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Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells

¹ Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine; ² Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California and ³ CK Life Sciences Int'l., (Holdings), Inc., Hong Kong, China

Requests for reprints: Nils H. Thoennissen, Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, 8700 Beverly Boulevard, AC 1069, Los Angeles, CA 90048. Phone: 310-423-7736; Fax: 310-423-0225; E-mail: Nils.Thoennissen{at}cshs.org.

Key Words: cucurbitacin B • pancreatic cancer • JAK/STAT pathway

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^–7 mol/L, whereas clonogenic growth was significantly inhibited at 5 x 10^–8 mol/L. Cucurbitacin B caused dose- and time-dependent G₂-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. [Cancer Res 2009;69(14):5876–84]

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				Correction: Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells Cancer Res., November 1, 2009; 69(21): 8527 - 8527. [Full Text] [PDF]