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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 (ED50) of 5 human GBM cell lines in liquid culture at ˜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. © 2008 Wiley-Liss, Inc.