Identification of a Novel Curcumin Derivative Influencing Notch Pathway and DNA Damage as a Potential Therapeutic Agent in T-ALL
by
, , , , and
Nadezda Zhdanovskaya
1,†,‡, 
Sara Lazzari
1,†,
Diego Caprioglio
2
,
Mariarosaria Firrincieli
1,
Chiara Maioli
2,
Eleonora Pace
1,
Daniela Imperio
2
,
Claudio Talora
1,
Diana Bellavia
1,
Saula Checquolo
3,
Mattia Mori
4
,
Isabella Screpanti
1,
Alberto Minassi
2,*
and
Rocco Palermo
1,* 1
Department of Molecular Medicine, Sapienza Università di Roma, 00161 Rome, Italy
2
Department of Pharmaceutical Sciences, University of Piemonte Orientale, 28100 Novara, Italy
3
Department of Medico-Surgical Sciences and Biotechnology, Sapienza Università di Roma, 04100 Latina, Italy
4
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
Present address: Department of Translational and Precision Medicine, Sapienza Università di Roma, 00161 Rome, Italy.
Cancers 2022, 14(23), 5772; https://doi.org/10.3390/cancers14235772
Submission received: 26 October 2022
/
Revised: 16 November 2022
/
Accepted: 21 November 2022
/
Published: 24 November 2022
(This article belongs to the Section Cancer Therapy)
Simple Summary
The overall survival rate in T-cell acute lymphoblastic leukemia (T-ALL) patients is relatively high. However, the therapeutic options for refractory and relapsed cases with poor prognosis are still limited. Therefore, novel therapies are required to improve high-risk patient outcomes. Natural products can play a crucial role in developing novel drug candidates. The proven preclinical efficacy of the phytochemical compound curcumin, mediated through modulation of multiple molecular targets, including Notch signaling, is well known. However, limited data are available regarding its anti-cancer effects and its relationship with Notch in T-ALL. Our study provides evidence that curcumin reduces Notch activity and exerts anti-cancer effects in T-ALL cells by favouring DNA damage-dependent cell death. Furthermore, we identified the curcumin derivative CD2066, which is endowed with potentiated anti-growth, anti-Notch, and DNA-damaging activities. Although CD2066 anti-leukemia activity requires further investigation, our study highlights the potential of curcumin-based bioactive agents for Notch-dependent leukemia treatment.
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.
