Cucurbitacin B markedly inhibits growth and rapidly affects the cytoskeleton in glioblastoma multiforme.
Glioblastoma Multiforme (GBM) is almost inevitably a fatal tumor of the brain with most individuals dying within 1 year of diagnosis. It is the most frequent brain tumor in adults. Dose-response studies showed that Cucurbitacin B inhibited 50% growth (ED(50)) of 5 human GBM cell lines in liquid culture at approximately 10(-7) M. Soft-gel assays demonstrated that nearly all of the GBM clonogenic cells were inhibited at 10(-8) M of Cucurbitacin B. FACS analysis found that the compound (10(-7) M, 24 hr) caused G2/M arrest. The GBM cells underwent profound morphologic changes within 15-30 min after exposure to Cucurbitacin B (10(-7) M), rounding up and losing their pseudopodia associated with disruption of actin and microtubules, as observed by immunoflourescence. Cucurbitacin B (10(-7) M) caused prominent multinucleation of the cells after they were pulse-exposed (48 hr) to the drug, washed and cultured in normal medium for an additional 2 days. The drug (10(-7) M, 3-24 hr) increased levels of p-p38, p-JNK and p-JUN in U87 and T98G GBM cell lines as seen by Western blot. Interestingly, alterations in cell morphology caused by Cucurbitacin B (10(-7) M) were blocked by the JNK inhibitor SP600125. In summary, Cucurbitacin B has a prominent anti-proliferative activity on GBM cells; and at least in part, the mode of action is by affecting the cytoskeleton, as well as, the JNK pathway. Clinical trails of this drug should be pursued in GBM.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA. dong.yin@cshs.org
Dong
D
Yin
Naoki
N
Wakimoto
Hongtao
H
Xing
Daning
D
Lu
Thien
T
Huynh
Xiao
X
Wang
Keith L
KL
Black
H Phillip
HP
Koeffler
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000187:drug effects; D018613:Microscopy, Confocal; D008517:Phytotherapy; D010936:Plant Extracts / Q000494:pharmacology; D016755:Proto-Oncogene Proteins c-jun / Q000187:drug effects; D029778:Trichosanthes / Q000737:chemistry*; D014315:Triterpenes / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D016755:Proto-Oncogene Proteins c-jun; D014315:Triterpenes; C041246:cucurbitacin B; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases