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Parthenolide enhances dacarbazine activity against melanoma cells

Koprowska, Kamila*; Hartman, Mariusz L.*; Sztiller-Sikorska, Malgorzata; Czyz, Malgorzata E.

doi: 10.1097/CAD.0b013e3283635a04
Preclinical Reports

Dacarbazine induces a clinical response only in 15% of melanoma patients. New treatment strategies may involve combinations of drugs with different modes of action to target the tumor heterogeneity. We aimed to determine whether the combined treatment of heterogeneous melanoma cell populations in vitro with the alkylating agent dacarbazine and the nuclear factor-κB inhibitor parthenolide could be more effective than either drug alone. A panel of melanoma cell lines, including highly heterogeneous populations derived from surgical specimens, was treated with dacarbazine and parthenolide. The effect of drugs on the viable cell number was examined using an acid phosphatase activity assay, and the combination effect was determined by median-effect analysis. Cell death and cell-cycle arrest were assessed by flow cytometry. Gene expression was measured by real-time PCR and changes in the protein levels were evaluated by western blotting. Secretion of vascular endothelial growth factor and interleukin-8 was determined using an enzyme-linked immunosorbent assay. The self-renewing capacity was assessed using a clonogenic assay. Dacarbazine was less effective in heterogeneous melanoma populations than in the A375 cell line. Parthenolide and dacarbazine synergistically reduced the viable cell numbers. Both drugs induced cell-cycle arrest and apoptotic cell death. Importantly, parthenolide abrogated the baseline and dacarbazine-induced vascular endothelial growth factor secretion from melanoma cells in heterogeneous populations, whereas interleukin-8 secretion was not significantly affected by either drug. Parthenolide eradicated melanoma cells with self-renewing capacity also in cultures simultaneously treated with dacarbazine. The combination of parthenolide and dacarbazine might be considered as a new therapeutic modality against metastatic melanoma.

Department of Molecular Biology of Cancer, Medical University of Lodz, Lodz, Poland

*Kamila Koprowska and Mariusz L. Hartman contributed equally to the writing of this article.

Correspondence to Malgorzata E. Czyz, PhD, Department of Molecular Biology of Cancer, Medical University of Lodz, 6/8 Mazowiecka Street, 92-215 Lodz, Poland Tel: +48 42 272 57 02; fax: +48 42 272 56 94; e-mail: malgorzata.czyz@umed.lodz.pl

Received March 7, 2013

Accepted May 17, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins