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

Mol Cancer Ther. 2010 Nov;9(11):2879-92. doi: 10.1158/1535-7163.MCT-10-0504. Epub 2010 Nov 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / metabolism*
  • Aldehyde Dehydrogenase 1 Family
  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / radiation effects
  • Carcinoma / pathology
  • Carcinoma / radiotherapy
  • Carcinoma, Squamous Cell
  • Down-Regulation / drug effects
  • Gamma Rays / therapeutic use
  • Head and Neck Neoplasms / pathology
  • Head and Neck Neoplasms / radiotherapy
  • Humans
  • Hyaluronan Receptors / metabolism*
  • Isoenzymes / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Neoplasms, Squamous Cell / pathology
  • Neoplasms, Squamous Cell / radiotherapy
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neoplastic Stem Cells / 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


  • Hyaluronan Receptors
  • Isoenzymes
  • Radiation-Sensitizing Agents
  • Triterpenes
  • Aldehyde Dehydrogenase 1 Family
  • Aldehyde Dehydrogenase
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • cucurbitacin I