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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

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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 Experimental Therapeutics, Molecular Targets, and Chemical Biology Cucurbitacin B Induces Apoptosis by Inhibition of the JAK/STAT Pathway and Potentiates Antiproliferative Effects of Gemcitabine on Pancreatic Cancer Cells Nils H. Thoennissen,1 Gabriela B. Iwanski,1 Ngan B. Doan,2 Ryoko Okamoto,1 Patricia Lin,1 Sam Abbassi,1 Jee Hoon Song,1 Dong Yin,1 Melvin Toh,3 Wei Dong Xie,3 Jonathan W. Said,2 and H. Phillip Koeffler1 1Division of Hematology and Oncology, Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine; 2Department of Pathology and Laboratory Medicine, Santa Monica-University of California-Los Angeles Medical Center, Los Angeles, California and 3CK Life Sciences Int’l., (Holdings), Inc., Hong Kong, China Abstract annual incidence still is almost identical to the mortality rate. The Pancreatic cancer is an aggressive malignancy that is low survival rate is due to insensitivity of pancreatic cancer to most generally refractory to chemotherapy, thus posing experimen- therapies, such as chemotherapy, radiotherapy, and immunother- tal and clinical challenges. In this study, the antiproliferative apy (1, 2). The single-agent gemcitabine is known to be an effect of the triterpenoid compound cucurbitacin B was tested acceptable standard in advanced and metastatic pancreatic cancer, in vitro and in vivo against human pancreatic cancer cells. but the benefit is small. Even the addition of other chemo- Dose-response studies showed that the drug inhibited 50% therapeutics or monoclonal antibodies with gemcitabine has not À growth of seven pancreatic cancer cell lines at 10 7 mol/L, resulted in a meaningful improvement in survival of pancreatic whereas clonogenic growth was significantly inhibited at cancer patients (2). À 5  10 8 mol/L. Cucurbitacin B caused dose- and time- Signal transducers and activators of transcription (STAT) belong to a family of transcription factors that relay cytokine receptor- dependent G2-M-phase arrest and apoptosis of pancreatic cancer cells. This was associated with inhibition of activated generated signals into the nucleus. The phosphorylation of Janus WAF1 JAK2, STAT3, and STAT5, increased level of p21 even in kinases (JAK) via the activation of cytokine receptors creates cells with nonfunctional p53, and decrease of expression of receptor docking sites for recruitment of cytoplasmic STAT cyclin A, cyclin B1, and Bcl-XL with subsequent activation proteins. Additionally, activation of STAT signaling is also of the caspase cascade. Interestingly, the combination of modulated by several growth factors such as epidermal growth cucurbitacin B and gemcitabine synergistically potentiated factor, hepatocyte growth factor, and platelet-derived growth the antiproliferative effects of gemcitabine on pancreatic factor. The activated STATs translocate to the nucleus in a dimer cancer cells. Moreover, cucurbitacin B decreased the volume form, bind to specific DNA response elements, and finally modulate of pancreatic tumor xenografts in athymic nude mice by 69.2% cell growth and differentiation (3, 4). Recent studies showed (P < 0.01) compared with controls without noticeable drug aberrant signaling of the JAK/STAT pathway in pancreatic cancer toxicities. In vivo activation of JAK2/STAT3 was inhibited and (4, 5), which therefore may provide a novel therapeutic strategy for expression of Bcl-XL was decreased, whereas caspase-3 and this type of aggressive cancer. caspase-9 were up-regulated in tumors of drug-treated mice. Biochemists and biologists have been investigating a variety of In conclusion, we showed for the first time that cucurbitacin B purified compounds from herbs as possible sources of new has profound in vitro and in vivo antiproliferative effects anticancer drugs. Naturally occurring cucurbitacins constitute a against human pancreatic cancer cells, and the compound groupof oxygenated triterpenes,which are characterized by the may potentate the antiproliferative effect of the chemother- tetracyclic cucurbitane nucleus skeleton and present in many h apeutic agent gemcitabine. Further clinical studies are plants as -glucosides. Cucurbitacin B, a member of the necessary to confirm our findings in patients with pancreatic cucurbitacins, is extracted from Trichosanthes kirilowii Maximo- cancer. [Cancer Res 2009;69(14):5876–84] wicz (Cucurbitaceae family), a plant that has long been used in oriental medicine for its anti-inflammatory, antidiabetic, and abortifacient effects. This active ingredient has antiproliferative Introduction effects on several types of malignancies and is known to be an dual inhibitor of the activation of both JAK2 and STAT3 in some Pancreatic cancer is a severe health problem and a leading cause malignancies (3). Recently, we were able to show that cucurbi- of cancer-related deaths (1). Despite recent advances in the tacin B has antiproliferative activity against human breast cancer, understanding of the molecular biology of pancreatic cancer, the glioblastoma multiforme, and myeloid leukemia cells (6–8). In the present study, we show that cucurbitacin B markedly Note: Supplementary data for this article are available at Cancer Research Online inhibits the proliferation of seven human pancreatic cancer cell (http://cancerres.aacrjournals.org/). lines. The growth-inhibitory effects of this compound were N.H. Thoennissen and G.B. Iwanski contributed equally to this work. associated with a significant G -M-phase arrest and increase in Requests for reprints: Nils H. Thoennissen, Division of Hematology and Oncology, 2 Cedars-Sinai Medical Center, University of California-Los Angeles School of Medicine, apoptosis by inhibition of JAK2, STAT3, and STAT5 and subsequent 8700 Beverly Boulevard, AC 1069, Los Angeles, CA 90048. Phone: 310-423-7736; activation of the caspase cascade. Moreover, the compound Fax: 310-423-0225; E-mail: [email protected]. I2009 American Association for Cancer Research. significantly potentiated the antiproliferative effects of gemcitabine doi:10.1158/0008-5472.CAN-09-0536 on pancreatic cancer cells. We further confirmed our in vitro Cancer Res 2009;69: (14). July 15, 2009 5876 www.aacrjournals.org Downloaded from cancerres.aacrjournals.org on September 30, 2021. © 2009 American Association for Cancer Research. Cucurbitacin B Induces Apoptosis in Pancreatic Cancer observations by showing profound antitumor activity of cucurbi- After being trypsinized and washed twice with ice-cold PBS, the cells were tacin B in a murine xenograft model with no apparent toxicity to fixed in 70% methanol overnight. The fixed samples were treated with the animals. RNase A, stained with propidium iodide, and analyzed by flow cytometry (FACScan; Becton Dickinson) with the ModFitLT V2.0 software (Verity). For clonogenic assays, three pancreatic cancer cell lines (MiaPaCa-2, Materials and Methods PL45, and Panc-1) were plated into 24-well plates using a two-layer soft agar  3 Cell culture and compounds. Human pancreatic cancer cell lines were system with a total of 3 10 cells per well in a volume of 400 AL/well as obtained from the American Type Culture Collection. Monolayer cultures described previously (10). After 10 days of incubation with different À9 À7 of MiaPaCa-2, PL45, and Panc-1 were maintained in DMEM (Life concentrations of cucurbitacin B (10 À10 mol/L), the colonies were Technologies), SU86.86 and AsPC-1 were maintained in RPMI 1640, and counted. Panc-03.27 and Panc-10.05 were maintained in RPMI 1640 supplemented Cell cycle analysis and measurement of apoptosis. Two pancreatic 5 with 2 mmol/L L-glutamine adjusted to contain 1.5 g/L sodium cancer cell lines (10 cells; Panc-1 and MiaPaCa-2) were analyzed for bicarbonate, 4.5 g/L glucose, 10 mmol/L HEPES, 1.0 mmol/L sodium alterations in their cell cycle after treating the cells for 24, 48, and 72 h with  À8 À7 pyruvate, and 10 units/mL human insulin. Heat-inactivated fetal bovine cucurbitacin B (5 10 and 10 mol/L). After the cells were fixed in 70% serum (10%, v/v; Gemini Bio-Products) was added to all cell cultures, and methanol, the samples were treated with RNase A and exposed to they were maintained at 37jC in a humidified chamber of 95% air and 5% propidium iodide for analysis by flow cytometry. CO2. Pancreatic adenocarcinoma cells growing as a monolayer were We used the Annexin V assay (Annexin V-FITC Apoptosis Detection Kit; detached from the flask surface using 2.5% trypsin-EDTA solution. Cell BD Pharmingen) for the measurement of cellular apoptosis. The pancreatic 5 counts were determined using a hemocytometer (Allegiance Healthcare), cancer cell lines Panc-1, MiaPaCa-2, and PL45 (10 cells) were cultured with  À7 and only cells in the logarithmic phase of growth were used for all studies. cucurbitacin B (2 10 mol/L) for either 24, 48, 72, or 96 h. Annexin V- In this study, we used highly purified cucurbitacin B (CKBP002; FITC and propidium iodide labeling followed, which was done according to molecular weight 558.7; C32H46O8; Fig. 1) synthesized by CK Life Sciences the manufacturer’s instructions. Percentage of apoptosis in both diluent Int’l. CKBP002 consists of cucurbitacin B with >99% purity as confirmed by control and cucurbitacin B-treated cells was analyzed by flow cytometry. high-performance liquid chromatography (data provided on request by CK Western blotting. Panc-1 pancreatic cancer cells with a known p53 Life Sciences Int’l.). The drug was dissolved in DMSO at a stock mutation were harvested for Western blotting, and proteins were extracted À concentration
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