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A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells
A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production wi...th dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 M induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.
Keywords:
Cd(II) complex / Hydrazones / Apoptosis / Cancer stem cells / DNA interactions / HSA interactions
Source:
Journal of Inorganic Biochemistry, 2019, 190, 45-66
TY - JOUR
AU - Bjelogrlić, Snežana K.
AU - Todorović, Tamara
AU - Cvijetić, Ilija
AU - Rodić, Marko V.
AU - Vujčić, Miroslava
AU - Marković, Sanja
AU - Araskov, Jovana
AU - Janović, Barbara
AU - Emhemmed, Fathi
AU - Muller, Christian D.
AU - Filipović, Nenad R.
PY - 2019
UR - http://cer.ihtm.bg.ac.rs/handle/123456789/2623
AB - A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 M induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.
PB - Elsevier Science Inc, New York
T2 - Journal of Inorganic Biochemistry
T1 - A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells
VL - 190
SP - 45
EP - 66
DO - 10.1016/j.jinorgbio.2018.10.002
ER -
@article{
author = "Bjelogrlić, Snežana K. and Todorović, Tamara and Cvijetić, Ilija and Rodić, Marko V. and Vujčić, Miroslava and Marković, Sanja and Araskov, Jovana and Janović, Barbara and Emhemmed, Fathi and Muller, Christian D. and Filipović, Nenad R.",
year = "2019",
abstract = "A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 M induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.",
publisher = "Elsevier Science Inc, New York",
journal = "Journal of Inorganic Biochemistry",
title = "A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells",
volume = "190",
pages = "45-66",
doi = "10.1016/j.jinorgbio.2018.10.002"
}
Bjelogrlić, S. K., Todorović, T., Cvijetić, I., Rodić, M. V., Vujčić, M., Marković, S., Araskov, J., Janović, B., Emhemmed, F., Muller, C. D.,& Filipović, N. R.. (2019). A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells. in Journal of Inorganic Biochemistry
Elsevier Science Inc, New York., 190, 45-66.
https://doi.org/10.1016/j.jinorgbio.2018.10.002
Bjelogrlić SK, Todorović T, Cvijetić I, Rodić MV, Vujčić M, Marković S, Araskov J, Janović B, Emhemmed F, Muller CD, Filipović NR. A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells. in Journal of Inorganic Biochemistry. 2019;190:45-66.
doi:10.1016/j.jinorgbio.2018.10.002 .
Bjelogrlić, Snežana K., Todorović, Tamara, Cvijetić, Ilija, Rodić, Marko V., Vujčić, Miroslava, Marković, Sanja, Araskov, Jovana, Janović, Barbara, Emhemmed, Fathi, Muller, Christian D., Filipović, Nenad R., "A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells" in Journal of Inorganic Biochemistry, 190 (2019):45-66,
https://doi.org/10.1016/j.jinorgbio.2018.10.002 . .
