Ursolic acid differentially modulates apoptosis in skin melanoma and retinal pigment epithelial cells exposed to UV–VIS broadband radiation

Abstract

The signaling pathways via mTOR (mammalian target of rapamycin) and AMPK (AMP-activated protein kinase) play key roles in transcription, translation and carcinogenesis, and may be activated by light exposure. These pathways can be modulated by naturally occurring compounds, such as the triterpenoid, ursolic acid (UA). Previously, the transcription factors p53 and NF-κB, which transactivate mitochondrial apoptosis-related genes, were shown to be differentially modulated by UA. UA-modulated apoptosis, following exposure to UV-VIS radiation (ultraviolet to visible light broadband radiation, hereafter abbreviated to UVR), is observed to correspond to differential levels of oxidative stress in retinal pigment epithelial (RPE) and skin melanoma (SM) cells. The cellular response to this phytochemical was characterized using western blot, flow cytometry, microscopy with reactive oxidative species probes MitoTracker and dihydroethidium, and membrane permeability assay. UA pretreatment potentiated cell cycle arrest and UVR-induced apoptosis selectively in SM cells while reducing photo-oxidative stress in the DNA of RPE cells presumably by antioxidant activity of UA. Mechanistically, the nuclear transportation of p65 and p53 was reduced by UA administration prior to UVR exposure while the levels of p65 and p53 nuclear transportation in SM cells were sustained at a substantially higher level. Finally, the mitochondrial functional assay showed that UVR induced the collapse of the mitochondrial membrane potential, and this effect was exacerbated by rapamycin or UA pretreatment in SM preferentially. These results were consistent with reduced proliferation observed in the clonogenic assay, indicating that UA treatment enhanced the phototoxicity of UVR, by modulating the activation of p53 and NF-κB and initiating a mitogenic response to optical radiation that triggered mitochondria-dependent apoptosis, particularly in skin melanoma cells. The study indicates that this compound has multiple actions with the potential for protecting normal cells while sensitizing skin melanoma cells to UV irradiation.

The impact of oleanolic and ursolic acid on corneal epithelial cells in vitro

“…On the other hand, ursolic acid significantly reduced the viability of cells even at the lowest (5 µM) concentration used. These results are in agreement with literature data showing that UA modulates mitochondrial redox activity and decreases mitochondrial membrane potential; this results in cell cycle phase arrest and consequently apoptosis of cells [11,12]. Moreover, UA treatment of cells may decrease the anti-apop-www.journals.viamedica.pl/ophthalmology_journal totic Bcl-2 protein level by its phosphorylation and degradation, but it does not affect pro-apoptotic Bcl-xS or Bax protein amounts.…”

Potential Protective Effects of Ursolic Acid against Gamma Irradiation-Induced Damage Are Mediated through the Modulation of Diverse Inflammatory Mediators

“…Our observations could be supported by a recent study from Manna et al (2015), who showed that naringin inhibited gamma radiation-caused inflammation and oxidative DNA damage by controlling p53 and NF-κB signaling pathways in murine splenocytes (Manna et al, 2015). In another report, Lee et al (2014) showed that UV light exposure produced a loss of proliferation and an activation of NF-κB in the skin melanoma cells, while pre-treatment with UA significantly reduced the amount of phosphorylated NF-κB at 24 h post-exposure (Lee et al, 2014). These pieces of evidence support our hypothesis that the protective effects of UA against gamma radiation induced damage through the inhibition of oxidative stress cascade including ROS production, lipid peroxidation, DNA damage, and NF-kB activation.…”

In Vitro Antiproliferative Activity of Extracts of Carlina acaulis subsp. caulescens and Carlina acanthifolia subsp. utzka

“…It was shown that ursolic acid induced apoptosis of melanoma MM200, Mel-RM, Me4405, and A375 cell lines (Mahmoud et al, 2015). Moreover, it exhibited potential for protecting normal cells and sensitizing skin melanoma cells to UV irradiation (Lee et al, 2014). Apoptotic death of human malignant melanoma cells was also observed after incubation with oleanolic acid (A375 cells) (Cijo George et al, 2014) and betulinic acid (UISO-MEL-1 cells) (Tan et al, 2003).…”

“…There are also reports on the cytotoxic activity of amyrin and lupeol against different human melanoma cells (Saleem et al, 2008; Chaabane et al, 2013). Chlorogenic acid has been shown to inhibit proliferation and act cytotoxically to melanoma cell line B16 (Lee et al, 2014). However, the cytotoxicity of the tested extracts against the UACC-903, UACC-647, and C32 lines is probably not associated with the presence of chlorogenic acid because the extract from roots that contained a high amount of this compound exhibited low or no cytotoxicity and did not induce apoptosis of the investigated cell lines.…”