The curcumin analog DM-1 induces apoptotic cell death in melanoma

Author(s)

Faiao-Flores, Fernanda ^{[1, 2]} ; Quincoces Suarez, Jose Agustin ^[3] ; Maria-Engler, Silvya Stuchi ^[4] ; Soto-Cerrato, Vanessa ^[5] ; Perez-Tomas, Ricardo ^[5] ; Maria, Durvanei Augusto ^[2]

Affiliation

^[1] Univ Sao Paulo, Fac Med, Sao Paulo - Brazil

^[2] Butantan Inst, Biochem & Biophys Lab, BR-05503900 Sao Paulo - Brazil

^[3] Univ Bandeirante Sao Paulo, Organ Synth Lab, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Sch Pharmaceut Sci, Dept Clin Chem & Toxicol, Sao Paulo - Brazil

^[5] Univ Barcelona, Dept Pathol & Expt Therapeut, Canc Cell Biol Res Grp, Barcelona - Spain

• Document type: Journal article
• Source: TUMOR BIOLOGY; v. 34, n. 2, p. 1119-1129, APR 2013.
• Web of Science Citations: 15

Abstract

The main difficulty in the successful treatment of metastatic melanoma is that this type of cancer is known to be resistant to chemotherapy. Chemotherapy remains the treatment of choice, and dacarbazine (DTIC) is the best standard treatment. The DM-1 compound is a curcumin analog that possesses several curcumin characteristics, such as antiproliferative, antitumor, and antimetastatic properties. The objective of this study was to evaluate the signaling pathways involved in melanoma cell death after treatment with DM-1 compared to the standard agent for melanoma treatment, DTIC. Cell death was evaluated by flow cytometry for annexin V and iodide propide, cleaved caspase 8, and TNF-R1 expression. Hoechst 33342 staining was evaluated by fluorescent microscopy; lipid peroxidation and cell viability (MTT) were evaluated by colorimetric assays. The antiproliferative effects of the drugs were evaluated by flow cytometry for cyclin D1 and Ki67 expression. Mice bearing B16F10 melanoma were treated with DTIC, DM-1, or both therapies. DM-1 induced significant apoptosis as indicated by the presence of cleaved caspase 8 and an increase in TNF-R1 expression in melanoma cells. Furthermore, DM-1 had antiproliferative effects in this the same cell line. DTIC caused cell death primarily by necrosis, and a smaller melanoma cell population underwent apoptosis. DTIC induced oxidative stress and several physiological changes in normal melanocytes, whereas DM-1 did not significantly affect the normal cells. DM-1 antitumor therapy in vivo showed tumor burden decrease with DM-1 monotherapy or in combination with DTIC, besides survival rate increase. Altogether, these data confirm DM-1 as a chemotherapeutic agent with effective tumor control properties and a lower incidence of side effects in normal cells compared to DTIC. (AU)

• FAPESP's process: 08/58817-4 - Generation of human artificial skins and invasive melanomas as a platform for pharmacological testing
• Grantee: Silvya Stuchi Maria-Engler
• Support Opportunities: Regular Research Grants
• FAPESP's process: 11/50435-8 - Synthesis of biologically active phenols and derivatives
• Grantee: José Agustín Pablo Quincoces Suárez
• Support Opportunities: Regular Research Grants