Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma

Abstract

Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl2-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future.

Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma

“…In our previous study, we examined GEM-resistant PDAC cell lines induced by continuous GEM treatment and observed multiple drug resistance; however, we did not observe the induction of known resistance genes, such as multiple drug resistant gene or deoxycytidine kinase [8,9]. Furthermore, altered energy metabolism and enhanced stemness in these resistant cell lines contribute to anticancer drug resistance in PDAC [8,9].…”

“…We investigated MAST4, which showed the most significant increase. Further examination of MAST4 expression in other established GEM-resistant cell lines [8] revealed a MAST4 overexpression in comparison to all parental cells. Increased MAST4 expression correlated with increased IC50 after GEM sensitivity evaluation (Figure 2B).…”

“…Statistical differences were calculated using Student's t-test. PDAC, pancreatic ductal adenocarcinoma; MIA-P, parental MIA-PaCa-2; MIA-GEM, GEM-resistant MIA-PaCa-2; MIAA, MIAB; GEM-resistant MIA-PaCa-2 [8]; Panc1G, GEM-resistant Panc1 [8]…”

“…GEM-resistant MIA-GEM, a MIAA, MIAB, PANC1G, and Capan2G cells were established by continuous treatment with GEM (1 µm, Sigma-Aldrich Inc., St. Louis, MO, USA) and CoCl2 (150 µm, Wako, Osaka, Japan), exceeding 40 passages. [8]. These cell lines are passaged to ensure that MIA-P cells and MIA-GEM cells have the same passage.…”

Involvement of Ferroptosis Induction and Oxidative Phosphorylation Inhibition in the Anticancer-Drug-Induced Myocardial Injury: Ameliorative Role of Pterostilbene

“…In our data, TFAM level was decreased by anticancer drugs. TFAM is an mtDNA-binding protein that is involved in repair; its levels decrease with DNA damage [ 57 , 58 , 59 , 60 ]. This suggests that mtDNA damage is induced by anticancer drugs targeting nucleic acids.…”