Honokiol in combination with radiation targets notch signaling to inhibit colon cancer stem cells.
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.
Department of Molecular and Integrative Physiology, The University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
Sivapriya
S
Ponnurangam
Joshua M V
JM
Mammen
Satish
S
Ramalingam
Zhiyun
Z
He
Youcheng
Y
Zhang
Shahid
S
Umar
Dharmalingam
D
Subramaniam
Shrikant
S
Anant
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000498:Allyl Compounds; D010636:Phenols
D001713:Biphenyl Compounds; D004365:Drugs, Chinese Herbal; D017705:Lignans; D019001:Nitric Oxide Synthase; C005499:honokiol; D000498:Allyl Compounds; D010636:Phenols