Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres.
Although cancer stem-like cells (CSCs) are rare, they can enter a non-proliferative or dormant state and resist therapy. Furthermore, quiescent CSCs are responsible for metastases that can appear after curative surgical treatment of a primary tumor. Because of drug resistance of CSCs, the development of novel therapies is urgently required that specifically target CSCs.


OBJECTIVE
The aim of the present study was to investigate the potential of a panel of natural products and derivatives to inhibit CSC-enriched mammospheres of MCF-7 breast cancer cells.


METHODS
CD44(high)/CD24(low) cells were identified by flow cytometry and maintained as mammospheres. As a control, we used two clinically established anticancer drugs (5-fluorouracil and docetaxel). A panel of natural products, shikonin, two cajanin stilbene acid (CSA) derivatives and artesunate were tested by resazurin assay on CSC-enriched mammospheres and MCF-7 monolayer cells. Besides, cellular shikonin uptake experiments were performed by flow cytometry.


RESULTS
We found two CSA derivatives (Nos. 6 and 19) to be active cancer stem-like MCF-7 mammospheres. Especially, CSA derivative No. 19 clearly showed collateral sensitivity in mammospheres compared to monolayer cells.


CONCLUSIONS
Phytochemicals which provoke collateral sensitivity in cancer-stem like cells are worth more detailed investigations in the future, since there is a great potential for improved chemotherapy to eradicate tumors and prolong cancer patients' survival times.
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Ean-Jeong
EJ
Seo
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Benjamin
B
Wiench
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany.
Rebecca
R
Hamm
Cytometry Core Facility, Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany.
Malte
M
Paulsen
Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Hexing Road 26, 150040 Harbin, China.
Yuangang
Y
Zu
Key Laboratory of Forest Plant Ecology, Ministry of Education, Northeast Forestry University, Hexing Road 26, 150040 Harbin, China.
Yujie
Y
Fu
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, Staudinger Weg 5, 55128 Mainz, Germany. Electronic address: efferth@uni-mainz.de.
Thomas
T
Efferth
D000970:Antineoplastic Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D000077332:Artesunate; D006801:Humans; D061986:MCF-7 Cells; D009285:Naphthoquinones / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D064209:Phytochemicals / Q000494:pharmacology*; D012459:Salicylates / Q000494:pharmacology; D018874:Spheroids, Cellular / Q000187:drug effects*; D013267:Stilbenes / Q000494:pharmacology
C549543:3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid; D000970:Antineoplastic Agents; D037621:Artemisinins; D009285:Naphthoquinones; D064209:Phytochemicals; D012459:Salicylates; D013267:Stilbenes; C016101:shikonin; D000077332:Artesunate
Artesunate; Cajanin stilbene acid (CSA); Cancer stem-like cells; Drug resistance; Mammospheres; Shikonin