Terfenadine induces apoptosis and autophagy in melanoma cells through ROS-dependent and -independent mechanisms

Abstract

Previously we found that terfenadine, an H1 histamine receptor antagonist, acts as a potent apoptosis inducer in melanoma cells through modulation of Ca2+ homeostasis. In this report, focusing our attention on the apoptotic mechanisms activated by terfenadine, we show that this drug can potentially activate distinct intrinsic signaling pathways depending on culture conditions. Serum-deprived conditions enhance the cytotoxic effect of terfenadine and caspase-4 and -2 are activated upstream of caspase-9. Moreover, although we found an increase in ROS levels, the apoptosis was ROS independent. Conversely, terfenadine treatment in complete medium induced ROS-dependent apoptosis. Caspase-4, -2, and -9 were simultaneously activated and p73 and Noxa induction were involved. ROS inhibition prevented p73 and Noxa expression but not p53 and p21 expression, suggesting a role for Noxa in p53-independent apoptosis in melanoma cells. Finally, we found that terfenadine induced autophagy, that can promote apoptosis. These findings demonstrate the great potential of terfenadine to kill melanoma cells through different cellular signaling pathways and could contribute to define new therapeutic strategies in melanoma.

Autophagy Involvement in Olanzapine-Mediated Cytotoxic Effects in Human Glioma Cells

“…Antagonists of H1 receptor and activators of AMPK can induce autophagy (Nicolau-Galmes et al, 2011;Alers et al, 2012), thereby making olanzapine a promising target for glioma treatment. Evidences in recent years indicate that autophagy played a dual role in cancer cells depending on cell type, context or stage of tumor development (Mathew et al, 2007).…”

Antioxidant Role of p53 and of Its Target TP53INP1

“…As mentioned above, Tomasini et al demonstrated in 2005 that TP53INP1 gene is a transcriptional target of p73, and that in turn, TP53INP1 modulates p73-induced cell cycle arrest and apoptosis by modulating p73 transcriptional activity, independently of p53. Several authors showed that p73 was induced in response to oxidative stress and was implicated in oxidative cellular response [50,51]. TP53INP1 could regulate redox status by activating p73 and thus transcription of target genes implicated against oxidative stress.…”

Stimulating Effect of Terfenadine on Erythrocyte Cell Membrane Scrambling

“…Besides blocking the H1 receptor, Terfenadine may interfere with degranulation of mast cells and thus decrease histamine release [5]. Terfenadine and related substances may further trigger apoptosis [11][12][13][14][15][16][17][18] and may thus be effective against malignancy [12-15, 17, 19-21]. The effect is unrelated to antihistaminergic activity [11].…”

“…The effect is unrelated to antihistaminergic activity [11]. Instead, Terfenadine is in part effective by mitochondrial depolarization [16], cytochrome c release [16], oxidative stess [12], increase of cytotosolic Ca 2+ activity ([Ca 2+ ] i ) [11] and activation of caspases [12,15,16].…”