: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy considered curable by modern clinical management. Nevertheless, the prognosis for T-ALL high-risk cases or patients with relapsed and refractory disease is still dismal. Therefore, there is a keen interest in developing more efficient and less toxic therapeutic approaches. T-ALL pathogenesis is associated with Notch signaling alterations, making this pathway a highly promising target in the fight against T-ALL. Here, by exploring the anti-leukemic capacity of the natural polyphenol curcumin and its derivatives, we found that curcumin exposure impacts T-ALL cell line viability and decreases Notch signaling in a dose- and time-dependent fashion. However, our findings indicated that curcumin-mediated cell outcomes did not depend exclusively on Notch signaling inhibition, but might be mainly related to compound-induced DNA-damage-associated cell death. Furthermore, we identified a novel curcumin-based compound named CD2066, endowed with potentiated anti-proliferative activity in T-ALL compared to the parent molecule curcumin. At nanomolar concentrations, CD2066 antagonized Notch signaling, favored DNA damage, and acted synergistically with the CDK1 inhibitor Ro3306 in T-ALL cells, thus representing a promising novel candidate for developing therapeutic agents against Notch-dependent T-ALL.

Identification of a novel curcumin derivative influencing notch pathway and DNA damage as a potential therapeutic agent in T-ALL / Zhdanovskaya, Nadezda; Lazzari, Sara; Caprioglio, Diego; Firrincieli, Mariarosaria; Maioli, Chiara; Pace, Eleonora; Imperio, Daniela; Talora, Claudio; Bellavia, Diana; Checquolo, Saula; Mori, Mattia; Screpanti, Isabella; Minassi, Alberto; Palermo, Rocco. - In: CANCERS. - ISSN 2072-6694. - 14:23(2022). [10.3390/cancers14235772]

Identification of a novel curcumin derivative influencing notch pathway and DNA damage as a potential therapeutic agent in T-ALL

Zhdanovskaya, Nadezda
Co-primo
Writing – Original Draft Preparation
;
Lazzari, Sara
Co-primo
Investigation
;
Firrincieli, Mariarosaria
Investigation
;
Pace, Eleonora
Investigation
;
Imperio, Daniela
Investigation
;
Talora, Claudio
Writing – Review & Editing
;
Bellavia, Diana
Writing – Review & Editing
;
Checquolo, Saula
Writing – Review & Editing
;
Mori, Mattia
Writing – Review & Editing
;
Screpanti, Isabella
Writing – Review & Editing
;
Palermo, Rocco
Ultimo
Funding Acquisition
2022

Abstract

: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy considered curable by modern clinical management. Nevertheless, the prognosis for T-ALL high-risk cases or patients with relapsed and refractory disease is still dismal. Therefore, there is a keen interest in developing more efficient and less toxic therapeutic approaches. T-ALL pathogenesis is associated with Notch signaling alterations, making this pathway a highly promising target in the fight against T-ALL. Here, by exploring the anti-leukemic capacity of the natural polyphenol curcumin and its derivatives, we found that curcumin exposure impacts T-ALL cell line viability and decreases Notch signaling in a dose- and time-dependent fashion. However, our findings indicated that curcumin-mediated cell outcomes did not depend exclusively on Notch signaling inhibition, but might be mainly related to compound-induced DNA-damage-associated cell death. Furthermore, we identified a novel curcumin-based compound named CD2066, endowed with potentiated anti-proliferative activity in T-ALL compared to the parent molecule curcumin. At nanomolar concentrations, CD2066 antagonized Notch signaling, favored DNA damage, and acted synergistically with the CDK1 inhibitor Ro3306 in T-ALL cells, thus representing a promising novel candidate for developing therapeutic agents against Notch-dependent T-ALL.
2022
DNA damage; Notch signaling; T-ALL; anti-cancer therapy; cancer; curcumin; curcuminoids; drug discovery; inhibitors; leukemia; natural products
01 Pubblicazione su rivista::01a Articolo in rivista
Identification of a novel curcumin derivative influencing notch pathway and DNA damage as a potential therapeutic agent in T-ALL / Zhdanovskaya, Nadezda; Lazzari, Sara; Caprioglio, Diego; Firrincieli, Mariarosaria; Maioli, Chiara; Pace, Eleonora; Imperio, Daniela; Talora, Claudio; Bellavia, Diana; Checquolo, Saula; Mori, Mattia; Screpanti, Isabella; Minassi, Alberto; Palermo, Rocco. - In: CANCERS. - ISSN 2072-6694. - 14:23(2022). [10.3390/cancers14235772]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1664088
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