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.
Highlights
We have recently demonstrated that the induction of Reactive oxygen species (ROS) is one of the mechanisms of GEM antitumor action and that pancreatic adenocarcinoma cell lines with lower basal levels of ROS are more resistant to GEM compared with cells with higher ROS levels.[5]
We have investigated the effect of the combination between GEM and three different CB ligands, arachidonoyl cyclopropamide (ACPA) and SR141716 (SR1) for cannabinoid receptor-1 (CB1), and GW405833 (GW) for cannabinoid receptor-2 (CB2) on pancreatic adenocarcinoma cell growth
The antiproliferative effect of the synthetic cannabinoids GW, ACPA, and SR1 in combination with GEM was examined on six pancreatic adenocarcinoma cell lines characterized by different sensitivities to GEM
Summary
A causal relationship between ROS production and cell death has been demonstrated in cannabinoidinduced cell growth inhibition In this regard, Sarker et al.[11] have shown that the cannabinoid anandamide induces apoptosis of PC-12 cells by increasing superoxide levels. Recent findings have shown that the tumor growth-inhibiting activity of cannabinoids relies on the upregulation of the endoplasmic reticulum (ER) stress pathway[13] and that ROS enhancement can determine perturbations of ER homeostasis affecting protein folding, causing ER stress.[14]. The other sensors of ER stress are the transmembrane proteins PERK (RNA-dependent protein kinase-like ER kinase) and ATF-6 (activating transcription factor-6).[16] In concert, these three pathways stimulate the expression of a set of proteins involved in ER stress response including the luminal ER chaperone Grp[78] (glucose-regulated protein 78 kDa; BiP).[17]. We demonstrate that all the three cannabinoids determine ROS production, ER stress, and autophagic cell death, and that these effects are potentiated by GEM. These data strongly support the development of GEM/cannabinoid treatment in the management of pancreatic cancer
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