p53-Dependent anticancer effects of leptomycin B on lung adenocarcinoma.
OBJECTIVE
Leptomycin B (LMB) and/or its derivatives are considered a novel class of cancer therapeutics through blocking chromosome maintenance region 1, which mediates p53 nuclear export. The objectives of the present study were to first evaluate the cytotoxic effects of LMB on a normal human lung epithelial cell line (BEAS-2B) and three human lung adenocarcinoma cell lines with various p53 status (wild type: A549, mutant: NCI-H522, and null: NCI-H358) and then to identify LMB-induced gene expression alterations in human p53 signaling pathway.


METHODS
Cells were treated with 0.01-100 nM LMB or 0.1% ethanol (vehicle control) for 4-72 h. Gene expression analyses using gene array for 84 genes involved in p53-mediated signaling pathways were performed in A549 and NCI-H358 after treatment with 20 nM LMB or vehicle control for 24 h.


RESULTS
Cytotoxic results from MTS assays revealed a significant dose- and time-dependent effect of LMB on all cell lines. However, this effect was more pronounced in cancer cells than in normal cells, and cancer cells with p53 wild type tended to be less sensitive than those with p53 mutant or null. A total of 23 genes, predominantly involved in apoptosis and cell cycle/proliferation, were significantly altered in A549 after LMB treatment, while no strong modulating effects were observed in NCI-H358. The protein expression of two selected genes, p21 and survivin, was further confirmed by Western blots.


CONCLUSIONS
Our results suggest that LMB has anti-cancer potential and provides a new regimen of individualized therapy for lung cancer treatment.
Shao
Changxia
C
Department of Environmental Toxicology, The Institute of Environmental and Human Health, Texas Tech University, Box 41163, Lubbock, TX 79409, USA.
Lu
Chuanwen
C
Chen
Lixia
L
Koty
Patrick P
PP
Cobos
Everardo
E
Gao
Weimin
W
D000230:Adenocarcinoma; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis; D008175:Lung Neoplasms; D009154:Mutation; D015398:Signal Transduction / Q000235:genetics; D000077022:Survivin; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; C107489:BIRC5 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D005231:Fatty Acids, Unsaturated; D051034:Inhibitor of Apoptosis Proteins; D000077022:Survivin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C038753:leptomycin B