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Patient Derived Cell Culture and Isolation of CD133+ Putative Cancer Stem Cells from Melanoma
Published on: March 13, 2013
Resveratrol Can Differentiate Human Melanoma Stem-like Cells from Spheroids Treated With All-trans Retinoic Acid
Mina Kanai1, Akiho Shinagawa1,2, Masako Ota3
1Laboratory of Molecular Bromacology, Graduate School of Food Life Sciences, Toyo University, Gunma, Japan.
Background/Aim:
Stem-like cancer cells are believed to be the leading cause of therapy resistance in malignant melanoma (MM). All-trans retinoic acid (ATRA) differentiation therapy is considered a promising approach to eradicate stem-like cancer cells, but some melanoma cells are resistant to ATRA. This study aimed to examine whether resveratrol (RS), a natural polyphenol compound, could improve the response of MM stem-like cells to ATRA and explore the possible underlying mechanisms.
Materials And Methods:
MM stem-like cells were established from a spheroid model of A375 human MM cell line. The response to RES alone and in combination with ATRA, was examined through analysis of cancer stemness, cell viability, and protein expression.
Results:
The stem-like cells showed resistance to the anticancer drug docetaxel; however, the combination of RES and ATRA augmented the effects of docetaxel. Accordingly, these combinatorial effects were associated with significant inhibition of the expression levels of stemness markers CD133, OCT4, CD271, and ABCG2. The tested combinations also led to a significant increase in melanocyte differentiation marker SOX9, while efficiently suppressing the dedifferentiation marker SOX10. Notably, RES alone effectively up-regulated retinoic acid receptor beta (RARβ) expression and down-regulated crucial mediators like DNMT1, polycomb-group proteins EZH2, and BMI-1, which mechanistically explain how RES enhanced the differentiation-inducing effects of ATRA.
Conclusion:
The resistance of MM stem-like cells to ATRA can be attenuated by RES and combined applications of ATRA and RES provide a promising strategy for MM treatment.
Insights
Resveratrol (RS) enhances all-trans retinoic acid (ATRA) therapy for resistant malignant melanoma (MM) stem-like cells. This combination targets cancer stemness markers and promotes melanocyte differentiation, offering a promising MM treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Malignant melanoma (MM) stem-like cells drive therapy resistance.
- All-trans retinoic acid (ATRA) shows promise for eradicating these cells, but resistance occurs.
- Resveratrol (RS), a natural compound, is investigated for its potential to overcome ATRA resistance.
Purpose of the Study:
- To evaluate if resveratrol (RS) can improve the efficacy of ATRA in treating MM stem-like cells.
- To explore the underlying molecular mechanisms by which RS affects MM stem-like cell response to ATRA.
Main Methods:
- Established MM stem-like cells using a spheroid model of the A375 cell line.
- Assessed the effects of RS alone and in combination with ATRA on cancer stemness, cell viability, and protein expression.
- Analyzed key stemness markers (CD133, OCT4, CD271, ABCG2) and differentiation markers (SOX9, SOX10).
Main Results:
- RS and ATRA combination therapy augmented docetaxel's effects and significantly inhibited stemness markers.
- The combination increased melanocyte differentiation marker SOX9 and suppressed dedifferentiation marker SOX10.
- RS alone upregulated retinoic acid receptor beta (RARβ) and downregulated DNMT1, EZH2, and BMI-1, explaining enhanced ATRA differentiation effects.
Conclusions:
- Resveratrol (RS) can attenuate the resistance of malignant melanoma (MM) stem-like cells to ATRA.
- Combined application of ATRA and RS presents a promising therapeutic strategy for MM treatment.
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