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

2019
Authors
Bjelogrlić, Snežana
Todorović, Tamara R.

Cvijetić, Ilija N.

Rodić, Marko V.

Vujcić, Miroslava
Marković, Sanja

Araskov, Jovana

Janović, Barbara
Emhemmed, Fathi
Muller, Christian D.

Filipović, Nenad

Article (Published version)

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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 interactionsSource:
Journal of Inorganic Biochemistry, 2019, 190, 45-66Publisher:
- Elsevier Science Inc, New York
Funding / projects:
DOI: 10.1016/j.jinorgbio.2018.10.002
ISSN: 0162-0134
PubMed: 30352315
WoS: 000452938900006
Scopus: 2-s2.0-85055090720
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Poljoprivredni fakultetTY - JOUR AU - Bjelogrlić, Snežana AU - Todorović, Tamara R. AU - Cvijetić, Ilija N. AU - Rodić, Marko V. AU - Vujcić, Miroslava AU - Marković, Sanja AU - Araskov, Jovana AU - Janović, Barbara AU - Emhemmed, Fathi AU - Muller, Christian D. AU - Filipović, Nenad PY - 2019 UR - http://aspace.agrif.bg.ac.rs/handle/123456789/5050 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 EP - 66 SP - 45 VL - 190 DO - 10.1016/j.jinorgbio.2018.10.002 ER -
@article{ author = "Bjelogrlić, Snežana and Todorović, Tamara R. and Cvijetić, Ilija N. and Rodić, Marko V. and Vujcić, Miroslava and Marković, Sanja and Araskov, Jovana and Janović, Barbara and Emhemmed, Fathi and Muller, Christian D. and Filipović, Nenad", 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", pages = "66-45", volume = "190", doi = "10.1016/j.jinorgbio.2018.10.002" }
Bjelogrlić, S., Todorović, T. R., Cvijetić, I. N., Rodić, M. V., Vujcić, M., Marković, S., Araskov, J., Janović, B., Emhemmed, F., Muller, C. D.,& Filipović, N.. (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 S, Todorović TR, Cvijetić IN, Rodić MV, Vujcić M, Marković S, Araskov J, Janović B, Emhemmed F, Muller CD, Filipović N. 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, Todorović, Tamara R., Cvijetić, Ilija N., Rodić, Marko V., Vujcić, Miroslava, Marković, Sanja, Araskov, Jovana, Janović, Barbara, Emhemmed, Fathi, Muller, Christian D., Filipović, Nenad, "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 . .