HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Cucurbitacin I suppressed stem-like property and enhanced radiation-induced apoptosis in head and neck squamous carcinoma--derived CD44(+)ALDH1(+) cells.

Abstract
Head and neck squamous cell carcinoma (HNSCC) is a prevalent cancer worldwide. Signal transducers and activators of transcription 3 (STAT3) signaling is reported to promote tumor malignancy and recurrence in HNSCC. Cucurbitacins, triterpenoid derivatives, are strong STAT3 inhibitors with anticancer properties. Recent studies have shown aldehyde dehydrogenase 1 (ALDH1) to be a marker of cancer stem cells (CSC) in HNSCC. The aim of this study was to investigate the therapeutic effect of cucurbitacin I in HNSCC-derived CSCs. Using immunohistochemical analysis, we firstly showed that CD44, ALDH1, and phosphorylated STAT3 (p-STAT3) were higher in high-grade HNSCCs, and that triple positivity for CD44/ALDH1/p-STAT3 indicated a worse prognosis for HNSCC patients. Secondly, CD44(+)ALDH1(+) cells isolated from seven HNSCC patients showed greater tumorigenicity, radioresistance, and high expression of stemness (Bmi-1/Oct-4/Nanog) and epithelial-mesenchymal-transitional (Snail/Twist) genes as p-STAT3 level increased. Furthermore, we found that cucurbitacin I (JSI-124) can effectively inhibit the expression of p-STAT3 and capacities for tumorigenicity, sphere formation, and radioresistance in HNSCC-CD44(+)ALDH1(+). Notably, 150 nmol/L cucurbitacin I effectively blocked STAT3 signaling and downstream survivin and Bcl-2 expression, and it induced apoptosis in HNSCC-CD44(+)ALDH1(+). Moreover, microarray data indicated that 100 nmol/L cucurbitacin I facilitated CD44(+)ALDH1(+) cells to differentiate into CD44⁻ALDH1⁻ and enhanced the radiosensitivity of HNSCC-CD44(+)ALDH1(+). Xenotransplant experiments revealed that cucurbitacin I combined with radiotherapy significantly suppressed tumorigenesis and lung metastasis and further improved the survival rate in HNSCC-CD44(+)ALDH1(+)-transplanted immunocompromised mice. Taken together, our data show that cucurbitacin I, STAT3 inhibitor, reduces radioresistant, distant-metastatic, and CSC-like properties of HNSCC-CD44(+)ALDH1(+) cells. The potential of cucurbitacin I as a radiosensitizer should be verified in future anti-CSC therapy.
AuthorsYi-Wei Chen, Kuan-Hsuan Chen, Pin-I Huang, Yu-Chih Chen, Guang-Yu Chiou, Wen-Liang Lo, Ling-Ming Tseng, Han-Sui Hsu, Kuo-Wei Chang, Shih-Hwa Chiou
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 11 Pg. 2879-92 (Nov 2010) ISSN: 1538-8514 [Electronic] United States
PMID21062915 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright©2010 AACR.
Chemical References
  • Hyaluronan Receptors
  • Isoenzymes
  • Radiation-Sensitizing Agents
  • Triterpenes
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • cucurbitacin I
Topics
  • Aldehyde Dehydrogenase (metabolism)
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Apoptosis (drug effects, radiation effects)
  • Carcinoma (pathology, radiotherapy)
  • Carcinoma, Squamous Cell
  • Down-Regulation (drug effects)
  • Gamma Rays (therapeutic use)
  • Head and Neck Neoplasms (pathology, radiotherapy)
  • Humans
  • Hyaluronan Receptors (metabolism)
  • Isoenzymes (metabolism)
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Squamous Cell (pathology, radiotherapy)
  • Neoplastic Stem Cells (drug effects, metabolism, pathology, physiology)
  • Radiation Tolerance (drug effects)
  • Radiation-Sensitizing Agents (pharmacology)
  • Retinal Dehydrogenase
  • Squamous Cell Carcinoma of Head and Neck
  • Triterpenes (pharmacology)
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: