Acetylsalicylic acid and salicylic acid present anticancer properties against melanoma by promoting nitric oxide-dependent endoplasmic reticulum stress and apoptosis

Melanoma is the most aggressive and fatal type of skin cancer due to being highly proliferative. Acetylsalicylic acid (ASA; Aspirin) and salicylic acid (SA) are ancient drugs with multiple applications in medicine. Here, we showed that ASA and SA present anticancer effects against a murine model of...

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Bibliographic Details
Published in:	Scientific reports Vol. 10; no. 1; p. 19617
Main Authors:	Ausina, Priscila, Branco, Jessica R., Demaria, Thainá M., Esteves, Amanda M., Leandro, João Gabriel B., Ochioni, Alan C., Mendonça, Ana Paula M., Palhano, Fernando L., Oliveira, Marcus F., Abou-Kheir, Wassim, Sola-Penna, Mauro, Zancan, Patricia
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 12-11-2020 Nature Publishing Group
Subjects:	631/67/1813/1634 631/80/82/23 631/80/82/39 631/80/86/2366 Acetylsalicylic acid Acids AKT protein AMP-Activated Protein Kinases - metabolism Animal models Animals Antineoplastic Agents Apoptosis Apoptosis - drug effects Aspirin Aspirin - pharmacology Aspirin - therapeutic use CCAAT/enhancer-binding protein Cell Line, Tumor Disease Models, Animal Endoplasmic reticulum Endoplasmic Reticulum Stress - drug effects Humanities and Social Sciences Male Melanoma Melanoma - drug therapy Melanoma - etiology Melanoma - pathology Mice, Inbred C57BL Molecular Targeted Therapy multidisciplinary Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type III - metabolism Nitric-oxide synthase NOS3 protein Proto-Oncogene Proteins c-akt - metabolism Reactive oxygen species Salicylic acid Salicylic Acid - pharmacology Salicylic Acid - therapeutic use Science Science (multidisciplinary) Skin cancer Skin Neoplasms - drug therapy Skin Neoplasms - etiology Skin Neoplasms - pathology TOR protein TOR Serine-Threonine Kinases - metabolism Up-Regulation - drug effects
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Summary:	Melanoma is the most aggressive and fatal type of skin cancer due to being highly proliferative. Acetylsalicylic acid (ASA; Aspirin) and salicylic acid (SA) are ancient drugs with multiple applications in medicine. Here, we showed that ASA and SA present anticancer effects against a murine model of implanted melanoma. These effects were also validated in 3D- and 2D-cultured melanoma B16F10 cells, where the drugs promoted pro-apoptotic effects. In both in vivo and in vitro models, SA and ASA triggered endoplasmic reticulum (ER) stress, which culminates with the upregulation of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). These effects are initiated by ASA/SA-triggered Akt/mTOR/AMPK-dependent activation of nitric oxide synthase 3 (eNOS), which increases nitric oxide and reactive oxygen species production inducing ER stress response. In the end, we propose that ASA and SA instigate anticancer effects by a novel mechanism, the activation of ER stress.
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-020-76824-6