Parthenolide Complements the Cell Death-inducing Activity of Doxorubicin in Melanoma Cells

Background: Melanoma is characterized by high resistance to chemotherapy. The aim of this study was to investigate combined effects of doxorubicin and parthenolide on melanoma cells. Materials and Methods: Thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometry were used to evaluate viability. The p53 levels and Poly-ADP ribose polymerase (PARP) cleavage were assessed by western blot. Electrophoretic mobility shift assay (EMSA) and quantitative real-time polymerase chain reaction (qRT-PCR) were used to evaluate changes in nuclear factor-kappa B (NF-kappa B) activity and gene expression, respectively. Results: Both drugs reduced the viability of melanoma cells and induced apoptosis. Expression of the ATP-binding cassette sub-family B member-5 (ABCB5) transporter was enhanced by doxorubicin. Doxorubicin induced activity of p53 and NF-kappa B. Parthenolide markedly reduced the constitutive and doxorubicin-induced NF-kappa B activity measured as the nuclear NF-kappa B, and expression of matrix metalloproteinase-9 (MMP9) and it had no effect on p53. Discussion: Doxorubicin and parthenolide affected distinct pathways in melanoma, and parthenolide was capable of combating some pro-survival effects of doxorubicin in the combined treatment. This provides a rationale for in vivo investigation of this drug combination.