Bersavine: A Novel Bisbenzylisoquinoline Alkaloidwith Cytotoxic, Antiproliferative and Apoptosis-Inducing Effects on Human Leukemic Cells.

Darja Koutova,Martina Majorosova,Monika Kulhava,Anna Hošťálková,Lucie Cahlikova,Klara Habartova,Karel Královec,Martina Řezáčová,Lubomír Opletal,Radim Havelek

doi:10.3390/molecules25040964

Darja Koutova, Martina Majorosova + Show 8 more

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https://doi.org/10.3390/molecules25040964

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Abstract

Bersavine is the new bisbenzylisoquinoline alkaloid isolated from the Berberis vulgaris L. (Berberidaceae) plant. The results of cytotoxicity screening 48 h post-treatment showed that bersavine considerably inhibits the proliferation and viability of leukemic (Jurkat, MOLT-4), colon (HT-29), cervix (HeLa) and breast (MCF-7) cancer cells with IC50 values ranging from 8.1 to 11 µM. The viability and proliferation of leukemic Jurkat and MOLT-4 cells were decreased after bersavine treatment in a time- and dose-dependent manner. Bersavine manifested concentration-dependent antiproliferative activity in human lung, breast, ovarian and hepatocellular carcinoma cell lines using a xCELLigence assay. Significantly higher percentages of MOLT-4 cells exposed to bersavine at 20 µM for 24 h were arrested in the G1 phase of the cell cycle using the flow cytometry method. The higher percentage of apoptotic cells was measured after 24 h of bersavine treatment. The upregulation of p53 phosphorylated on Ser392 was detected during the progression of MOLT-4 cell apoptosis. Mechanistically, bersavine-induced apoptosis is an effect of increased activity of caspases, while reduced proliferation seems dependent on increased Chk1 Ser345 phosphorylation and decreased Rb Ser807/811 phosphorylation in human leukemic cells.

Highlights

Over the past decades, drugs derived from plants have continued to have beneficial health effects in the prevention and treatment of many diseases
The cytotoxic effect of bersavine and berbamine were evaluated using a panel of human cancer cells, including cell lines from solid tumours (A549, HT-29, PANC-1, A2780, HeLa, MCF-7, SAOS-2), and blood cancers (Jurkat, MOLT-4) in a single-dose exposure at 10 μM, using the cell proliferation and viability water-soluble tetrazolium salt WST-1 reagent
Sensitivity to the antiproliferative activities of bersavine and berbamine following a single-dose exposure at a concentration of 10 μM was calculated as a mean growth percent (GP) value for each cell line

Summary

Introduction

Drugs derived from plants have continued to have beneficial health effects in the prevention and treatment of many diseases. Natural products and plants have made an enormous impact on the discovery of anticancer drugs. Plants have been identified as a sound source of anticancer agents, the promise of combinational chemistry and modern synthetic technologies has overshadowed natural product research as a source of new drugs [2]. Plants historically stand at the core of medicine, and they are Molecules 2020, 25, 964; doi:10.3390/molecules25040964 www.mdpi.com/journal/molecules still a major source of prospective new drug leads. Plants represent a superb source of the most effective anticancer drugs, such as vinca vinca alkaloids, alkaloids, taxanes, taxanes, podophyllotoxin podophyllotoxin derivatives and others, a large number of plant-derived compounds have barely been studied and still need to be investigated [3]

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