Introduction: Temozolomide is used in the first-line chemotherapy regimen for glioblastoma. However patient survival has not substantially improved, due to the emergence of treatment resistance. Objective: The synthesis of new Cu(I) and Cu(II) complexes as potential agents for the treatment of glioblastoma. Materials & Methods: the new ligand L2Ad, obtained by conjugating the bifunctional species bis(3,5- dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of Cu complexes 1-5. U87, T98 and U251 glioma cell lines and the non-tumoral BV2 cells were treated with Cu complexes. Their cytotoxic effect, used alone or in combination with Temozolomide, was determined using viability and colony assays, and flow cytometry analyses. Results: Cu(II) complex 3 and especially Cu(I) complex 5 decreased glioma cell viability, affecting cell growth, proliferation and death; besides, they showed significantly lower toxicity in normal BV2 cells. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their activity. Both complexes were able to increase the ROS production, leading to DNA damage and death. Interestingly, our finding demonstrated that non-toxic doses of 3 or 5 enhanced the chemosensitivity to temozolomide. Conclusion: Based on these findings, the resistance to TMZ could be decreased thanks to Cu complexes, providing patients with an effective therapeutic option.

Copper Complexes with Adamantane Ring- Conjugated Ligands as Promising Agents for the Treatment of Glioblastoma

Maria Beatrice Morelli
;
Miriam Caviglia;Carlo Santini;Jo’ Del Gobbo;Laura Zeppa;Fabio Del Bello;Gianfabio Giorgioni;Alessandro Piergentili;Wilma Quaglia;Maura Pellei
Ultimo
2024-01-01

Abstract

Introduction: Temozolomide is used in the first-line chemotherapy regimen for glioblastoma. However patient survival has not substantially improved, due to the emergence of treatment resistance. Objective: The synthesis of new Cu(I) and Cu(II) complexes as potential agents for the treatment of glioblastoma. Materials & Methods: the new ligand L2Ad, obtained by conjugating the bifunctional species bis(3,5- dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of Cu complexes 1-5. U87, T98 and U251 glioma cell lines and the non-tumoral BV2 cells were treated with Cu complexes. Their cytotoxic effect, used alone or in combination with Temozolomide, was determined using viability and colony assays, and flow cytometry analyses. Results: Cu(II) complex 3 and especially Cu(I) complex 5 decreased glioma cell viability, affecting cell growth, proliferation and death; besides, they showed significantly lower toxicity in normal BV2 cells. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their activity. Both complexes were able to increase the ROS production, leading to DNA damage and death. Interestingly, our finding demonstrated that non-toxic doses of 3 or 5 enhanced the chemosensitivity to temozolomide. Conclusion: Based on these findings, the resistance to TMZ could be decreased thanks to Cu complexes, providing patients with an effective therapeutic option.
2024
THE 8TH CANCER WORLD CONGRESS
274
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/488783
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