Gemcitabina (GEM) è attualmente il chemioterapico standard per il trattamento dell'adenocarcinoma pancreatico, anche se ha un tasso di risposta inferiore al 20%. Lo scopo di questa tesi è stato quello di migliorare l'attività della GEM con l'aggiunta di cannabinoidi, una nuova classe di composti antitumorali. Questo lavoro mostra che GEM è in grado di indurre entrambi i recettori dei cannabinoidi CB1 e CB2 tramite un meccanismo NF-B-dipendente e che la sua associazione coi cannabinoidi inibisce sinergisticamente la crescita di cellule di adenocarcinoma pancreatico aumentando le specie reattive dell’ossigeno (ROS) indotte dai singoli trattamenti. Questo effetto è inibito dall’antiossidante N-acetyl-L-cysteine e dallo specifico inibitore di NF-B, BAY 11-7085, dimostrando che l’induzione di ROS dalla combinazione GEM/cannabinoidi e di NF-B da GEM è richiesta per la sinergia antiproliferativa. Né meccanismi apoptotici né citostatici sono responsabili della inibizione sinergica della crescita cellulare, che risulta invece strettamente associata all’aumento di stress del reticolo e alla morte cellulare autofagica. La sinergia antiproliferativa è più forte nelle linee cellulari di pancreas resistenti alla GEM rispetto a quelle più sensibili e nessuna sinergia si osserva nei fibroblasti primari normali. Il trattamento combinato inibisce fortemente la crescita di cellule tumorali di pancreas umane xenotrapiantate in topi nudi senza apparenti effetti tossici.
Gemcitabine (GEM) is currently the standard treatment for advanced pancreatic adenocarcinoma, one of the most aggressive human tumors, although it has a response rate of less than 20%. The purpose of this thesis was to improve GEM activity by addition of cannabinoids, a novel class of antitumor compounds. This work shows that GEM induces both CB1 and CB2 receptors by an NF-B-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. This effect is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-B inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-B by GEM is required for the antiproliferative synergism. Neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated to the enhancement of endoplasmic reticulum stress and autophagic cell death. . Noteworthy, the antiproliferative synergism is stronger in GEM-resistant compared to GEM-sensitive pancreatic cancer cell lines and no synergism is observed in normal primary fibroblasts. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects.
Endoplasmic reticulum stress induced by gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS mediated mechanism.
ZANIBONI, Tatyana
2011-01-01
Abstract
Gemcitabine (GEM) is currently the standard treatment for advanced pancreatic adenocarcinoma, one of the most aggressive human tumors, although it has a response rate of less than 20%. The purpose of this thesis was to improve GEM activity by addition of cannabinoids, a novel class of antitumor compounds. This work shows that GEM induces both CB1 and CB2 receptors by an NF-B-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. This effect is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-B inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-B by GEM is required for the antiproliferative synergism. Neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated to the enhancement of endoplasmic reticulum stress and autophagic cell death. . Noteworthy, the antiproliferative synergism is stronger in GEM-resistant compared to GEM-sensitive pancreatic cancer cell lines and no synergism is observed in normal primary fibroblasts. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects.File | Dimensione | Formato | |
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Tesi dottorato in Bioscienze_Tatyana Zaniboni.pdf
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