Purpose: Peroxisome proliferator-activated receptors (PPAR) regulate lipid and glucose metabolism but their anticancer properties have been recently studied as well.We previously reported the antimetastatic activity of the PPARa ligand, fenofibrate, against melanoma tumors in vivo.Here we investigated possible molecular mechanisms of fenofibrate anti metastatic action. Experimental Design: Monolayer cultures of mouse (B16F10) and human (SkMell88) melanoma cell lines, soft agar assay, and cell migration assay were used in this study. In addition, we analyzed PPARa expression and its transcriptional activity in response to fenotibrate by using Western blots and liciferase-based reporter system. Results: Fenofibrate inhibited migration of B16F10 and SkMel188 cells in Transwell chambers and colony formation in soft agar.These effects were reversed by PPAR inhibitor, GW9662. Western blot analysis revealed time-dependent down-regulation of Akt and extracellular signal^regu-lated kinase l/2 phosphorylation in fenofibrate-treated cells. A B16F10 cell line stably expressing constitutively active Akt mutant was resistant to fenofibrate. In contrast, Akt gene silencing with siRNA mimicked the fenofibrate action and reduced the migratory ability of B16F1O cells. In addition, fenofibrate strongly sensitized BI6FIO cells to the proapoptotic drug staurosporine, further supporting the possibility that fenofibrate-induced down-regulation of Akt function contributes to fenofibrate-mediated inhibition of metastatic potential in this experimental model. Conclusions: Our results show that the PPAR-dependent antimetastatic activity of fenofibrate involves down-regulation of Akt phosphorylation and suggest that supplementation with this drug may improve the effectiveness of melanoma chemotherapy.
Progress in the photodynamic therapy (PDT) of cancer should benefit from a rationale to predict the most efficient of a series of photosensitizers that strongly absorb light in the phototherapeutic window (650-800 nm) and efficiently generate reactive oxygen species (ROS = singlet oxygen and oxygen-centered radicals). We show that the ratios between the triplet photosensitizer-O2 interaction rate constant (kD) and the photosensitizer decomposition rate constant (kd), kD/kd, determine the relative photodynamic activities of photosensitizers against various cancer cells. The same efficacy trend is observed in vivo with DBA/2 mice bearing S91 melanoma tumors. The PDT efficacy intimately depends on the dynamics of photosensitizer-oxygen interactions: charge transfer to molecular oxygen with generation of both singlet oxygen and superoxide ion (high kD) must be tempered by photostability (low kd). These properties depend on the oxidation potential of the photosensitizer and are suitably combined in a new fluorinated sulfonamide bacteriochlorin, motivated by the rationale.
New halogenated and sulfonated bacteriochlorins and their analogous porphyrins are employed as photosensitizers of singlet oxygen and the superoxide ion. The mechanisms of energy and electron transfer are clarified and the rates are measured. The intermediacy of a charge-transfer (CT) complex is proved for bacteriochlorins, but excluded for porphyrins. The energies of the intermediates and the rates of their interconversions are measured, and are used to obtain the efficiencies of all the processes. The mechanism of formation of the hydroxyl radical in the presence of bacteriochlorins is proposed to involve a photocatalytic step. The usefulness of these photosensitizers in the photodynamic therapy (PDT) of cancer is assessed, and the following recommendations are given for the design of more effective PDT protocols employing such photosensitizers: 1) light doses should be given over a more extended period of time when the photosensitizers form CT complexes with molecular oxygen, and 2) Fe(2+) may improve the efficiency of such photosensitizers if co-located in the same cell organelle assisting with an in vivo Fenton reaction.
Chlorin and bacteriochlorin derivatives of 5,10,15,20-tetrakis(2-chloro-5-sulfophenyl)porphyrin have intense absorptions in the phototherapeutic window, high water solubility, high photostability, low fluorescence quantum yield, long triplet lifetimes, and high singlet oxygen quantum yields. Biological studies revealed their negligible dark cytotoxicity, yet significant photodynamic effect against A549 (human lung adenocarcinoma), MCF7 (human breast carcinoma) and SK-MEL-188 (human melanoma) cell lines upon red light irradiation (cutoff λ<600 nm) at low light doses. Time-dependent cellular accumulation of the chlorinated sulfonated chlorin reached a plateau at 2 h, as previously observed for the related porphyrin. However, the optimal incubation time for the bacteriochlorin derivative was significantly longer (12 h). The spectroscopic, photophysical, and biological properties of the compounds are discussed in relevance to their PDT activity, leading to the conclusion that the bacteriochlorin derivative is a promising candidate for future in vivo experiments.
The effect of fenofibrate, a ligand of peroxisome proliferator-activated receptor (PPAR) alpha, on the growth and metastatic potential of Bomirski hamster melanoma s.c. tumors, pigmented line (BHM Ma) was investigated in vivo. RT-PCR and Western-blot analyses revealed the presence of mRNA and protein of PPAR alpha in BHM Ma cells. The animals treated orally with fenofibrate developed significantly fewer metastatic foci in the lungs, as compared to the control group; however, primary tumor growth remained unaltered. This observation is interesting in respect of the potential use of fenofibrate in melanoma chemoprevention.
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