A New Hybrid δ-Lactone Induces Apoptosis and Potentiates Anticancer Activity of Taxol in HL-60 Human Leukemia Cells.

Katarzyna Gach-Janczak,Joanna Drogosz-Stachowicz,Anna Janecka,Rafał Jakubowski,Angelika Długosz-Pokorska,Jacek Szymański,Tomasz Janecki

doi:10.3390/molecules25071479

Abstract

In the search for new drug candidates, researchers turn to natural substances isolated from plants which may be either used directly or may serve as a source for chemical modifications. An interesting strategy in the design of novel anticancer agents is based on the conjugation of two or more biologically active structural motifs into one hybrid compound. In this study, we investigated the anticancer potential of 4-benzyl-5,7-dimethoxy-4-methyl-3-methylidene-3,4-dihydro-2H-chroman-2-one (DL-247), a new hybrid molecule combining a chroman-2-one skeleton with an exo-methylidene bond conjugated with a carbonyl group, in human myeloid leukemia HL-60 cell line. The cytotoxicity of the new compound was tested using MTT assay. The effect of DL-247 on cell proliferation and apoptosis induction were studied by flow cytometry, fluorometric assay and ELISA analysis. DL-247 displayed high cytotoxic activity (IC50 = 1.15 µM, after 24 h incubation), significantly inhibited cell proliferation and induced apoptosis by both, the intrinsic and extrinsic pathways. A combination of DL-247 with taxol exhibited a strong synergistic effect on DNA damage generation, apoptosis induction and inhibition of cell growth.

Highlights

Millions of new cancer cases are being diagnosed each year worldwide and this number is still increasing
Menadione, used as a positive control, caused a 11-fold enhancement of Reactive Oxygen Species (ROS) production, while DL-247 did not significantly change the level of ROS at either of the tested concentrations (1.15 μM and 2.30 μM) (Figure 5D). These results indicate that DL-247-induced apoptosis was not associated with ROS generation
The study demonstrated that the synthetic chroman-2-one DL-247 produced potent cytotoxic effect and inhibited proliferation in HL-60 cells

Summary

Introduction

Millions of new cancer cases are being diagnosed each year worldwide and this number is still increasing. A large number of anti-cancer agents selected for clinical trials are plant-derived compounds [1]. The cytotoxic effect of both natural coumarins and their synthetic derivatives was shown in various cancer cell lines, such as lung (A549, H727), renal (ACHN, breast (MCF7), leukemia (U-937 and HL-60) and in experimental animal models of cancer [2,4,5].

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Conclusion