4-4-difluoro-4-bora-3a-4a-diaza-s-indacene and Melanoma

Melanoma is the most threatening form of metastatic skin cancer that develops from melanocytes and causes a large majority of deaths due to poor therapeutic prognosis. It has significant limitations in treatment because it shows great resistance to chemotherapy, radiotherapy, and other therapeutic methods. A noninvasive and clinically accepted therapeutic modality, photodynamic therapy (PDT), is a promising treatment option, but it is limitedly applied for melanoma skin cancer treatment. This is because most of the photosensitizers are unlikely to be expected to have a remarkable effect on melanoma due to drug efflux by melanin pigmentation and intrinsic antioxidant defense mechanisms. Moreover, melanin is a dominant absorber in the spectral region of 500-600 nm that can cause the decreased photoreaction efficiency of photosensitizers. Herein, to overcome these drawbacks, we have developed a phenylthiourea-conjugated BODIPY photosensitizer (

Topics: Antineoplastic Agents; Biocompatible Materials; Boron Compounds; Cell Line, Tumor; Cell Survival; Drug Screening Assays, Antitumor; Humans; Materials Testing; Melanoma; Melanoma, Cutaneous Malignant; Molecular Structure; Monophenol Monooxygenase; Particle Size; Phenylthiourea; Photochemotherapy; Photosensitizing Agents; Skin Neoplasms

Topics: Animals; Boron Compounds; Fluorescent Dyes; Indoles; Isoindoles; Melanoma; Mice; Molecular Structure; Pyrenes; Tumor Cells, Cultured

The oxidized phospholipids (oxPL) 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) are generated from 1-palmitoyl-2-arachidonoyl-phosphatidylcholine under conditions of oxidative stress. These oxPL are components of oxidized low density lipoprotein. They are cytotoxic in cells of the arterial wall thus playing an important role in the development and progression of atherosclerosis. The toxic lipid effects include inflammation and under sustained exposure apoptosis. The aim of this study was to find out whether such toxic effects, especially apoptosis, are also elicited by oxPL in melanocytic cells in order to assess their potential for therapeutic intervention. FACS analysis after staining with fluorescent markers was performed to identify the mode of lipid-induced cell death. Activation of sphingomyelinase which generates apoptotic ceramide was measured using an established fluorescence assay. Ceramide profiles were determined by mass spectrometry. We found that 50μM POVPC induce cell death in human melanoma cells isolated from different stages of tumor progression but affect primary human melanocytes to a much lesser extent. In contrast, 50μM PGPC was only apoptotic in two out of four cell lines used in this study. The toxicity of both compounds was associated with efficient lipid uptake into the tumor cells and activation of acid sphingomyelinase. In several but not all melanoma cell lines used in this study, activation of the sphingomyelin degrading enzyme correlated with an increase in the concentration of the apoptotic mediator ceramide. The individual patterns of the newly formed ceramide species were also cell line-specific. PGPC and POVPC may be considered potential drug candidates for topical skin cancer treatment. They are toxic in malignant cells. The respective oxidized phospholipids are naturally formed in the body and resistance to these compounds is not likely to occur.

Topics: Apoptosis; Boron Compounds; Cell Line, Tumor; Ceramides; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Humans; Lipoproteins, LDL; Melanoma; Microscopy, Fluorescence; Oxidation-Reduction; Phosphatidylcholines; Phospholipid Ethers; Sphingomyelin Phosphodiesterase