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: Francesca Nicolau-Galmés, Aintzane Asumendi, Erika Alonso-Tejerina, Gorka Pérez-Yarza, Shawkat-Muhialdin Jangi, Jesús Gardeazabal, Yoana Arroyo-Berdugo, Jesús María Careaga, Jose Luís Díaz-Ramón, Aintzane Apraiz, María D Boyano
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 16 Issue 12 Pg. 1253-67 (Dec 2011) ISSN: 1573-675X [Electronic] Netherlands
• PMID: 21861192 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Terfenadine
• Caspases

Topics

• Apoptosis (drug effects)
• Autophagy (drug effects)
• Caspases (metabolism)
• Cell Line, Tumor
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Melanoma (genetics, metabolism, physiopathology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects)
• Terfenadine (pharmacology)