Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer
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Wallace, David
Spandidos, Demetrios A.
Tsatsakis, Aristidis
Schweitzer, Amie
Đorđević, Vladimir
Buha-Đorđević, Aleksandra
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 M) followed by MTT assay. For the confirmation of mitochondrial toxicity, we measured the release of ATP following exposure to CdCl2. Initial experiment...s confirmed that exposure to CdCl2 did not reduce the viability of either cell line until a concentration of >10 M was used. Non-linear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 M compared to 42 M in the AsPC-1 cells (P lt 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.
Warburg effect / oxidative stress / cadmium / glycolysis / oxidative phosphorylation / cytotoxicity
International Journal of Molecular Medicine, 2019, 44, 1, 145-156
Spandidos Publ Ltd, Athens
OSU - 154333-7
DOI: 10.3892/ijmm.2019.4204
AU  - Wallace, David
AU  - Spandidos, Demetrios A.
AU  - Tsatsakis, Aristidis
AU  - Schweitzer, Amie
AU  - Đorđević, Vladimir
AU  - Buha-Đorđević, Aleksandra
AB  - 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 M) 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 M was used. Non-linear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 M compared to 42 M in the AsPC-1 cells (P lt 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.
PB  - Spandidos Publ Ltd, Athens
T2  - International Journal of Molecular Medicine
T1  - Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer
DO  - 10.3892/ijmm.2019.4204
author = "Wallace, David and Spandidos, Demetrios A. and Tsatsakis, Aristidis and Schweitzer, Amie and Đorđević, Vladimir and Buha-Đorđević, Aleksandra",
abstract = "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 M) 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 M was used. Non-linear analysis of the response curves revealed lethal concentration 50% (LC50) values for CdCl2 in the HPNE cells of 77 M compared to 42 M in the AsPC-1 cells (P lt 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.",
publisher = "Spandidos Publ Ltd, Athens",
journal = "International Journal of Molecular Medicine",
title = "Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer",
doi = "10.3892/ijmm.2019.4204"
Wallace, D., Spandidos, D. A., Tsatsakis, A., Schweitzer, A., Đorđević, V.,& Buha-Đorđević, A.. (2019). Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer. in International Journal of Molecular Medicine
Spandidos Publ Ltd, Athens., 44(1), 145-156.
https://doi.org/10.3892/ijmm.2019.4204
Wallace D, Spandidos DA, Tsatsakis A, Schweitzer A, Đorđević V, Buha-Đorđević A. Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer. in International Journal of Molecular Medicine. 2019;44(1):145-156.
doi:10.3892/ijmm.2019.4204 .
Wallace, David, Spandidos, Demetrios A., Tsatsakis, Aristidis, Schweitzer, Amie, Đorđević, Vladimir, Buha-Đorđević, Aleksandra, "Potential interaction of cadmium chloride with pancreatic mitochondria: Implications for pancreatic cancer" in International Journal of Molecular Medicine, 44, no. 1 (2019):145-156,
https://doi.org/10.3892/ijmm.2019.4204 . .