Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer

Pancreatic cancer (PC) is insidious with a high mortality rate due to the lack of symptomology prior to diagnosis. Mitochondrial involvement in PC development is becoming accepted, and exposure to cadmium (Cd) is suspected of being a risk factor for the development of PC; however, the mechanisms involved remain unclear. In this study, we examined the role of Cd as a mitochondrial toxicant and whether alterations in mitochondrial function may be an underlying cause for the development of PC. In this study, cadmium chloride (CdCl₂)-mediated toxicity in hTERT-HPNE and AsPC-1 pancreatic cell lines was determined by MTT assay. We also investigated the release of LDH and the generation of free radicals. Mitochondrial toxicity assays were performed in media containing glucose (25 mM) or galactose (10 mM) and following exposure to CdCl₂ (0-100 µM) followed by MTT assay. For the confirmation of mitochondrial toxicity, we measured the release of ATP following exposure to CdCl₂. Initial experiments confirmed that exposure to CdCl₂ did not reduce the viability of either cell line until a concentration of >10 µM was used. Non-linear analysis of the response curves revealed lethal concentration 50% (LC₅₀) values for CdCl₂ in the HPNE cells of 77 µM compared to 42 µM in the AsPC-1 cells (P<0.01). The CdCl₂-mediated mitochondrial toxic effects were greater in the HPNE cells, suggesting a heightened sensitivity to the effects of CdCl₂, not due to elevated oxidative stress. Increased mitochondrial toxic sensitivity was indicated by a 73.4% reduction in IC₅₀ values in the HPNE cells cultured in galactose compared to culture in glucose media, whereas the AsPC-1 cells exhibited a 58.8% reduction in IC₅₀ values. In addition, the higher concentration of CdCl₂ elicited a significant cell-dependent effect on ATP release in both cell lines, suggestive of CdCl₂ being a mitochondrial toxicant. Cell survival was unaffected following exposure to low concentrations of CdCl₂; however, exposure did alter mitochondrial function (control cells > tumor cells). Therefore, the findings of this study indicate that the mitochondria may be a site of action for cadmium in promoting tumor development.