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Published on: May 11, 2016
Butylidenephthalide Abrogates the Snail-Induced Cancer Stemness in Oral Carcinomas
Pei-Yin Chen1,2, Shih-Chi Chao3,4, Pei-Ling Hsieh5
1School of Dentistry, Chung Shan Medical University, Taichung 402, Taiwan.
Abstract:
Oral cancer is one of the most common cancers worldwide, especially in South Central Asia. It has been suggested that cancer stem cells (CSC) play crucial roles in tumor relapse and metastasis, and approaches to target CSC may lead to promising results. Here, aldehyde dehydrogenase 1 (ALDH1) and CD44 were utilized to isolate CSCs of oral cancer. Butylidenephthalide, a bioactive phthalide compound from Angelica sinensis, was tested for its anti-CSC effects. MTT assay showed that a lower concentration of butylidenephthalide was sufficient to inhibit the proliferation of patient-derived ALDH1+/CD44+ cells without affecting normal cells. Administration of butylidenephthalide not only reduced ALDH1 activity and CD44 expression, it also suppressed the migration, invasion, and colony formation abilities of ALDH1+/CD44+ cells using a transwell system and clonogenic assay. A patient-derived xenograft mouse model supported our in vitro findings that butylidenephthalide possessed the capacity to retard tumor development. We found that butylidenephthalide dose-dependently downregulated the gene and protein expression of Sox2 and Snail. Our results demonstrated that overexpression of Snail in ALDH1-/CD44- (non-CSCs) cells induced the CSC phenotypes, whereas butylidenephthalide treatment successfully diminished the enhanced self-renewal and propagating properties. In summary, this study showed that butylidenephthalide may serve as an adjunctive for oral cancer therapy.
Insights
Butylidenephthalide, derived from Angelica sinensis, effectively targets oral cancer stem cells (CSCs) by inhibiting proliferation and metastasis. This compound shows promise as an adjunctive therapy for oral cancer.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Natural Product Chemistry
Background:
- Oral cancer is a global health concern, particularly in South Central Asia.
- Cancer stem cells (CSCs) are implicated in oral cancer relapse and metastasis.
- Targeting CSCs presents a promising therapeutic strategy.
Purpose of the Study:
- To investigate the anti-CSC effects of butylidenephthalide, a compound from Angelica sinensis.
- To evaluate butylidenephthalide's impact on aldehyde dehydrogenase 1 (ALDH1)-positive and CD44-positive oral cancer stem cells.
- To explore the potential of butylidenephthalide as an adjunctive therapy for oral cancer.
Main Methods:
- Isolation of oral cancer stem cells using ALDH1 and CD44 markers.
- In vitro assays (MTT, transwell, clonogenic) to assess butylidenephthalide's effects on CSC proliferation, migration, and invasion.
- In vivo studies using patient-derived xenograft mouse models.
- Analysis of gene and protein expression (Sox2, Snail).
Main Results:
- Butylidenephthalide inhibited proliferation of patient-derived ALDH1+/CD44+ cells without affecting normal cells.
- The compound reduced ALDH1 activity, CD44 expression, and suppressed CSC migration, invasion, and colony formation.
- Butylidenephthalide dose-dependently downregulated Sox2 and Snail expression, diminishing CSC self-renewal and propagation properties.
- In vivo models confirmed butylidenephthalide's capacity to retard tumor development.
Conclusions:
- Butylidenephthalide exhibits significant anti-CSC activity in oral cancer.
- The compound targets key pathways involved in CSC self-renewal and metastasis.
- Butylidenephthalide demonstrates potential as an adjunctive agent in oral cancer treatment.
