title: Gemcitabine/cannabinoid combination triggers autophagy in pancreatic cancer cells through a ROS-mediated mechanism.
abstract: Gemcitabine (GEM, 2',2'-difluorodeoxycytidine) is currently used in advanced pancreatic adenocarcinoma, with a response rate of < 20%. The purpose of our work was to improve GEM activity by addition of cannabinoids. Here, we show that GEM induces both cannabinoid receptor-1 (CB1) and cannabinoid receptor-2 (CB2) receptors by an NF-κB-dependent mechanism and that its association with cannabinoids synergistically inhibits pancreatic adenocarcinoma cell growth and increases reactive oxygen species (ROS) induced by single treatments. The antiproliferative synergism is prevented by the radical scavenger N-acetyl-L-cysteine and by the specific NF-κB inhibitor BAY 11-7085, demonstrating that the induction of ROS by GEM/cannabinoids and of NF-κB by GEM is required for this effect. In addition, we report that neither apoptotic nor cytostatic mechanisms are responsible for the synergistic cell growth inhibition, which is strictly associated with the enhancement of endoplasmic reticulum stress and autophagic cell death. Noteworthy, the antiproliferative synergism is stronger in GEM-resistant pancreatic cancer cell lines compared with GEM-sensitive pancreatic cancer cell lines. The combined treatment strongly inhibits growth of human pancreatic tumor cells xenografted in nude mice without apparent toxic effects. These findings support a key role of the ROS-dependent activation of an autophagic program in the synergistic growth inhibition induced by GEM/cannabinoid combination in human pancreatic cancer cells.
authors.affiliation: Department of Life and Reproduction Sciences, Biochemistry Section, University of Verona, Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Donadelli
authors.forename: I
authors.initials: I
authors.lastname: Dando
authors.forename: T
authors.initials: T
authors.lastname: Zaniboni
authors.forename: C
authors.initials: C
authors.lastname: Costanzo
authors.forename: E
authors.initials: E
authors.lastname: Dalla Pozza
authors.forename: M T
authors.initials: MT
authors.lastname: Scupoli
authors.forename: A
authors.initials: A
authors.lastname: Scarpa
authors.forename: S
authors.initials: S
authors.lastname: Zappavigna
authors.forename: M
authors.initials: M
authors.lastname: Marra
authors.forename: A
authors.initials: A
authors.lastname: Abbruzzese
authors.forename: M
authors.initials: M
authors.lastname: Bifulco
authors.forename: M
authors.initials: M
authors.lastname: Caraglia
authors.forename: M
authors.initials: M
authors.lastname: Palmieri
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002186:Cannabinoids / Q000008:administration & dosage; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D014158:Transcription, Genetic / Q000187:drug effects; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
chemical_list: D002186:Cannabinoids; D017382:Reactive Oxygen Species; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D003841:Deoxycytidine; D000093542:Gemcitabine