Abstract
BackgroundFlavonoids are widely proposed as very interesting compounds with possible chemopreventive and therapeutic capacities.Methods & ResultsIn this study, we showed that in vitro treatment with the flavonoid Luteolin induced caspase-dependent cell death in a model of human cutaneous squamous cell carcinoma (SCC) derived cells, representing a matched pair of primary tumor and its metastasis. Notably, no cytotoxic effects were observed in normal human keratinocytes when treated with similar doses of Luteolin. Luteolin-induced apoptosis was accompanied by inhibition of AKT signaling, and sensitivity decreased with tumor progression, as the primary MET1 SCC cells were considerably more sensitive to Luteolin than the isogenic metastatic MET4 cells. Extensive intracellular vacuolization was observed in Luteolin-treated MET4 cells, which were characterized as acidic lysosomal vacuoles, suggesting the involvement of autophagy. Transmission electron microscopy, mRFP-GFP-LC3 assay and p62 protein degradation, confirmed that Luteolin stimulated the autophagic process in the metastatic MET4 cells. Blocking autophagy using chloroquine magnified Luteolin-induced apoptosis in the metastatic SCC cells.ConclusionTogether, these results suggest that Luteolin has the capacity to induce selectively apoptotic cell death both in primary cutaneous SCC cells and in metastatic SCC cells in combination with chloroquine, an inhibitor of autophagosomal degradation. Hence, Luteolin might be a promising agent for the treatment of cutaneous SCC.
Highlights
Recent biochemical en preclinical studies provide evidence that flavonoids, bioactive compounds which can be derived from a variety of plants, possess multiple pharmacological activities, including antioxidant, anti-inflammatory and anticancer effects
Together, these results suggest that Luteolin has the capacity to induce selectively apoptotic cell death both in primary cutaneous squamous cell carcinoma (SCC) cells and in metastatic SCC cells in combination with chloroquine, an inhibitor of autophagosomal degradation
Even though we demonstrated that the flavonoid LUT is a strong apoptosis inducing agent in primary SCC cells (MET1), MET4 cells showed higher resistance to LUT due to the induction of autophagy as survival mechanism
Summary
Recent biochemical en preclinical studies provide evidence that flavonoids, bioactive compounds which can be derived from a variety of plants, possess multiple pharmacological activities, including antioxidant, anti-inflammatory and anticancer effects. Luteolin (LUT), one of the most common flavonoids, has the ability to induce apoptosis, to prevent carcinogenesis and to reduce tumorigenesis, which suggests its potential use as a therapeutic treatment [1], even in multidrug resistant cells [2]. To their role as conventional hydrogen-donation antioxidants [3,4], growing data have revealed that flavonoids exert their effects predominately through modulation of protein kinase signaling pathways [5,6]. Flavonoids are widely proposed as very interesting compounds with possible chemopreventive and therapeutic capacities
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