Cytotoxicity of natural products and derivatives toward MCF-7 cell monolayers and cancer stem-like mammospheres

Phytomedicine. 2015 Apr 15;22(4):438-43. doi: 10.1016/j.phymed.2015.01.012. Epub 2015 Feb 21.


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.

Purpose: 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.

Conclusion: 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.

Keywords: Artesunate; Cajanin stilbene acid (CSA); Cancer stem-like cells; Drug resistance; Mammospheres; Shikonin.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Artemisinins / pharmacology
  • Artesunate
  • Humans
  • MCF-7 Cells
  • Naphthoquinones / pharmacology
  • Neoplastic Stem Cells / drug effects*
  • Phytochemicals / pharmacology*
  • Salicylates / pharmacology
  • Spheroids, Cellular / drug effects*
  • Stilbenes / pharmacology


  • 3-hydroxy-4-prenyl-5-methoxystilbene-2-carboxylic acid
  • Antineoplastic Agents
  • Artemisinins
  • Naphthoquinones
  • Phytochemicals
  • Salicylates
  • Stilbenes
  • shikonin
  • Artesunate