Aspirin reduces the outcome of anticancer therapy in Meth A-bearing mice through activation of AKT-glycogen synthase kinase signaling.
Aspirin displays, at millimolar concentrations, several mechanisms independent from its ability to inhibit cyclooxygenases. Occasionally, the mechanisms displayed in vitro have been clearly related to an effect of clinical relevance in vivo. An expanding literature has been focusing on the cytoprotective effect of aspirin in neurodegenerative disorders and the activation of AKT pathway in neuroprotection and induction of resistance to anticancer drugs. In this work, we tested the ability of aspirin to activate the AKT survival pathway in methylcholanthrene-induced fibrosarcoma cells (Meth A) transplanted into BALB/c nude mice and the clinical effect of aspirin cotreatment during etoposide (VP-16)-based anticancer therapy. We found that cotreatment with aspirin reduced VP-16-induced apoptosis and activated AKT in vitro and in vivo. In Meth A-bearing mice, aspirin administration also activated glycogen synthase kinase-3 and reduced the activity and the efficacy of anticancer therapy in VP-16 cotreated animals. Our data suggest that the antiapoptotic effect of aspirin operates in vivo through the activation of AKT-glycogen synthase kinase pathway causing a decrease in the outcome of VP-16-based therapy. These findings could have clinical relevance in treatment of human malignancies.
di Palma
Antonella
A
Dipartimento di Biologia e Patologia Cellulare e Molecolare L. Califano, Università Federico II, via S. Pansini 5, 80131 Naples, Italy. angacqua@unina.it
Matarese
Giuseppe
G
Leone
Vincenza
V
Di Matola
Tiziana
T
Acquaviva
Fabio
F
Acquaviva
Angela Maria
AM
Ricchi
Paolo
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D001241:Aspirin / Q000378:metabolism / Q000494:pharmacology*; D005047:Etoposide / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D005260:Female; D005354:Fibrosarcoma / Q000139:chemically induced / Q000378:metabolism; D038341:Glycogen Synthase Kinases / Q000378:metabolism*; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D008748:Methylcholanthrene; D005047:Etoposide; D019869:Phosphatidylinositol 3-Kinases; D038341:Glycogen Synthase Kinases; D051057:Proto-Oncogene Proteins c-akt; D001241:Aspirin