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 microg/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-ylmethyl-3(3,4,5-trimethoxyl-benzylidene)-dihydro-furan-2-one), was isolated from BS-AE and identified from spectral evidence ((1)H NMR, (13)C NMR, IR, and MS) and by comparison with authentic synthetic standards. Isochaihulactone was cytotoxic (IC(50)=10-50 microM) 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 cdc25C. 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.
Chen
Yi-Lin
YL
Institute of Medical Sciences, Buddhist Tzu-Chi University, Hualien, Taiwan.
Lin
Shinn-Zong
SZ
Chang
Jang-Yang
JY
Cheng
Yeung-Leung
YL
Tsai
Nu-Man
NM
Chen
Shee-Ping
SP
Chang
Wen-Liang
WL
Harn
Horng-Jyh
HJ
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052117:Benzodioxoles / Q000737:chemistry / Q000494:pharmacology*; D029972:Bupleurum / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D017705:Lignans / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D018517:Plant Roots / Q000737:chemistry; D014404:Tubulin / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D000972:Antineoplastic Agents, Phytogenic; D052117:Benzodioxoles; D017705:Lignans; D010936:Plant Extracts; D014404:Tubulin; C512868:isochaihulactone; D015107:4-Butyrolactone