Toxicity of organic and inorganic nickel in pancreatic cell cultures: Comparison to cadmium

Abstract

Nickel compounds are Group 1 carcinogens and possibly cancer-causing in the pancreas. We examined the toxicity of nickel in both 2-D and 3-D pancreatic cell cultures, to determine the LD50 for organic and inorganic nickel in normal and cancerous cells. Assays with cadmium chloride were performed to be a comparison to potential nickel-induced toxicity. Cells were exposed to twelve concentrations of NiCl2 or Ni-(Ac)2 for 48h (2-D), or six concentrations for 48 hours (3-D). There was a significant (P=0.0016) difference between HPNE and AsPC-1 LD50 values after cadmium exposure, at 69.9 µM and 29.2 µM, respectively. Neither form of nickel exhibited toxicity in 2-D or 3-D cultures, but after 48h, changes in spheroid morphology were observed. The inability of Ni to reduce viable cell numbers suggests a toxic mechanism that differs from cadmium, also a Group 1 carcinogen. The cell microenvironment was not a factor in nickel toxicity with no changes in viable cells in either 2-D or 3-D cultures. These studies only examined cytotoxicity, and not genotoxicity, a potential mechanism of nickel carcinogenicity. Alterations in DNA function or the expression of apoptotic proteins/processes would take longer to manifest. Current work focuses on cellular changes following extended nickel exposure.

Nickel’s Role in Pancreatic Ductal Adenocarcinoma: Potential Involvement of microRNAs

“…A growing body of evidence suggests that Ni and Ni-containing compounds are carcinogenic, a fact recognized by international organisations [ 13 ]. The toxicity and carcinogenicity of Ni is supported by our previous data [ 10 , 11 , 18 , 60 ], as well as other reports using different cell-line models representing different cancers [ 92 , 93 , 94 , 95 ]. The similarity between toxic mechanisms and our work in PDAC cell lines suggests that Ni may work through the Akt pathway, which is independent of FOXO1 activation [ 92 , 94 ].…”

“…Considering the above results, elevated Ni levels in the body may cause a disturbance of Fe homeostasis, thereby increasing the concentration of this bio-element; this can be a starting point for a further cascade of events that leads to the development of pancreatic cancer. Another recent study suggested that the role of Ni should be further investigated by considering its possible epigenetic effects [ 18 ]. The study implied that Ni could be involved in the malignant transformation of pancreatic cell cultures, but also highlighted the importance of toxicants affecting the cells at the same time as Ni, as the endpoint seemed to depend on the presence of other toxicants, as well as Ni concentration.…”

“…Moreover, the molecular mechanisms of Ni-induced carcinogenesis comprise hypoxia-inducible factor pathways and the generation of oxidative stress, which further lead to DNA damage and the targeting of DNA repair pathways [ 15 , 16 ]. A previous study has suggested a link between Ni content and PDAC [ 17 ], while increasing evidence has suggested Ni involvement in several pancreas-related dysfunctions [ 18 ].…”

“…Our previous studies have shown that environmental toxins, such as Cd, can promote their toxicity through miRs [ 12 , 18 , 60 ]. Toxic metals such as Ni have not been studied as extensively as Cd, and, therefore, only a small number of miRs associated with Ni exposure has been characterized.…”

MicroRNA-Regulated Signaling Pathways: Potential Biomarkers for Pancreatic Ductal Adenocarcinoma

“…Some of these risks include chronic pancreatitis development, diabetes mellitus, and some infectious diseases [19]. Additionally, environmental exposures can induce PDAC development through various mechanisms, such as the inhalation of cigarette smoke, exposure to mutagenic nitrosamines or chlorinated hydrocarbon solvents, and exposure to toxic metals such as arsenic, nickel, and cadmium [20][21][22][23][24][25][26].…”