Phloretin, a dihydrochalcone flavonoid, possesses anti-inflammatory activity and inhibits the growth of various cancers. However, the flavonoid's effect on cervical cancer metastasis and angiogenesis remains unknown.

PURPOSE:

In this study, we provide molecular evidence associated with the antimetastatic and antiangiogenic effects of phloretin.

METHODS:

In this study, the anti-invasive effect of phloretin (0-60 μM) in cervical cancer cells was evaluated using the Matrigel invasion assay, gelatin zymography, cell-matrix adhesion assay, wound healing assay, and Western blotting. Antiangiogenic potential of phloretin (0-100 μM) was assessed by the Matrigel tube formation assay. The in vivo antitumor effect of phloretin (10 or 20 mg/kg) was fed by oral gavage and determined using subcutaneous inoculation and tail vein injection in immunodeficient nude mice.

RESULTS:

Phloretin (60 μM) showed marked suppression of invasion and migration through downregulation of matrix metalloproteinase (MMP)-2, MMP-3, and cathepsin S in human SiHa cervical cancer cells. Phloretin (60 μM) reversed the epithelial-mesenchymal transition induced by transforming growth factor-β1 and downregulated mesenchymal markers, such as fibronectin, vimentin, and RhoA. Phloretin (100 μM) treatment significantly inhibited the aldehyde dehydrogenase 1 activity of SiHa cells, reduced the self-renewal properties and stemness signatures of CD44 and Sox-2 in sphere-forming cervical cancer-derived tumor-initiating cells, and inhibited the invasion, MMP-2 activity, and tube formation capacity of human umbilical vein endothelial cells. The ability of phloretin (20 mg/kg) to suppress lung metastasis and tumor growth in SiHa cells was evidenced by tail vein injection and subcutaneous inoculation in a tumor xenograft model.

CONCLUSION:

In summary, the findings indicate that phloretin inhibits the metastatic and angiogenic abilities and cancer stemness of SiHa cells, thereby suggesting that this flavonoid is a promising therapeutic agent for the treatment of human cervical cancer cells.

• Authors: Yi-Hsuan Hsiao, Ming-Ju Hsieh, Shun-Fa Yang, Shao-Pin Chen, Wen-Chi Tsai, Pei-Ni Chen
• Journal: Phytomedicine : international journal of phytotherapy and phytopharmacology (Phytomedicine) Vol. 62 Pg. 152964 (Sep 2019) ISSN: 1618-095X [Electronic] Germany
• PMID: 31153059 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier GmbH. All rights reserved.

Chemical References

• Antineoplastic Agents
• Matrix Metalloproteinases
• Phloretin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Epithelial-Mesenchymal Transition (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Human Umbilical Vein Endothelial Cells
• Humans
• Lung Neoplasms (prevention & control, secondary)
• Matrix Metalloproteinases (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasm Invasiveness (prevention & control)
• Neoplasm Metastasis (prevention & control)
• Neovascularization, Pathologic (drug therapy)
• Phloretin (administration & dosage)
• Uterine Cervical Neoplasms (drug therapy, pathology)
• Xenograft Model Antitumor Assays