Pancreatic cancer is an aggressive malignancy that is generally refractory to chemotherapy, thus posing experimental and clinical challenges. In this study, the antiproliferative effect of the triterpenoid compound cucurbitacin B was tested in vitro and in vivo against human pancreatic cancer cells. Dose-response studies showed that the drug inhibited 50% growth of seven pancreatic cancer cell lines at 10 À7 mol/L, whereas clonogenic growth was significantly inhibited at 5 Â 10 À8 mol/L. Cucurbitacin B caused dose-and timedependent G 2 -M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated JAK2, STAT3, and STAT5, increased level of p21 WAF1 even in cells with nonfunctional p53, and decrease of expression of cyclin A, cyclin B1, and Bcl-XL with subsequent activation of the caspase cascade. Interestingly, the combination of cucurbitacin B and gemcitabine synergistically potentiated the antiproliferative effects of gemcitabine on pancreatic cancer cells. Moreover, cucurbitacin B decreased the volume of pancreatic tumor xenografts in athymic nude mice by 69.2% (P < 0.01) compared with controls without noticeable drug toxicities. In vivo activation of JAK2/STAT3 was inhibited and expression of Bcl-XL was decreased, whereas caspase-3 and caspase-9 were up-regulated in tumors of drug-treated mice. In conclusion, we showed for the first time that cucurbitacin B has profound in vitro and in vivo antiproliferative effects against human pancreatic cancer cells, and the compound may potentate the antiproliferative effect of the chemotherapeutic agent gemcitabine. Further clinical studies are necessary to confirm our findings in patients with pancreatic cancer.

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Cucurbitacins and their derivatives are triterpenoids found in medicinal plants known for their diverse pharmacological and biological activities, including anticancer effects, throughout human history. Although initial attention to cucurbitacin as a potential anticancer drug withered for decades, recent discoveries showing that cucurbitacin is a strong STAT3 (Signal Transducers and Activators of Transcription-3) inhibitor have reclaimed the attention of the drug industry one more time. There is increasing evidence showing that some cucurbitacins not only inhibit the JAK-STAT pathway, but also affect other signaling pathways, such as the MAPK pathway, which are also known to be important for cancer cell proliferation and survival. Moreover, some reports have shown the synergistic effect of cucurbitacins with known chemotherapeutic agents, such as doxorubicin and gemcitabine. In this review, we will summarize the recent discoveries regarding molecular mechanisms of action of cucurbitacins in human cancer cells and discuss the possibilities of cucurbitacin as a future anticancer drug in clinical settings.