title: Natural compounds' activity against cancer stem-like or fast-cycling melanoma cells.
abstract: BACKGROUND
  Accumulating evidence supports the concept that melanoma is highly heterogeneous and sustained by a small subpopulation of melanoma stem-like cells. Those cells are considered as responsible for tumor resistance to therapies. Moreover, melanoma cells are characterized by their high phenotypic plasticity. Consequently, both melanoma stem-like cells and their more differentiated progeny must be eradicated to achieve durable cure. By reevaluating compounds in heterogeneous melanoma populations, it might be possible to select compounds with activity not only against fast-cycling cells but also against cancer stem-like cells. Natural compounds were the focus of the present study.
  
  
  METHODS
  We analyzed 120 compounds from The Natural Products Set II to identify compounds active against melanoma populations grown in an anchorage-independent manner and enriched with cells exerting self-renewing capacity. Cell viability, cell cycle arrest, apoptosis, gene expression, clonogenic survival and label-retention were analyzed.
  
  
  RESULTS
  Several compounds efficiently eradicated cells with clonogenic capacity and nanaomycin A, streptonigrin and toyocamycin were effective at 0.1 µM. Other anti-clonogenic but not highly cytotoxic compounds such as bryostatin 1, siomycin A, illudin M, michellamine B and pentoxifylline markedly reduced the frequency of ABCB5 (ATP-binding cassette, sub-family B, member 5)-positive cells. On the contrary, treatment with maytansine and colchicine selected for cells expressing this transporter. Maytansine, streptonigrin, toyocamycin and colchicine, even if highly cytotoxic, left a small subpopulation of slow-dividing cells unaffected. Compounds selected in the present study differentially altered the expression of melanocyte/melanoma specific microphthalmia-associated transcription factor (MITF) and proto-oncogene c-MYC.
  
  
  CONCLUSIONS
  Selected anti-clonogenic compounds might be further investigated as potential adjuvants targeting melanoma stem-like cells in the combined anti-melanoma therapy, whereas selected cytotoxic but not anti-clonogenic compounds, which increased the frequency of ABCB5-positive cells and remained slow-cycling cells unaffected, might be considered as a tool to enrich cultures with cells exhibiting melanoma stem cell characteristics.
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Sztiller-Sikorska
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Koprowska
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Kinga
authors.initials: K
authors.lastname: Majchrzak
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Czyz
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001688:Biological Products / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D055808:Drug Discovery / Q000379:methods*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051739:Microphthalmia-Associated Transcription Factor; D009285:Naphthoquinones / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D000090063:Proto-Oncogene Mas; D013308:Streptonigrin / Q000494:pharmacology; D014127:Toyocamycin / Q000494:pharmacology; D000095622:Benzoisochromanequinones
chemical_list: D001688:Biological Products; D051739:Microphthalmia-Associated Transcription Factor; D009285:Naphthoquinones; D000090063:Proto-Oncogene Mas; D013308:Streptonigrin; D014127:Toyocamycin; C000715470:MAS1 protein, human; C008638:nanaomycin A; D000095622:Benzoisochromanequinones