Deoxyelephantopin, a novel multifunctional agent, suppresses mammary tumour growth and lung metastasis and doubles survival time in mice.
OBJECTIVE
Elephantopus scaber L. (Asteraceae) is a traditional herbal medicine with anti-cancer effects. We evaluated the in vitro and in vivo efficacy of a major sesquiterpene lactone constituent of E. scaber, deoxyelephantopin (DET), against mammary adenocarcinoma and the underlying molecular mechanism.


METHODS
A variety of cellular assays, immunoblotting and immunohistochemistry, as well as both orthotopic and metastatic TS/A tumour models in BALB/c mice, were used. Test mice were pretreated and post-treated with DET or paclitaxel and mammary tumour growth evaluated.


RESULTS
DET (< or =2 microg x mL(-1)) significantly inhibited colony formation, cell proliferation, migration and invasion of TS/A cells and induced G(2)/M arrest and apoptosis in TS/A cells. c-Jun N-terminal kinase-mediated p21(Waf1/Cip1) expression and caspase activation cascades were up-regulated by DET, effects suppressed by N-acetyl-L-cysteine. Moreover, tumour necrosis factor alpha-induced matrix metalloproteinase-9 enzyme activity and expression and nuclear factor-kappa B activation were abolished by DET. Pretreatment with DET was more effective than paclitaxel, for profound suppression of orthotopic tumour growth (99% vs. 68% reduction in tumour size) and lung metastasis of TS/A cells (82% vs. 63% reduction in metastatic pulmonary foci) and prolonged median survival time (56 vs. 37 days, P < 0.01) in mice. The levels of cyclooxygenase-2 and vascular endothelial growth factor in metastatic lung tissues of TS/A-bearing mice were attenuated by DET.


CONCLUSIONS
Our data provide evidence for the suppression of mammary adenocarcinoma by DET with several mechanisms and suggest that DET has potential as a chemopreventive agent for breast cancer.
Huang
Chi-Chang
CC
Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
Lo
Chiu-Ping
CP
Chiu
Chih-Yang
CY
Shyur
Lie-Fen
LF
D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D017239:Paclitaxel / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007783:Lactones; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C528427:deoxyelephantopin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases; D020780:Matrix Metalloproteinase 9; D017239:Paclitaxel