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Haidan Liu - One of the best experts on this subject based on the ideXlab platform.
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Deguelin suppresses non-small cell lung cancer by inhibiting EGFR signaling and promoting GSK3β/FBW7-mediated Mcl-1 destabilization.
Cell death & disease, 2020Co-Authors: Feng Gao, Wenbin Liu, Li Zhou, Haidan LiuAbstract:Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human non-small cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound Deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. The in silico docking study indicated that Deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, Deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that Deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, Deguelin promoted the interaction between Mcl-1 and E3 ligase SCFFBW7, which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised Deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.
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Deguelin suppresses non small cell lung cancer by inhibiting egfr signaling and promoting gsk3β fbw7 mediated mcl 1 destabilization
Cell Death and Disease, 2020Co-Authors: Feng Gao, Wenbin Liu, Li Zhou, Haidan LiuAbstract:Activating mutations of epidermal growth factor receptor (EGFR) play crucial roles in the oncogenesis of human non-small cell lung cancer (NSCLC). By screening 79 commercially available natural products, we found that the natural compound Deguelin exhibited a profound anti-tumor effect on NSCLC via directly down-regulating of EGFR-signaling pathway. Deguelin potently inhibited in vitro EGFR kinase activity of wild type (WT), exon 19 deletion, and L858R/T790M-mutated EGFR. The in silico docking study indicated that Deguelin was docked into the ATP-binding pocket of EGFRs. By suppression of EGFR signaling, Deguelin inhibited anchorage-dependent, and independent growth of NSCLC cell lines, and significantly delayed tumorigenesis in vivo. Further study showed that Deguelin inhibited EGFR and downstream kinase Akt, which resulted in the activation of GSK3β and eventually enhanced Mcl-1 phosphorylation at S159. Moreover, Deguelin promoted the interaction between Mcl-1 and E3 ligase SCFFBW7, which enhanced FBW7-mediated Mcl-1 ubiquitination and degradation. Additionally, phosphorylation of Mcl-1 by GSK3β is a prerequisite for FBW7-mediated Mcl-1 destruction. Depletion or pharmacological inactivation of GSK3β compromised Deguelin-induced Mcl-1 ubiquitination and reduction. Taken together, our data indicate that enhancement of ubiquitination-dependent Mcl-1 turnover might be a promising approach for cancer treatment.
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Deguelin attenuates non small cell lung cancer cell metastasis through inhibiting the ctsz fak signaling pathway
Cellular Signalling, 2018Co-Authors: Li Xie, Zhenkun Xia, Lijun Liu, Jian Wang, Huiling Zhou, Xinmin Zhou, Yifeng Yang, Haidan LiuAbstract:Abstract Lung cancer is the leading cause of cancer-related death among both men and women every year, mainly due to metastasis. Although natural compound Deguelin has been reported to inhibited cell migration and invasion in various cancer cells, the details of this regulation progress remain to be fully elucidated. In this study, we investigated the underlying mechanism of Deguelin-suppressed metastasis of non-small cell lung cancer (NSCLC) cells. Our results demonstrate that Deguelin inhibits NSCLC cell migration, invasion, and metastasis both in vitro and in vivo. These inhibitory effects of Deguelin were mediated by suppressing of Cathepsin Z (CtsZ) expression and interrupting the interaction of CtsZ with integrin β3. Moreover, Deguelin inhibits the activation of CtsZ downstream FAK/Src/Paxillin signaling. Knockdown of CtsZ mimicked the effect of Deguelin on NSCLC cells migration and invasion. Our study reveals that Deguelin exerts its anti-metastatic effect both in vitro and in vivo is partly dependent on the suppression of CtsZ signaling. Deguelin would be a potential anti-metastasis agent against NSCLC.
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Deguelin, an Aurora B Kinase Inhibitor, Exhibits Potent Anti-Tumor Effect in Human Esophageal Squamous Cell Carcinoma
EBioMedicine, 2017Co-Authors: Qi Liang, Li Zhou, Wenbin Liu, Haidan LiuAbstract:Aurora B kinase has emerged as a key regulator of mitosis and deregulation of Aurora B activity is closely related to the development and progression of human cancers. In the present study, we found that Aurora B is overexpressed in human esophageal squamous cell carcinoma (ESCC), high levels of Aurora B protein were associated with a worse overall survival rate in ESCC patients. Depleting of Aurora B blunted the malignant phenotypes in ESCC cells. Importantly, we demonstrated that a natural compound, Deguelin, has a profound anti-tumor effect on ESCC via inhibiting Aurora B activity. Deguelin potently inhibited in vitro Aurora B kinase activity. The in silico docking study further indicated that Deguelin was docked into the ATP-binding pocket of Aurora B. Inhibition of Aurora B activity attenuated growth of ESCC cells, resulted in G2/M cell cycle arrest, polyploidy cells formation, and apoptosis induction. Knocking down of Aurora B decreased the sensitivity of ESCC cells to Deguelin. The in vivo results showed that Deguelin blocked the phosphorylation of histone H3 and inhibited the growth of ESCC tumor xenografts. Overall, we identified Deguelin as an effective Aurora B inhibitor, which deserves further studies in other animal models and ESCC treatment.
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Deguelin suppresses angiogenesis in human hepatocellular carcinoma by targeting HGF-c-Met pathway.
Oncotarget, 2017Co-Authors: Ting Liu, Haidan Liu, Gang Deng, Wenbin Liu, Feng GaoAbstract:Angiogenesis plays a crucial role in the development of human hepatocellular carcinoma (HCC). In the present study, we found a natural compound, Deguelin, has a profound anti-angiogenesis effect on HCC. Deguelin suppressed vascular endothelial growth factor (VEGF)-induced human umbilical vascular endothelial cells (HUVECs) proliferation, migration, invasion, and capillary-like tube formation in vitro and reduced tumor angiogenesis in vivo. We discovered that VEGF receptor-mediated signal transduction cascades in HUVECs were inhibited by Deguelin. Deguelin decreased the autocrine of VEGF in HCC cells in a time- and dose-dependent manner. Additionally, Deguelin suppressed HGF-induced activation of the c-Met signaling pathway. Knocking down c-Met or inhibition of c-Met activation impaired HGF-mediated VEGF production. Importantly, we produced patient-derived hepatocellular carcinoma xenografts to evaluate the therapeutic effect of Deguelin in vivo. Taken together, these results indicate that Deguelin could inhibit HCC through suppression of angiogenesis on vascular endothelial cells and reduction of proangiogenic factors in cancer cells.
Ho-young Lee - One of the best experts on this subject based on the ideXlab platform.
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Deguelin inhibits vasculogenic function of endothelial progenitor cells in tumor progression and metastasis via suppression of focal adhesion.
Oncotarget, 2015Co-Authors: Minh Phuong Nguyen, Ho-young Lee, Dongjin Lee, Se-hyung Lee, Hye Eun Lee, You Mie LeeAbstract:// Minh Phuong Nguyen 1, 3 , Dongjin Lee 1 , Se-Hyung Lee 1 , Hye-Eun Lee 1 , Ho-Young Lee 2 , You Mie Lee 1, 3 1 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu 702–701, Republic of Korea 2 College of Pharmacy, Seoul National University, Seoul, 151–742, Republic of Korea 3 School of Life Sciences and Biotechnology, College of Natural Sciences, Kyungpook National University, Daegu 702–701, Republic of Korea Correspondence to: You Mie Lee, e-mail: lym@knu.ac.kr Keywords: Deguelin, endothelial progenitor cells, tumor vasculogenesis, focal adhesion, actin remodeling Received: March 4, 2015 Accepted: April 14, 2015 Published: April 27, 2015 ABSTRACT Deguelin is a nature-derived chemopreventive drug. Endothelial progenitor cells (EPCs) are bone-marrow (BM)-derived key components to induce new blood vessels in early tumorigenesis and metastasis. Here we determined whether Deguelin inhibits EPC function in vitro and in vivo at doses not affecting cancer cell apoptosis. Deguelin significantly reduced the number of EPC colony forming units of BM-derived c-kit+/sca-1+ mononuclear cells (MNCs), proliferation, migration, and adhesion to endothelial cell monolayers, and suppressed incorporation of EPC into tube-like vessel networks when co-cultured with endothelial cells. Deguelin caused cell cycle arrest at G1 without induction of apoptosis in EPC. In a mouse tumor xenograft model, tumor growth, lung metastasis and tumor-induced circulating EPCs were supressed by Deguelin treatment (2 mg/kg). In mice tranplanted with GFP-expressing BM-MNCs, Deguelin reduced the co-localization of CD31 and GFP, suggesting suppression of BM-derived EPC incoporation into tumor vessels. Interestingly, focal adhesion kinase (FAK)-integrin-linked kinase (ILK) activation and actin polymerization were repressed by Deguelin. Decreased number of focal adhesions and a depolarized morphology was found in Deguelin-treated EPCs. Taken together, our results suggest that the Deguelin inhibits tumorigenesis and metastasis via EPC suppression and that suppression of focal adhesion by FAK-integrin-ILK-dependent actin remodeling is a key underlying molecular mechanism.
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Liposomal Encapsulation of Deguelin: Evidence for Enhanced Antitumor Activity in Tobacco Carcinogen-Induced and Oncogenic K-ras-Induced Lung Tumorigenesis
Cancer prevention research (Philadelphia Pa.), 2009Co-Authors: Jong K. Woo, Dong Soon Choi, Hai T. Tran, Brian E. Gilbert, Waun Ki Hong, Ho-young LeeAbstract:Deguelin has shown promising chemopreventive and therapeutic activities in diverse types of cancers. However, the potential side effect of Deguelin over a certain dose could be the substantial hurdle in the practical application of the drug. One of the successful strategies for the use of Deguelin in clinical trials could be lung-specific delivery of the drug. The present study evaluates the efficacy of liposome-encapsulated Deguelin with a dose of 0.4mg/kg, which is 10 times less than the dose (4mg/kg) for preventive and therapeutic activities validated in previous in vivo studies. Liposomal Deguelin revealed cytotoxic activity in vitro in premalignant and malignant human bronchial epithelial (HBE) cells and non-small-cell lung cancer (NSCLC) cells through the same mechanistic pathway previously reported for Deguelin, i.e., suppression of the HSP90 chaperone function and induction of apoptosis. Delivery of liposomal Deguelin at a dose of 0.4mg/kg by intranasal instillation resulted in markedly increased drug partitioning to the lungs compared to that of 4mg/kg Deguelin or 0.4mg/kg liposomal Deguelin administered by oral gavage. Lung-specific delivery of Deguelin (0.4mg/kg) via nasal or intratracheal instillation in a liposomal formulation also showed significant chemopreventive and therapeutic activities in 4-(methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK)/benzo(a)pyrene (BaP)-treated A/J mice and K-rasLAC57Bl6/129/sv F1 mice with no detectable toxicity. Our findings support the potential use of Deguelin in a liposomal formulation via lung-specific delivery to improve efficacy and to reduce the potential side effects of the agent.
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Deguelin inhibits retinal neovascularization by down regulation of hif 1α in oxygen induced retinopathy
Journal of Cellular and Molecular Medicine, 2008Co-Authors: J. H. Kim, Ho-young Lee, Jung-won Shin, K.-w. KimAbstract:Retinal neovascularization is the most common cause of blindness; Retinopathy of pre-maturity (ROP) for children and diabetic retinopa-thy for young age group. ROP still remains as the most serious cause of vision loss in children. We provided that Deguelin significantly reduces retinal neovascularization in a mouse model of ROP. Deguelin never affected the transcriptional activity of hypoxia inducible factor (HIF)-1α, however, reduced HIF-1α expression, which led to the decrease of vascular endothelial growth factor expression. Deguelin effectively suppressed endothelial cell proliferation without cytotoxic effect under therapeutic concentration range. In addition, Deguelin demonstrated no reduction or retardation in normal retinal development and no retinal toxicity. These data suggest Deguelin is a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.
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Deguelin inhibits retinal neovascularization by down‐regulation of HIF‐1α in oxygen‐induced retinopathy
Journal of cellular and molecular medicine, 2008Co-Authors: J. H. Kim, Ho-young Lee, Jung-won Shin, K.-w. KimAbstract:Retinal neovascularization is the most common cause of blindness; Retinopathy of pre-maturity (ROP) for children and diabetic retinopa-thy for young age group. ROP still remains as the most serious cause of vision loss in children. We provided that Deguelin significantly reduces retinal neovascularization in a mouse model of ROP. Deguelin never affected the transcriptional activity of hypoxia inducible factor (HIF)-1α, however, reduced HIF-1α expression, which led to the decrease of vascular endothelial growth factor expression. Deguelin effectively suppressed endothelial cell proliferation without cytotoxic effect under therapeutic concentration range. In addition, Deguelin demonstrated no reduction or retardation in normal retinal development and no retinal toxicity. These data suggest Deguelin is a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.
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Identification of novel antiangiogenic anticancer activities of Deguelin targeting hypoxia‐inducible factor‐1 alpha
International journal of cancer, 2008Co-Authors: Jong K. Woo, Kyu-won Kim, Waun Ki Hong, Quanri Jin, Hyejin Kang, Joo-won Jeong, Ho-young LeeAbstract:Hypoxia-inducible factor 1 (HIF-1) plays an essential role in tumor angiogenesis and growth by regulating the transcription of several genes in response to hypoxic stress and changes in growth factors. This study was designed to investigate the effects of Deguelin on tumor growth and angiogenesis, and the mechanisms underlying the antitumor activities of Deguelin. We show here that orally administered Deguelin inhibits tumor growth and blocks tumor angiogenesis in mice. Deguelin decreased expression of HIF-1α protein and its target genes, such as VEGF, in a subset of cancer cell lines, including H1299 lung cancer cells, and vascular endothelial cells in normoxic and hypoxic conditions. Overexpression of vascular endothelial growth factor by adenoviral vector infection abolished the antiangiogenic effects of Deguelin on H1299 nonsmall cell lung cancer cells. Deguelin inhibited de novo synthesis of HIF-1α protein and reduced the half-life of the synthesized protein. MG132, a proteasome inhibitor, protected the hypoxia- or IGF-induced HIF-1α protein from Deguelin-mediated degradation. Our findings suggest that Deguelin is a promising antiangiogenic therapeutic agent in cancer targeting HIF-1α. Considering that HIF-1α is overexpressed in a majority of human cancers, Deguelin could offer a potent therapeutic agent for cancer. © 2007 Wiley-Liss, Inc.
Sanjay K Srivastava - One of the best experts on this subject based on the ideXlab platform.
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Deguelin Suppresses Pancreatic Tumor Growth and Metastasis by Inhibiting Epithelial to Mesenchymal Transition in an
2016Co-Authors: Orthotopic Model, Srinivas Reddy Boreddy Ph. D, Sanjay K SrivastavaAbstract: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
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abstract 2566 critical role of autophagy proteins beclin 1 and lc3b in Deguelin induced apoptosis in pancreatic tumor cellsin vitroandin vivo a new paradigm
Cancer Research, 2012Co-Authors: Srinivas Reddy Boreddy, Prabodh K Kandala, Kartick C Pramanik, Parul Gupta, Sanjay K SrivastavaAbstract:Deguelin is known to inhibit cell growth by inducing apoptosis in various cancer models primarily by inhibiting AKT, but its role in autophagy is largely unknown. In the present study, we evaluated the role of autophagy in Deguelin-induced apoptosis in pancreatic cancer. Our results reveal that PanC-1, AsPC-1 and BxPC-3 cells that were treated with Deguelin show significant increase in autophagosome vacuoles (AV) formation and increase in the expression of Beclin1, ATG5 and LC3B. In general, induction of autophagy is considered to be a protective mechanism; however, few recent studies have indicated the pro-apoptotic role of autophagy as well. To address this question, cells were pretreated with specific inhibitors of autophagy such as chloroquine and 3-methyladenine prior to Deguelin treatment and apoptosis was evaluated. Surprisingly, inhibition of autophagy by all the above-mentioned inhibitors significantly blocked Deguelin-induced apoptosis, indicating that apoptosis induction by Deguelin was dependent on autophagy. To establish that Deguelin-mediated autophagy was involved in apoptosis, Beclin1, ATG5 and LC3B were silenced and treated with Deguelin. Consistent with our inhibitor data, silencing of Beclin1 and LC3B made the cells resistant to Deguelin-induced apoptosis, however silencing of ATG5 provided modest protection, indicating that Beclin1 and LC3B play a critical role in Deguelin-induced apoptosis in pancreatic cancer cells. Previous studies have shown that Beclin1 is cleaved by caspases into N-terminal and C-terminal fragments. C-terminal translocates to mitochondria and cause cytochrome C release to trigger apoptosis. In agreement, our results show that the C-terminal fragment of Beclin1 was increased, whereas cytochrome C levels were decreased in mitochondrial fraction, indicating that Beclin1 acts as a proapoptotic protein in our model. Similarly, LC3B has been shown to induce apoptosis by releasing Fas from caveolin1 to form DISC and trigger extrinsic apoptosis. To test this possibility, DISC formation was evaluated in Deguelin treated control and LC3B-silenced PanC-1 cells. Interestingly, DISC formation was significantly reduced in LC3B silenced PanC-1 cells, as compared to LC3B expressing cells. To further validate our observations in vivo, PanC-1-luc cells were orthotopically implanted into the pancreas of nu/nu mice and treated with 5mg/kg Deguelin (i.p., daily). After 42 days of treatment, Deguelin treated mice showed substantially reduced tumor growth as compared to control mice. In addition, tumors of Deguelin treated mice exhibited increased levels of Beclin1 and LC3B. Taken together, our results demonstrate that Deguelin-induced apoptosis in pancreatic tumor cells was mediated through autophagy. [Supported in part by R01 grants CA129038 and CA106953 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2566. doi:1538-7445.AM2012-2566
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abstract 3705 Deguelin suppresses epithelial to mesenchymal transition emt in pancreatic cancer cells by snail repression and rkip induction pivotal role of nf kb
Cancer Research, 2011Co-Authors: Srinivas Reddy Boreddy, Sanjay K SrivastavaAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Metastatic disease is a primary cause of death for most cancer patients and is associated with the loss of epithelial features and the acquisition of mesenchymal characteristics, a process known as epithelial to mesenchymal transition (EMT). Hence, targeting EMT would be a novel therapeutic modality in cancer prevention. Previous reports have shown that Deguelin, a derivative of rotenone induces apoptosis in cancer cells by inhibiting AKT but its potential as anti-metastatic agent remained elusive. In the present study we investigated the anti-metastatic (EMT) properties of Deguelin in PanC-1 and MIA PaCa-2 pancreatic cancer cells. Our results show that Deguelin significantly (P<0.0001) suppressed the migration of PanC-1 and MIA PaCa-2 cells in a wound healing assay. Further, Deguelin treated PanC-1 and MIA PaCa-2 cells show reduced expression of E-cadherin and cytokeratin 18, the markers of epithelial cell phenotype. On the other hand, the expression of mesenchymal markers N-cadherin and vimentin were up regulated by degulin treatment in both the cell lines. Furthermore, Deguelin significantly reduced the expression of Snail, a known EMT inducer, and increased the expression of RKIP, a tumor suppressor gene in both the cell lines. Since NF-kB hyperactivation is associated with tumor metastasis via regulation of EMT, we evaluated whether Deguelin inhibit the phosphorylation of NF-kB in PanC-1 and MIA PaCa-2 cells. Our results show that Deguelin significantly suppressed the constitutive phosphorylation of NF-kB at Ser-536. Inhibition of NF-kB activation by Deguelin was further confirmed by DNA binding activity and EMSA. IL-1β has been shown to activate NF-κB and its transcriptional target Snail leading to increase in the expression of E-cadherin. Treatment of PanC-1 cells with IL-1β significantly attenuated Deguelin induced E-cadherin repression and N-cadherin induction, indicating the involvement of NF-kB in Deguelin mediated anti-metastatic activity. Ectopic expression of either Snail or NF-kB completely abolished EMT protection offered by Deguelin in PanC-1 cells confirming the role of NF-kB and Snail in Deguelin induced EMT inhibition. Taken together our results provide convincing evidence on the anti-metastsis properties of Deguelin in pancreatic cancer. [Supported in part by R01 grants CA106953 and CA129038 (to S.K.S) awarded by the National Cancer Institute]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3705. doi:10.1158/1538-7445.AM2011-3705
Yan Chen - One of the best experts on this subject based on the ideXlab platform.
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Deguelin Induced Differentiation of NPM1-Mutant AML In Vivo and in Vitro
Blood, 2016Co-Authors: Xia Zhang, Zichu Zhao, Lu Wen, Jun Ruan, Jun Fang, Yan ChenAbstract:Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy due to abnormal proliferation of hematopoietic progenitor cells, with difficulty in treatment and high mortality. Nucleophosmin 1 (NPM1), a restricted nucleolar localization protein, shuttles between nucleus and cytoplasm. NPM1-mutant protein, aberrant cytoplasmic dislocation of nucleophosmin, occurs in about one third of AML. Deguelin exhibits significant inhibitory effects and induces apoptosis in a variety of cancer cell lines in vitro and in vivo. Our previous researches showed Deguelin induced differentiation of NPMc+ AML cells potentially by targeting NPM1-mutant protein. Thus, we extend our investigations of Deguelin-induced differentiation activity to an AML xenograft mouse model and clinical samples. After sub-lethal whole body radiation, OCI/AML3 cells were injected intravenously in NOD/SCID mice. 7 days later, either Deguelin or vehicle (2%DMSO) was injected intraperitoneally every day. Kaplan-Meier estimates showed 1mg/kg/day Deguelin extended the longest survival of mice. The percentage of CD11b+ cells was 17.73%±3.03% in control group, 41.33%±13.22% and 76.15%±10.25% after Deguelin-treated for 7 days and 14 days ( P < 0.05). Thus, we used 14 days in the following experiments. The percent of CD114+ cells in the vehicle- and Deguelin-treated group were 13.29%±10.79% and 47.36%±21.66%, respectively ( P < 0.05). The percentage of CD14+ cells in the vehicle- and Deguelin-treated group were 22.86%±15.54% and 83.49%±8.06%, respectively ( P < 0.05). Wright's Giemsa staining of mouse bone marrow cells showed differentiated. The ratios of differentiated cells were 36.92%±4.99% and 77.01%±1.98% in control and Deguelin group ( P < 0.01). Median OS of vehicle-treated group was 23 days, while that of Deguelin-treated group was 55 days (HR, 0.5818, 95% confidence interval [CI], 0.1623-1.001). Survival of Deguelin-treated mice was significantly longer compared with mice injected with vehicle ( P =0.0002). IHC and IF staining for mutated NPM1 protein showed bone marrow biopsy densities significantly reduced in Deguelin-treated mice which was further confirmed by western blot assay ( P < 0.05). We analyzed the toxicity of Deguelin (1mg/kg/day for 14 days) to healthy NOD/SCID mice. They had steady movement and no rigidity posture treated with Deguelin. HE staining indicated no pathological changes in striatum, substantia nigra pars compacta (SNpc), liver, kidney and heart in Deguelin-treated mice. Striatum and SNpc, subjected to immunostaining with anti-tyrosine hydroxylase (TH) antibody, showed Deguelin did not alter TH immunoreactivity in striatum and SNpc in vivo ( P >0.05). Plasmatic levels of liver enzymes (AST and ALT), renal function (Scr and BUN) and cardiac enzymes (CK-MB and cTnT) in Deguelin-treated group had not statistical difference comparing with control group ( P >0.05). Thus, Deguelin did not cause neurotoxicity, hepatotoxicity, nephrotoxicity and cardiotoxicity to mice. We collected 82 cases of patients with acute leukemia. 24 cases out of 68 AML patients carried mutated NPM1 gene (20 cases of type A; 1 case of type B; 2 cases of type D and 1 case of type I). Bone marrow mononuclear cells (BMMCs) of 6 AML patients were analyzed by FACS analysis. We analyzed patient (pt.) 1 to 4 with NPM1 mutation. FACS showed Deguelin increased the percentage of CD11b+ and CD14+ cells of pt.1 in a dose-dependent manner. The percent of CD11b+ and CD14+ cells were 55% and 57.9% separately at 16 nM. Deguelin increased CD14 but CD11b expression of BMMCs of pt.2 in the concentration of 8 nM, 12 nM, 16 nM and 20 nM. The highest percentage of CD14+ cells was 85.5%. The expression of CD14 in cells from pt.3 increased after treating with 16 nM or 20 nM and the highest percentage of CD14+ cells was 49.4%. Deguelin induced differentiation of BMMCs from pt.4. The maximum percent of CD11b+ cells was 42.5% at 16 nM. Moreover, FACS analysis showed Deguelin did not promote differentiation in BMMCs from pt.5 and 6 without NPM1 mutation. These results demonstrated Deguelin induced differentiation of BMMCs cells from AML patients with NPM1 mutation in vitro. Taken together, mutated NPM1 protein may be one of targets of Deguelin, which provides molecular basis for inducing differentiation in NPM1-mutant AML cells. Disclosures No relevant conflicts of interest to declare.
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nontoxic dose of Deguelin induce npmc aml cell differentiation by selectively targeting mt npm1 sirt1 instead of hdac1 3
Current Cancer Drug Targets, 2014Co-Authors: You Ping Wang, Guo-hui Cui, Zichu Zhao, Lu Wen, Jun Fang, Ben Ping Zhang, Fei Zhao, Chun Zhang, Yan ChenAbstract:AML with Mt NPM1 has relatively good responses to induction therapy. However, a proportion of NPMc+ AML cells cannot be cleared by conventional treatments. Therefore, we determined the therapeutic efficacy of Deguelin that has demonstrated extensive biological activity with low toxicity. We previously reported that Deguelin selectively reduces Mt NPM1, as well as induces differentiation and potentiates apoptosis in NPMc+ AML cells. Nevertheless, little information is available regarding the mechanism of Deguelin-induced differentiation. Here, we investigated the role of Deguelin in the induction of NPMc+ AML cell differentiation. Deguelin at the nontoxic concentration of 2 μM strongly inhibited cell growth but reduced apoptosis in OCI-AML3 cells carrying Mt NPM1, whereas the antiproliferative effect was minimal in OCIM2 cells harboring Wt NPM1. Compared with OCIM2 cells that showed no response, Deguelin-treated OCI-AML3 cells exhibited the morphological features of granulocytic/monocytic differentiation, increased expression of differentiation antigens, and a nitroblue tetrazolium reduction activity. Induction of differentiation was associated with downregulation of Mt NPM1 and SIRT1, but not Wt NPM1, which was accompanied by an increase in CEBPβ and G-CSFR expression, and further confirmed by sh-Mt NPM1 and sh-SIRT1. sh-Mt NPM1 treatment reduced SIRT1 expression, but did not change HDAC1/3 levels, suggesting that the decline of SIRT1 was partially accountable for the Deguelin-induced, Mt-NPM1-related differentiation. Moreover, Mt NPM1 overexpression blocked Deguelin-induced cell differentiation. Lastly, we showed that Deguelin reduced the expression of Mt NPM1 via the ubiquitin-proteasome pathway. Taken together, our results suggest that Deguelin may be a therapeutic candidate for NPMc+ AML.
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anti cancer effects of Deguelin on human leukemia k562 and k562 adm cells in vitro
Journal of Huazhong University of Science and Technology-medical Sciences, 2007Co-Authors: Yan Chen, Hongli LiuAbstract:In order to investigate the anti-cancer effects of Deguelin and on K562 and K562/ADM cells in vitro and the underlying molecular mechanism and compare the cytotoxicity of Deguelin on K562, K562/ADM cells and human peripheral blood mononuclear cells (PBMCs). The effects of Deguelin on cell proliferation were assessed by MTT assay. Apoptosis were detected by Annexin V/PI double-labeled cytometry. The effects of Deguelin on the cell cycle were studied by a propidium iodide method. Our study showed that Deguelin inhibited the proliferation of K562 cell and K562/ADM cell in a time- and dose-dependent manner and had minimal effects on normal human peripheral blood mononuclear cells. The ratio of IC50 value of Deguelin of 24 h on K562/ADM cells to K562 cells was only 1.27, which was significantly lower than the ratio of IC50 value of ADM (higher than 20). Deguelin could induce apoptosis of K562 cells and K562/ADM cells. K562 cells were arrested at G2/M phase while K562/ADM cells were arrested at G0/G1 phase. Our results suggested that Deguelin was a novel anti-leukemia agents with high efficacy and low toxicity and it is also a promising agent for reversing drug resistance.
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Effect of Deguelin on expression of nup98 in K562 cells
Journal of Experimental Hematology, 2007Co-Authors: Qiuling Wu, Wei-hua Chen, Yan Chen, Jing HeAbstract:: The study was purposed to investigate the effect of Deguelin on expression of nucleoporin 98 (nup98) in leukemia K562 cells. MTT assay was used to assess the effects of Deguelin on cell proliferation. FCM and RT-PCR were used to analyze the changes of nup98 mRNA and protein in K562 cells after treating with Deguelin. The results showed that Deguelin inhibited the proliferation of K562 cells in a time- and dose-dependent manner; mean fluorescence intensity of nup98 in blank group (34.22 +/- 1.63) was significantly higher than that in control group (2.83 +/- 0.02, P < 0.01), 10 nmol/L Deguelin could significantly inhibit the expression of nup98 protein; 10 nmol/L could not inhibit the expression of nup98 mRNA, 20, 40, 80, 160 nmol/L Deguelin could significantly inhibit the expression of nup98 mRNA in a dose-dependant manner. It is concluded that Deguelin inhibits the proliferation of K562 cell through inhibiting the expression of nup98, and may be considered as a new target for therapy of acute leukemia.
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Deguelin regulates cell cycle and nuclear pore complex protein Nup98 and Nup88 in U937 cells in vitro
Chinese Journal of Hematology, 2007Co-Authors: Yan Chen, Qiuling Wu, Jing He, Wei-hua ChenAbstract:OBJECTIVE: To investigate antitumor activity and molecular mechanism of Deguelin to the human U937 leukaemia cells and to explore the mechanisms regulating cell cycle and nucleoporin 98 (Nup98) and nucleoporin 88 (Nup88) in vitro. METHODS: The effects of Deguelin on the growth of U937 cells were studied by MTT assay, and the cell cycle of U937 cells by a propidium iodide method. The localization of the nuclear pore complex protein Nup98 and Nup88 was checked by immunofluorescence and immunoelectron microscopy. The expressions of Nup98 and Nup88 in U937 cells were checked by flow cytometry (FCM) and Western blot respectively. RESULTS: The proliferation of U937 cells was significantly inhibited in a time-dose dependent manner in Deguelin-treated group with a 24 h IC50 value of 21.61 nmol/L and 36 h IC50 value of 17.07 nmol/L. U937 cells treated with Deguelin showed reduction in the percentages of cells in G0/G1, whereas accumulation of cells in S and G2/M phase. The ratio of G1/G0 phase cells were 73.01%, 71.15%, 68.42%, 52.45%, 43.99% and 22.82%, and that of S phase cells were 17.18%, 16.30%, 18.09%, 27.56%, 31.21% and 46.85%, and that of G2/M phase cells were 9.75%, 12.31%, 13.09%, 18.99%, 24.83% and 27.79% at Deguelin concentrations of 0, 5, 10, 20, 40, 80 nmol/L respectively. Nup88 and Nup98 were found on both the nuclear and cytoplasmic side of the U937 cells. The expression of Nup98 was up-regulated and Nup88 down-regulated in Deguelin treated U937 cells. CONCLUSION: Deguelin is able to inhibit the proliferation of U937 cells by regulating the cell cycle. The antitumor activity of Deguelin was related to up-regulating the expression of Nup98 and down-regulating Nup88 protein.
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Deguelin impairs cell adhesion migration and invasion of human lung cancer cells through the nf κb signaling pathways
The American Journal of Chinese Medicine, 2018Co-Authors: Yung Ting Hsiao, Te Chun Hsia, Jincherng Lien, Ming Jen Fan, An Cheng Huang, Jen Jyh Lin, Jawchyun Chen, Jing Gung ChungAbstract:Deguelin, a rotenoid, is isolated from a natural plant species, and has biological activities including antitumor function. In the present study, we investigated the effect of Deguelin on the cell adhesion, migration and invasion of NCI-H292 human lung cancer cells in vitro. Cell viability was analyzed by using flow cytometer. Cell adhesion was determined by using the cell-matrix adhesion assay. Wound healing assay was used to examine cell migration. Cell migration and invasion were investigated using a Boyden chamber assay. The protein expression was measured by Western blotting and confocal laser microscopy. The electrophoretic mobility shift assay was used to measure NF-κB p65 binding to DNA.We selected the concentrations of Deguelin at 0, 0.5, 1.0, 1.5, 2.0 and 2.5μM and we found that those concentrations of Deguelin did not induce significant cytotoxic effects on NCI-H292 cells. Thus, we selected those concentrations of Deguelin for metastasis assay. We found that Deguelin inhibited cell adhesion, mi...
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antitumor effects of Deguelin on h460 human lung cancer cells in vitro and in vivo roles of apoptotic cell death and h460 tumor xenografts model
Environmental Toxicology, 2017Co-Authors: Yu Chieh Hsu, Jo Hua Chiang, Te Chun Hsia, Jincherng Lien, Kuang Chi Lai, Jing Gung ChungAbstract:Deguelin, a naturally occurring rotenoid of the flavonoid family, is known to be an Akt inhibitor, to have chemopreventive activities and anti-tumor effect on several cancers. In this study, investigation to elucidate the effect of Deguelin on apoptotic pathways in human lung cancer cells and on the anti-tumor effect in lung cancer xenograft nu/nu mice was performed. In vitro studies, found that Deguelin induced cell morphological changes, and decreased the percentage of viability through the induction of apoptosis in H460 lung cancer cells. Deguelin triggered apoptosis in H460 cells was also confirmed by DAPI staining, DNA gel electrophoresis, and Annexin V-FITC staining and these effects are dose-dependent manners. It was also found that Deguelin promoted the Ca2+ production and activation of caspase-3 but decreased the level of ΔΨm in H460 cells. Western blots indicated that the protein levels of cytochrome c, AIF, and pro-apoptotic Bax and Bak protein were increased, but the anti-apoptotic Bcl-2 and Bcl-x were decreased that may have led to apoptosis in H460 cells after exposure to Deguelin. It was also confirmed by confocal laser microscope examination that Deguelin promoted the release of AIF from mitochondria to cytosol. In vivo studies, found that in immunodeficient nu/nu mice bearing H460 tumor xenografts showed that the Deguelin significantly suppressed tumor growth. Deguelin might be a potential therapeutic agent for the treatment of lung cancer in the future. This finding might fully support a critical event for Deguelin via induction of apoptotic cell death and H460 tumor xenografts model against human lung cancer. © 2015 Wiley Periodicals, Inc. Environ Toxicol 32: 84-98, 2017.
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induction of dna damage by Deguelin is mediated through reducing dna repair genes in human non small cell lung cancer nci h460 cells
Oncology Reports, 2012Co-Authors: Su Tso Yang, Te Chun Hsia, Kuang Chi Lai, Jen Jyh Lin, Jai Sing Yang, Tungyuan Lai, Jing Gung ChungAbstract:It has been shown that Deguelin, one of the compounds of rotenoids from flavonoid family, induced cytotoxic effects through induction of cell cycle arrest and apoptosis in many types of human cancer cell lines, but Deguelin-affected DNA damage and repair gene expression (mRNA) are not clarified yet. We investigated the effects of Deguelin on DNA damage and associated gene expression in human lung cancer NCI-H460 cells in vitro. DNA damage was assayed by using the comet assay and DNA gel electrophoresis and the results indicated that NCI-H460 cells treated with 0, 50, 250 and 500 nM Deguelin led to a longer DNA migration smear based on the single cell electrophoresis and DNA fragmentation occurred based on the examination of DNA gel electrophoresis. DNA damage and repair gene expression (mRNA) were evaluated by using real-time PCR assay and the results indicated that 50 and 250 nM Deguelin for a 24-h exposure in NCI-H460 cells, decreased the gene levels of breast cancer 1, early onset (BRCA1), DNA-dependent serine/threonine protein kinase (DNA-PK), O6-methylguanine-DNA methyltransferase (MGMT), p53, ataxia telangiectasia mutated (ATM) and ataxia-telangiectasia and Rad3-related (ATR) mRNA expressions. Collectively, the present study showed that Deguelin caused DNA damage and inhibited DNA damage and repair gene expressions, which might be due to Deguelin-inhibited cell growth in vitro.