Parthenolide reduces the frequency of ABCB5-positive cells and clonogenic capacity of melanoma cells from anchorage independent melanospheres

摘要

Growing evidence suggests that the cancer stem cell phenotype in melanoma is dynamically regulated. Therefore, effective therapies have to target simultaneously bulk tumor cells and melanoma stem-like cells. The aim of the present study was to investigate the effects of parthenolide on heterogeneous cancer cell populations from anchorageindependent melanospheres. Cells derived from nodular melanoma specimens were grown under serum-free sphereforming conditions. The effects of parthenolide on cellular viability, immunophenotype and self-renewing capacity were assessed with cells from dissociated melanospheres. Its penetration capacity was evaluated with intact melanospheres. In melanoma cells that survived treatment with parthenolide, a different immunophenotype than that in untreated control was found. The frequency of cells expressing the ABCB5 transporter was markedly reduced. Most importantly, melanoma cells that survived parthenolide treatment lost their self-renewing capacity. Significantly lower influence of drug on cellular viability and frequency of ABCB5-positive cells was observed in intact melanospheres. The potential clinical significance of our findings is based on the ability of parthenolide to affect both bulk and melanoma stem-like cells with clonogenic capacity and high expression of the ABCB5 transporter. Its low penetration capacity, however, may limit its action to easily accessible melanoma cells, either circulating in the blood or those in the vicinity to blood vessels within the tumor. Because of limited penetration capacity of parthenolide, this drug should be further explored as a part of multimodal therapies rather than as a stand-alone therapeutic agent.