+ Site Statistics
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells

Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells

Molecular Cancer Therapeutics 11(4): 963-972

Cancer stem cells are implicated in resistance to ionizing radiation (IR) and chemotherapy. Honokiol, a biphenolic compound has been used in traditional Chinese medicine for treating various ailments. In this study, we determined the ability of honokiol to enhance the sensitivity of colon cancer stem cells to IR. The combination of honokiol and IR suppressed proliferation and colony formation while inducing apoptosis of colon cancer cells in culture. There were also reduced numbers and size of spheroids, which was coupled with reduced expression of cancer stem cell marker protein DCLK1. Flow cytometry studies confirmed that the honokiol-IR combination reduced the number of DCLK1+ cells. In addition, there were reduced levels of activated Notch-1, its ligand Jagged-1, and the downstream target gene Hes-1. Furthermore, expression of components of the Notch-1 activating γ-secretase complex, presenilin 1, nicastrin, Pen2, and APH-1 was also suppressed. On the other hand, the honokiol effects were mitigated when the Notch intracellular domain was expressed. To determine the effect of honokiol-IR combination on tumor growth in vivo, nude mice tumor xenografts were administered honokiol intraperitoneally and exposed to IR. The honokiol-IR combination significantly inhibited tumor xenograft growth. In addition, there were reduced levels of DCLK1 and the Notch signaling-related proteins in the xenograft tissues. Together, these data suggest that honokiol is a potent inhibitor of colon cancer growth that targets the stem cells by inhibiting the γ-secretase complex and the Notch signaling pathway. These studies warrant further clinical evaluation for the combination of honokiol and IR for treating colon cancers.

(PDF emailed within 0-6 h: $19.90)

Accession: 053577430

Download citation: RISBibTeXText

PMID: 22319203

DOI: 10.1158/1535-7163.MCT-11-0999

Related references

Inferring the Effects of Honokiol on the Notch Signaling Pathway in SW480 Colon Cancer Cells. Cancer Informatics 13(Suppl 5): 1-12, 2014

Honokiol inhibits melanoma stem cells by targeting notch signaling. Molecular Carcinogenesis 54(12): 1710-1721, 2016

A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Cell Stem Cell 12(5): 602-615, 2014

Quinomycin A targets Notch signaling pathway in pancreatic cancer stem cells. Oncotarget 7(3): 3217-3232, 2016

Inhibition of notch signaling in glioblastoma targets cancer stem cells via an endothelial cell intermediate. Stem Cells 28(6): 1019-1029, 2010

Radiation-induced Notch signaling in breast cancer stem cells. International Journal of Radiation Oncology, Biology, Physics 87(3): 609-618, 2013

Portulaca oleracea extract can inhibit nodule formation of colon cancer stem cells by regulating gene expression of the Notch signal transduction pathway. Tumour Biology 39(7): 1010428317708699, 2017

Honokiol Radiosensitizes Colon Cancer Stem Cells. 2012

Acute Lymphoblastic Leukemia Cells Inhibit the Differentiation of Bone Mesenchymal Stem Cells into Osteoblasts In Vitro by Activating Notch Signaling. Stem Cells International 2015: 162410, 2015

Notch signaling requires GATA-2 to inhibit myelopoiesis from embryonic stem cells and primary hemopoietic progenitors. Journal of Immunology 176(9): 5267-5275, 2006

Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway. Journal of Ethnopharmacology 209: 305-316, 2017

Human umbilical cord-derived mesenchymal stem cells inhibit proliferation but maintain survival of Jurkat leukemia cells in vitro by activating Notch signaling. Nan Fang Yi Ke Da Xue Xue Bao 34(4): 441-447, 2014

Honokiol suppresses renal cancer cells' metastasis via dual-blocking epithelial-mesenchymal transition and cancer stem cell properties through modulating miR-141/ZEB2 signaling. Molecules and Cells 37(5): 383-388, 2015

WNT antagonist, DKK2, is a Notch signaling target in intestinal stem cells: Augmentation of a negative regulation system for canonical WNT signaling pathway by the Notch-DKK2 signaling loop in primates. International Journal of Molecular Medicine 19(1): 197-201, 2007

Honokiol Eliminates Human Oral Cancer Stem-Like Cells Accompanied with Suppression of Wnt/ β -Catenin Signaling and Apoptosis Induction. Evidence-Based Complementary and Alternative Medicine 2013: 146136, 2013