title: 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 Ca(2+) 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.
authors.affiliation: Department of Cell Biology and Histology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Bizkaia, Spain.
authors.forename: Francesca
authors.initials: F
authors.lastname: Nicolau-Galmés
authors.forename: Aintzane
authors.initials: A
authors.lastname: Asumendi
authors.forename: Erika
authors.initials: E
authors.lastname: Alonso-Tejerina
authors.forename: Gorka
authors.initials: G
authors.lastname: Pérez-Yarza
authors.forename: Shawkat-Muhialdin
authors.initials: SM
authors.lastname: Jangi
authors.forename: Jesús
authors.initials: J
authors.lastname: Gardeazabal
authors.forename: Yoana
authors.initials: Y
authors.lastname: Arroyo-Berdugo
authors.forename: Jesús María
authors.initials: JM
authors.lastname: Careaga
authors.forename: Jose Luís
authors.initials: JL
authors.lastname: Díaz-Ramón
authors.forename: Aintzane
authors.initials: A
authors.lastname: Apraiz
authors.forename: María D
authors.initials: MD
authors.lastname: Boyano
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016593:Terfenadine / Q000494:pharmacology*
chemical_list: D017382:Reactive Oxygen Species; D016593:Terfenadine; D020169:Caspases