Mechanism of cytotoxic activity of chalcone derivatives against K562 leukemia cell lines

Novilla, Arina; Mustofa, .; Astuti, Indwiani; Jumina,; Suwito, Hery

doi:10.19106/jmedsci004904201701

Cited by 1 publication

(1 citation statement)

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“…The flavonoid subtype chalcone is considered as a privileged scaffold and is present in numerous natural products . Both natural and synthetic chalcones have illustrated many interesting biological activities with potential clinical applications for various diseases, including cancer. ,, Some chalcone derivatives, for example, have demonstrated promising activity toward T-cell acute lymphoblastic leukemia (T-ALL) , and CML cell lines.…”

Section: Resultsmentioning

confidence: 99%

Natural and Semisynthetic Chalcones as Dual FLT3 and Microtubule Polymerization Inhibitors

et al. 2020

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Activating mutations in FLT3 receptor tyrosine kinase are found in a third of acute myeloid leukemia (AML) patients and are associated with disease relapse and a poor prognosis. The majority of these mutations are internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3, which have been validated as a therapeutic target. The clinical success of selective inhibitors targeting oncogenic FLT3, however, has been limited due to the acquisition of drug resistance. Herein the identification of a dual FLT3/microtubule polymerization inhibitor, chalcone 4 (2′-allyloxy-4,4′-dimethoxychalcone), is reported through screening of 15 related chalcones for differential antiproliferative activity in leukemia cell lines dependent on FLT3-ITD (MV-4-11) or BCR-ABL (K562) oncogenes and by subsequent screening for mitotic inducers in the HCT116 cell line. Three natural chalcones (1–3) were found to be differentially more potent toward the MV-4-11 (FLT3-ITD) cell line compared to the K562 (BCR-ABL) cell line. Notably, the new semisynthetic chalcone 4, which is a 2′-O-allyl analogue of the natural chalcone 3, was found to be more potent toward the FLT3-ITD+ cell line and inhibited FLT3 signaling in FLT3-dependent cells. An in vitro kinase assay confirmed that chalcone 4 directly inhibited FLT3. Moreover, chalcone 4 induced mitotic arrest in these cells and inhibited tubulin polymerization in both cellular and biochemical assays. Treatment of MV-4-11 cells with this inhibitor for 24 and 48 h resulted in apoptotic cell death. Finally, chalcone 4 was able to overcome TKD mutation-mediated acquired resistance to FLT3 inhibitors in a MOLM-13 cell line expressing FLT3-ITD with the D835Y mutation. Chalcone 4 is, therefore, a promising lead for the discovery of dual-target FLT3 inhibitors.

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