Deguelin blocks cells survival signal pathways and induces apoptosis of HL-60 cells in vitro

Cao, Yan; Wu, Qing; Cui, Guohui; Chen, Yi-quan; Li, Rui

doi:10.1007/s12185-009-0307-4

Cited by 13 publications

(6 citation statements)

References 12 publications

(12 reference statements)

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“…Previous reports have shown that deguelin inhibits the growth of cancer cells (18, 21, 22). In the present study, we evaluated whether deguelin could inhibit the metastasis of pancreatic cancer along with primary tumor growth.…”

Section: Resultsmentioning

confidence: 94%

Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model

Boreddy

Srivastava

2012

Oncogene

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Deguelin is known to suppress the growth of cancer cells; however, its anti-metastatic effects have not been studied so far in any cancer model. In the present study, we aimed to evaluate the anti-metastatic potential of deguelin in vivo and in TGFβ1-stimulated cells. Our results demonstrate that tumor growth, peritoneal-dissemination and liver/lung metastasis of orthotopically implanted PanC-1-luc cells were significantly reduced in deguelin-treated mice along with the induction of apoptosis. Furthermore, deguelin-treated tumors showed increased epithelial signature such as increased expression of E-Cadherin and cytokeratin-18 and decreased expression of Snail. Similar observations were made when PanC-1, COLO-357 and L3.6pl cells were treated in vitro with deguelin. Moreover, E-cadherin was transcriptionally up-regulated and accumulated in the membrane fraction of deguelin-treated cells as indicated by increased interaction of E-Cadherin with β-catenin. TGFβ1-induced down-regulation of E-Cadherin and up-regulation of Snail were abrogated by deguelin treatment. In addition, deguelin inhibited TGFβ1-induced Smad3 phosphorylation and Smad4 nuclear translocation in PanC-1 cells. Furthermore, when TGFβ1-induced NFkB activation was inhibited, TGFβ1-induced Snail up-regulation or E-Cadherin down-regulation was blocked. Deguelin also significantly down regulated the constitutive phosphorylation and DNA binding of NFkB in a dose dependent manner. Interestingly, overexpression of either NFkB or Snail completely abrogated deguelin-mediated EMT inhibition, whereas overexpression of NFkB but not Snail rescued cells from deguelin-induced apoptosis. Hence, deguelin targets NFkB to induce reversal of EMT and apoptosis but downstream effectors might be different for both processes. Taken together, our results suggest that deguelin suppresses both pancreatic tumor growth and metastasis by inducing apoptosis and inhibiting epithelial to mesenchymal transition.

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Section: Resultsmentioning

confidence: 94%

Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model

Boreddy

Srivastava

2012

Oncogene

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“…Furthermore, deguelin was confirmed to have induced apoptosis by inhibiting PI3K activity and downregulating the pAkt-level, with no effects on MAPK pathways (10). Subsequent studies have demonstrated that deguelin induced apoptosis by inhibiting the PI3K/Akt pathway in human leukaemia HL-60, U937 and human breast cancer MCF-7 cells (11)(12)(13).…”

Section: Deguelin a Novel Anti-tumorigenic Agent Targeting Apoptosismentioning

confidence: 95%

Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention

Wang

Wen-ling

2012

Molecular and Clinical Oncology

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Deguelin is a natural compound of the flavonoid family products isolated from Lour. or (Leguminosae). It exhibited significant anti-tumorigenesis and anti-proliferative activity in various types of cancer both and. Deguelin induced cell apoptosis by blocking anti-apoptotic pathways, such as PI3K-Akt, IKK-IκBα-NF-κB and AMPK-mTOR-survivin, while inhibiting tumor cell propagation and malignant transformation through p27-cyclinE-pRb-E2F1 cell cycle control and HIF-1α-VEGF anti-angiogenic pathways. In pre-clinical trials, deguelin markedly decreased the tumor incidence. These biological findings identified deguelin as a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention and chemotherapy.

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“…Deguelin, a natural rotenoid isolated from Leguminosae plants like Mundulea sericea [ 15 ], has been shown to be effective in reducing the growth of several human tumor cell lines, both in vitro [ 16 , 17 ] and in tumor xenograft models such as breast or lung carcinomas [ 18 , 19 ]. Deguelin is a potent inhibitor of HSP90 [ 20 , 21 ] and mitochondrial bioenergetics [ 22 ], and decreases the activity of the AKT/NFκB pathway [ 23 ] leading to a reduced expression and function of several NFκB-regulated genes involved in cell survival and proliferation, such as BCL2, BCL-X L , XIAP, cIAP, survivin, CCND1 (cyclin D1), CCNE (cyclin E), or CDK4 [ 16 , 19 , 24 , 25 ]. Deguelin has been shown to promote apoptosis of CLL cells, promoting downregulation of IκBα [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

Rebolleda¹,

Losada-Fernandez²,

Pérez-Chacón

et al. 2016

PLoS ONE

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B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.

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Deguelin blocks cells survival signal pathways and induces apoptosis of HL-60 cells in vitro

Cited by 13 publications

References 12 publications

Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model

Deguelin suppresses pancreatic tumor growth and metastasis by inhibiting epithelial-to-mesenchymal transition in an orthotopic model

Deguelin, a novel anti-tumorigenic agent targeting apoptosis, cell cycle arrest and anti-angiogenesis for cancer chemoprevention

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

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