Abstract
Arylnaphthalene lignan lactones have attracted considerable interest because of their anti-tumor and anti-hyperlipidimic activities. However, to our knowledge, few studies have explored the effects of these compounds on human leukemia cell lines. In this study, five arylnaphthalene lignans including 6′-hydroxy justicidin A (HJA), 6′-hydroxy justicidin B (HJB), justicidin B (JB), chinensinaphthol methyl ether (CME) and Taiwanin E methyl ether (TEME) were isolated from Justicia procumbens and their effects on the proliferation and apoptosis of the human leukemia K562 cell line were investigated then used to assess structure-activity relationships. To achieve these aims, cytotoxicity was assayed using the MTT assay, while intracellular SOD activity was detected using the SOD Activity Assay kit. Apoptosis was measured by both the using a cycle TEST PLUS DNA reagent kit as well as the FITC Annexin V apoptosis detection kit in combination with flow cytometry. Activation of caspase-mediated apoptosis was evaluated using a FITC active Caspase-3 apoptosis kit and flow cytometry. The results indicated that HJB, HJA and JB significantly inhibited the growth of K562 cells by decreasing both proliferation and SOD activity and inducing apoptosis. The sequence of anti-proliferative activity induced by the five tested arylnaphthalenes by decreasing strength was HJB > HJA > JB > CME > TEME. HJB, HJA and JB also decreased SOD activity and induced apoptosis in a dose-dependent manner. Activation of caspase-3 further indicated that HJB, HJA and JB induced caspase-dependent intrinsic and/or extrinsic apoptosis pathways. Together, these assays suggest that arylnaphthalene lignans derived from Justicia procumbens induce apoptosis to varying degrees, through a caspase-dependent pathway in human leukemia K562 cells. Furthermore, analysis of structure-activity relationships suggest that hydroxyl substitution at C-1 and C-6′ significantly increased the antiproliferative activity of arylnaphthalene lignans while a methoxyl at C-1 significantly decreased the effect.
Highlights
Lignans are a large group of dimeric phenylpropanoids that are widely distributed in higher plants
We investigated the cytotoxicity of the five arylnaphthalene lignans on HL-60, L1210 and P388D1 cell lines
The results showed that hydroxy justicidin B (HJB) exhibited the most cytotoxicity within these cell lines, with an average IC50 ranging from 3.9 to 26.2 mM
Summary
Lignans are a large group of dimeric phenylpropanoids that are widely distributed in higher plants. Some cytotoxic lignan derivatives have reached phase I and II clinical trials as anti-tumor agents including GP-11 [3], NK-611 [4,5], TOP-53 [6], NPF [7], GL-331 [8,9,10,11,12]. The majority of natural arylnaphthalene lignans are lactones [14]. These have attracted considerable interest because of their anti-tumor and anti-hyperlipidemic activities [15]. Cytotoxicity as well as anti-cancer activity has been reported for arylnapthalene lignan isolated from several genus including Phyllantus, Cleistanthus, and Justicia [1,16,17]
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