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--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.

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“…Cannabinoids have been previously implicated in inducing autophagy in various cancer cell types: glioma [171] hepatocellular carcinoma [172], pancreatic adenocarcinoma [173], and these effects are at least, in part, dependent on the CB1 receptor. We have found an altered autophagosomal and lysosomal turnover in Cnr1 -/2 mice (A. Piyanova 2012, unpublished results), suggesting a regulatory role for endocannabinoid signalling in autophagy also in non-cancerous tissues.…”

Silver nanoparticles enhance the apoptotic potential of gemcitabine in human ovarian cancer cells: combination therapy for effective cancer treatment

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A User’s Guide to Cannabinoid Therapies in Oncology

“…Several authors have investigated cannabis extracts used in tandem with a variety of chemotherapy agents in vitro and in animal models, showing synergism in reducing cell numbers, and no negative effect on anticancer function. Cell cultures from pancreatic 64 , glioma 65 , gastric 66 , lung 67 , and colon 68 cancers have been investigated using a range of antineoplastic agents, including gemcitabine, temozolomide, paclitaxel, and 5-fluorouracil. Synergism in inducing cancer cell death is a common finding, which bodes well for the possibility of human clinical trials in future 62 .…”