In vitro and in vivo studies of a novel potential anticancer agent of isochaihulactone on human lung cancer A549 cells

We previously demonstrated that the crude acetone extract of Bupleurum scorzonerifolium (BS-AE) 60 mu g/ml has anti-proliferation activity and apoptotic effects on A549 non-small cell lung cancer (NSCLC). A novel lignan, isochaihulactone (4-benzo[1,3]dioxol-5-yl1methyl-3 (3,4,5-trimethoxyl-benzylidene)-dihydro-furan-2-one), was isolated from BS-AE and identified from spectral evidence (H-1 NMR, C-13 NMR, IR, and MS) and by comparison with authentic synthetic standards. Isochaihulactone was cytotoxic (IC50 = 10-50 mu M) in a variety of human tumor cell lines. In in Vitro and in vivo microtubule assembly assays, it inhibited tubulin polymerization in a concentration-dependent manner. As determined by flow cytometry, isochaihulactone caused G2/M phase arrest and apoptosis in a time- and concentration-dependent manner. G2/M arrest was correlated with increased p21/WAF1 levels, downregulation of the checkpoint proteins cyclin B1/cdc2 and mobility shift of cdc25G. Moreover, isochaihulactone (30 and 50 mg/kg) inhibited the growth of non-small cell lung carcinoma A549 xenograft in nude mice. These findings indicate isochaihulactone is. a promising new antimitotic anticancer compound with potential for clinical application in the future. (c) 2006 Elsevier Inc. All rights reserved.