Docosahexaenoic acid inhibits the proliferation of Kras/TP53 double mutant pancreatic ductal adenocarcinoma cells through modulation of glutathione level and suppression of nucleotide synthesis

Abstract

The treatment of cancer cells obtained by blocking cellular metabolism has received a lot of attention recently. Previous studies have demonstrated that Kras mutation-mediated abnormal glucose metabolism would lead to an aberrant cell proliferation in human pancreatic ductal adenocarcinoma (PDAC) cells. Previous literature has suggested that consumption of fish oil is associated with lower risk of pancreatic cancer. In this study, we investigated the anti-cancer effects of docosahexaenoic acid (DHA) in human PDAC cells in vitro and in vivo . Omega-3 polyunsaturated fatty acids (PUFAs) such as DHA and eicosapentaenoic acid (EPA) significantly inhibited the proliferation of human PDAC cells. The actions of DHA were evaluated through an induction of cell cycle arrest at G1 phase and noticed a decreased expression of cyclin A, cyclin E and cyclin B proteins in HPAF-II cells. Moreover, it was found that co-treatment of DHA and gemcitabine (GEM) effectively induced oxidative stress and cell death in HPAF-II cells. Interestingly, DHA leads to an increased oxidative glutathione /reduced glutathione (GSSG/GSH) ratio and induced cell apoptosis in HPAF-II cells. The findings in the study showed that supplementation of GSH or N-Acetyl Cysteine (NAC) could reverse DHA-mediated cell death in HPAF-II cells. Additionally, DHA significantly increased cellular level of cysteine, cellular NADP/NADPH ratio and the expression of cystathionase (CTH) and SLCA11/xCT antiporter proteins in HPAF-II cells. The action of DHA was, in part, associated with the inactivation of STAT3 cascade in HPAF-II cells. Treatment with xCT inhibitors, such as erastin or sulfasalazine (SSZ), inhibited the cell survival ability in DHA-treated HPAF-II cells. DHA also inhibited nucleotide synthesis in HPAF-II cells. It was demonstrated in a mouse-xenograft model that consumption of fish oil significantly inhibited the growth of pancreatic adenocarcinoma and decreased cellular nucleotide level in tumor tissues. Furthermore, fish oil consumption induced an increment of GSSG/GSH ratio, an upregulation of xCT and CTH proteins in tumor tissues. In conclusion, DHA significantly inhibited survival of PDAC cells both in vitro and in vivo through its recently identified novel mode of action, including an increment in the ratio of GSSG/GSH and NADP/NADPH respectively, and promoting reduction in the levels of nucleotide synthesis.

Sulfasalazine Sensitizes Polyhematoporphyrin-Mediated Photodynamic Therapy in Cholangiocarcinoma by Targeting xCT

“…SASP is an effective inhibitor of xCT and was first reported to be effective in lymphoma cells. Recently, more and more studies have reported that SASP-mediated xCT downregulation results in a variety of tumour suppressive effects in lung cancer (JI et al, 2018), gatric cancer (ZHUANG et al, 2021 and pancreatic cancer (HUNG et al, 2020). In addition, SASP can improve the efficacy of chemotherapy (SUGIYAMA et al, 2020).…”

Docosahexaenoic Acid Inhibits Cell Proliferation through a Suppression of c-Myc Protein in Pancreatic Ductal Adenocarcinoma Cells

“…Several studies demonstrated the inhibitory effects of DHA on the proliferation of pancreatic cancer cells [ 34 , 35 ]. Our previous study indicated that DHA could act as a potential agent for the treatment of pancreatic cancer [ 23 ]. However, the inhibitory effects of DHA on cell proliferation upon high glucose stimulation have not yet been well-studied.…”

“…The protocol for analysis of thiol compounds and nucleotides was based on the previous study [ 23 ]. For the analysis of thiol compounds, metabolite samples were mixed with the reaction solution, containing 20 mM sodium carbonate (pH 9.5) and 0.2 mM 13 C 6 -2-iodoacetaniline ( 13 C 6 -2-IAN).…”

“…However, the literature remains unclear regarding the anti-cancer actions of DHA in human PDAC cells. Our previous study indicated that DHA, one of N-3 polyunsaturated fatty acids (PUFAs), could inhibit the proliferation of human PDAC cells in vitro and in vivo [ 23 ]. This study aimed to investigate the inhibitory effects of DHA and novel mechanisms on the suppression of these candidate molecules including STAT3/CAMKII/c-Myc proteins in PDAC cells upon high glucose stimulation.…”

d-α-tocopheryl polyethylene glycol 1000 succinate surface scaffold polysarcosine based polymeric nanoparticles of enzalutamide for the treatment of colorectal cancer: In vitro, in vivo characterizations

“…Subsequent to treatment, cells underwent two washes with cold PBS. Resuspended cells were placed in 1X binding buffer at a concentration of 1x10^6 cells/ml, and the cells were divided into distinct groups, namely Unstained cells, Control group, Annexin only, PI only, and Treatment [ 59 ]. Following the division into labelled tubes, Annexin V FITC and PI were introduced to their respective tubes.…”