Farnesyl dimethyl chromanol targets colon cancer stem cells and prevents colorectal cancer metastasis.

Abstract

The activation and growth of tumour-initiating cells with stem-like properties in distant organs characterize colorectal cancer (CRC) growth and metastasis. Thus, inhibition of colon cancer stem cell (CCSC) growth holds promise for CRC growth and metastasis prevention. We and others have shown that farnesyl dimethyl chromanol (FDMC) inhibits cancer cell growth and induces apoptosis in vitro and in vivo. We provide the first demonstration that FDMC inhibits CCSC viability, survival, self-renewal (spheroid formation), pluripotent transcription factors (Nanog, Oct4, and Sox2) expression, organoids formation, and Wnt/β-catenin signalling, as evidenced by comparisons with vehicle-treated controls. In addition, FDMC inhibits CCSC migration, invasion, inflammation (NF-kB), angiogenesis (vascular endothelial growth factor, VEGF), and metastasis (MMP9), which are critical tumour metastasis processes. Moreover, FDMC induced apoptosis (TUNEL, Annexin V, cleaved caspase 3, and cleaved PARP) in CCSCs and CCSC-derived spheroids and organoids. Finally, in an orthotopic (cecum-injected CCSCs) xenograft metastasis model, we show that FDMC significantly retards CCSC-derived tumour growth (Ki-67); inhibits inflammation (NF-kB), angiogenesis (VEGF and CD31), and β-catenin signalling; and induces apoptosis (cleaved PARP) in tumour tissues and inhibits liver metastasis. In summary, our results demonstrate that FDMC inhibits the CCSC metastatic phenotype and thereby supports investigating its ability to prevent CRC metastases.

• Authors: Kazim Husain, Domenico Coppola, Chung S Yang, Mokenge P Malafa
• Journal: Scientific reports (Sci Rep) Vol. 11 Issue 1 Pg. 2185 (01 26 2021) ISSN: 2045-2322 [Electronic] England
• PMID: 33500430 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Chromans
• Transcription Factors
• beta Catenin
• 2,2,5,7,8-pentamethyl-1-hydroxychroman

Topics

• 3T3 Cells
• Animals
• Apoptosis (drug effects)
• Biomarkers, Tumor (metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Self Renewal (drug effects)
• Cell Shape (drug effects)
• Chromans (pharmacology)
• Colorectal Neoplasms (blood supply, pathology)
• Female
• Inflammation (pathology)
• Mice
• Mice, Nude
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Neoplastic Stem Cells (drug effects, pathology)
• Neovascularization, Pathologic (pathology)
• Organoids (drug effects, pathology)
• Spheroids, Cellular (drug effects, pathology)
• Transcription Factors (metabolism)
• Wnt Signaling Pathway (drug effects)
• beta Catenin (metabolism)