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Open AccessArticle

Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors

College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah 21955, Saudi Arabia
Dipartimento di Scienze, Università Degli Studi della Basilicata, 85100 Potenza, Italy
Dipartimento di Farmacia, Università Degli Studi di Salerno, 84084 Fisciano (SA), Italy
Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt
Faculty of Pharmacy, Al-Azhar University, Assiut, 71524, Egypt
College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
Author to whom correspondence should be addressed.
Academic Editors: Bartosz Tylkowski, Anna Bajek and Krzysztof Roszkowski
Molecules 2020, 25(9), 2220;
Received: 15 April 2020 / Revised: 29 April 2020 / Accepted: 5 May 2020 / Published: 8 May 2020
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA2020) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA2020, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA2020 and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA2020 propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia. View Full-Text
Keywords: acute myeloid leukemia (AML); Hsp90; cyclin-dependent kinases (CDK); dinaciclib acute myeloid leukemia (AML); Hsp90; cyclin-dependent kinases (CDK); dinaciclib
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Abdalla, A.N.; Abdallah, M.E.; Aslam, A.; Bader, A.; Vassallo, A.; Tommasi, N.D.; Malki, W.H.; Gouda, A.M.; Mukhtar, M.H.; El-Readi, M.Z.; Alkahtani, H.M.; Abdel-Aziz, A. .-M.; El-Azab, A.S. Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors. Molecules 2020, 25, 2220.

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