Abstract
BackgroundAccumulating 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.MethodsWe 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.FindingsSeveral 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.ConclusionSelected 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.
Highlights
The intratumoral phenotypic heterogeneity results from the genetic variation and from the plasticity of tumor cells that is observed in response to microenvironmental stimuli
As the phenotypic heterogeneity was shown to be highly dynamic in many tumors including melanoma [4,5,6,7] and the therapeutic eradication of cancer stem-like cells (CSCs) subpopulation may be followed by its regeneration from nonCSCs, both CSCs and the bulk population should be considered in developing the anticancer therapy [8,9,10,11,12,13,14]
As our study strongly suggests that nanaomycin A preferentially eradicates cells with selfrenewing capacity, it would be interesting to find out whether this drug could eliminate melanoma cells with stem cells characteristics via epigenetic regulation
Summary
The intratumoral phenotypic heterogeneity results from the genetic variation and from the plasticity of tumor cells that is observed in response to microenvironmental stimuli. Melanoma cells obtained directly from pathologically distinct specimens, nodular melanoma and superficial spreading melanoma, were grown in an anchorage-independent manner in stem cell medium and were enriched with cells exerting self-renewing capacity in comparison to serum-driven monolayers [15]. This in vitro three-dimensional model has been shown to preserve the heterogeneity of the original tumor more accurately than twodimensional monolayer cultures [16,17,18] and was an important element of novelty in the present in vitro screening of the natural compound library.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
